Vous êtes sur la page 1sur 50



Primary Immunodeficiency Diseases

Francisco A. Bonilla and Luigi D. Notarangelo

Severe Combined Immunodeficiency ENTEROPATHY X-LINKED SYNDROME
Other Forms of Combined Immunodeficiency with DEFECTS OF IL-2–MEDIATED SIGNALING
Diagnostic Approach ITCH DEFICIENCY
Hematopoietic Stem Cell Transplantation IMMUNODEFICIENCIES WITH IMPAIRED CELL-
Wiskott-Aldrich Syndrome
WAS Protein-interacting Protein Deficiency
DiGeorge Syndrome
FOXN1 Deficiency
Mendelian Susceptibility to Mycobacterial
Epidermodysplasia Verruciformis
Herpes Simplex Encephalitis
PATHWAY Susceptibility to Trypanosomiasis
THE SYNDROME OF WARTS, The Agammaglobulinemias
HYPOGAMMAGLOBULINEMIA, INFECTIONS, AND Other Predominantly Antibody Deficiency
HYPERIMMUNOGLOBULIN E SYNDROME CAUSED Management of Humoral Immunodeficiency
AUTOSOMAL RECESSIVE HYPER- Deficiency of Classical Complement Pathway
TYK2 MUTATIONS Deficiency of Alternative Complement Pathway
IMMUNODEFICIENCIES WITH SKELETAL Deficiency of Lectin Pathway Complement
IMMUNODEFICIENCIES ASSOCIATED WITH Deficiency of Terminal Complement Components
DISORDERS OF FOLATE AND COBALAMIN Deficiency of Complement Regulatory Factors
METABOLISM Diagnosis and Management of Complement


Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 887

Immune compromise arises either as a heritable genetic TABLE 24-1  Internet Sites with Information
defect (primary immune deficiency diseases, PIDDs) or as Relevant to Primary Immunodeficiency Diseases
a consequence of another pathologic process such as
infection, malignancy, malnourishment, or iatrogenic URL (http://+) Name/Description
immunosuppression (secondary immune deficiencies).
bioinf.uta.fi/idr/Immunology ImmunoDeficiency Resource,
Immune dysfunction in patients with PIDDs is most often .shtml University of Tampere,
manifested as recurrent and chronic infections; however, Finland
malignancy and autoimmunity are common and may be
www.aaaai.org American Academy of Allergy,
prominent in some disorders. In many cases, symptoms Asthma, and Immunology
and signs of immunodeficiency develop soon after birth
or early in childhood. However, in some forms of PIDD www.esid.org European Society for
clinical onset may be delayed into late childhood, adoles-
cence, or adulthood. Even though many patients with www.immunodeficiencysearch Searchable database, clinical
severe immunodeficiency suffer dramatic morbidity and .com algorithms, laboratory
mortality in infancy and early childhood, the majority of
patients with immunodeficiency have milder forms that www.info4pi.org Primary Immunodeficiency
Resource Center (sponsored
permit survival into adulthood, but often with reduced by the Jeffrey Modell
longevity because of infection, autoimmune disease, Foundation)
malignancy, or constitutional debility. Health-related
www.ipidnet.org Immune Phenotyping in
quality of life is significantly impaired in individuals with Primary Immunodeficiency
PIDDs may be classified with respect to the specific www.ipopi.org International Patient
Organization for Primary
immune effector mechanisms disrupted.3,4 In broadest Immunodeficiencies
terms, one may distinguish: (a) disorders that affect both
cellular and humoral components of specific immunity www.jmfworld.org Jeffrey Modell Foundation
(connects directly to Primary
(combined immunodeficiencies); (b) defects of antibody Immunodeficiency Resource
production (antibody deficiency syndromes): (c) disorders Center)
of innate immunity (phagocytic cell defects, disorders of
www.primaryimmune.org Immune Deficiency Foundation
Toll-like receptor (TLR) signaling, complement deficien-
cies). Moreover, some forms of PIDD are characterized www.usidnet.org US Immunodeficiency Network
by prominent immune dysregulation. Finally, in some (USIDNET)
cases impairment of immune function is part of a broader
spectrum of symptoms (syndromic immunodeficiency).
Discussed here are a broad range of PIDDs arising from
aberrant development and function of T and B cells, are normally nonpathogenic, such as Pneumocystis jir-
disorders with immune dysregulation, immunodeficiency oveci. Even attenuated vaccine organisms such as oral
syndromes, and complement deficiencies. Phagocytic dis- polio vaccine virus, rotavirus vaccine, varicella vaccine,
orders are the subject of Chapter 22. Table 24-1 lists and bacille Calmette-Guérin (BCG) can cause severe or
several Internet sites with information relevant to primary fatal infection. Transfusion of blood products containing
immunodeficiencies. viable lymphocytes may lead to fatal graft-versus-host
disease. Autoimmunity and other manifestations of
COMBINED IMMUNODEFICIENCIES immune dysregulation (e.g., skin rash) are frequently
observed, especially in patients with residual development
Severe Combined Immunodeficiency of T lymphocytes (“leaky” SCID). Patients with SCID are
The term severe combined immunodeficiency (SCID) des- also at increased risk of malignancies, including lympho-
ignates a genetically heterogeneous group of PIDDs char- proliferative disorders caused by Epstein-Barr virus (EBV)
acterized by impaired development and function of T and other tumors.
lymphocytes. In some cases, development of B or natural Typical symptoms of SCID are recurrent severe infec-
killer (NK) lymphocytes (or both) is also affected (Fig. tions, chronic diarrhea, and failure to thrive.4,5 Symptoms
24-1).3,5 However, because T cells play a critical role also are often seen in the first weeks of life but may be delayed
in most B-cell responses, serious T-cell dysfunction pre- by several months. Antibodies derived from the mother
cludes effective humoral immunity even in patients in by transfer across the placenta may provide some early
whom the genetic defect does not affect B-cell develop- protection. Physical examination may reveal foci of infec-
ment. Complete absence of specific cellular and humoral tion (e.g., thrush) and the absence of discernible lym-
immunity in patients with SCID leads to an extreme infec- phoid tissue. Hypogammaglobulinemia is often present
tious diathesis early in life. Mucocutaneous candidiasis but is not universal. Specific antibody responses are
is a common finding. Infections with common viral almost always severely impaired.
pathogens (e.g., varicella, herpes simplex, measles, adeno- SCID is most often classified according to the periph-
viruses, respiratory syncytial virus, influenza, and parain- eral blood lymphocyte phenotype—that is, absence or
fluenza) are often fatal. Patients are also susceptible to presence of the major lymphocyte types. T cells are absent
opportunistic infections with commensal organisms that (or very low) and nonfunctional in all classic forms of

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

Gamma-Delta T cell
TCRγδ, CD3

Helper T cell
TCRαβ, CD3, CD4

Myeloid Double- Double- Single-

Erythroid negative positive positive
Megakaryocytoid T cell, T cell, TCRαβ T cell, TCRαβ Cytotoxic T cell
lineages Pre-TCR, CD3 CD3, CD4, CD8 CD3, CD4, or CD8 TCRαβ, CD3, CD8

NK cell
CD16, CD56
Bone marrow Spleen

Mature B cell
CD19, CD20, IgM, IgD

Pluripotent Common Pre-B Immature Transitional

stem cell Lymphoid cell B cell B cell Memory B cell
Progenitor CD19, CD20
IgG, IgA, or IgE
Lymph node
Immunoglobulin Plasma cell
Figure 24-1  Diagram of lymphocyte development. Pluripotent stem cells give rise to all cellular blood elements. The common lymphoid progenitor
gives rise to the three principal lineages of lymphocytes: T cells, B cells, and natural killer (NK) cells. Most peripheral T cells express the αβ form
of the T-cell antigen receptor (TCR) and develop through distinct stages in the thymus. Mature helper T cells express the CD3 antigen coreceptor
complex along with the major histocompatibility complex (MHC) class II receptor CD4, whereas cytotoxic cells express the MHC class I receptor
CD8. A minority (1% to 5%) of peripheral T cells express the γδ form of the TCR along with CD3, but without CD4 or CD8; less is known about
their development. B cells develop initially in the bone marrow and pass through several stages before exiting to complete development in the spleen.
Mature B cells express distinct markers (CD19 and CD20) along with surface immunoglobulin M (IgM) and IgD. B cells are activated in germinal
centers to undergo class switching and become either memory B cells expressing IgG, IgA, or IgE or Ig-secreting plasma cells. Most IgG-producing
plasma cells reside in the bone marrow. NK cells are a distinct lineage of cytotoxic cells; little is known regarding their development from lymphoid

SCID, a phenotype designated “T−.” The presence or ADA deficiency accounts for approximately 10% to 15%
absence of B cells is indicated by adding “B+” or “B−,” of all patients with SCID, or approximately a third of
respectively. The same pattern applies for NK cells. Table SCID cases with autosomal recessive inheritance. PNP
24-2 lists the various lymphocyte phenotypes of SCID deficiency is quite rare, with approximately 70 cases
and the molecular defects associated with them. In as reported.11 Although PNP deficiency is mainly expressed
many as 40% of patients with SCID, maternal T cells as a somewhat selective defect in cellular immunity, it is
may have engrafted in the fetus during gestation, and this
situation may occasionally confuse the diagnostic
picture.6,7 Maternally derived T cells tend to be anergic, TABLE 24-2  Lymphocyte Phenotype
but they may also be associated with clinical manifesta- Classification of Severe Combined
tions similar to those of graft-versus-host disease, such Immunodeficiency and Associated Gene Defects
as eczematous rash, eosinophilia, and splenomegaly.6,7
In rare circumstances, maternal engraftment may lead Lymphocyte Phenotype Genes
to even more unusual clinical findings, such as IgA T−B−NK− ADA, AK2, NP*
monoclonal gammopathy, autoimmune cytopenias, and − − +
allograft rejection.7,8 T B NK DCLRE1C, LIG4, NHEJ1, PRKDC,
T− B− NK− Severe Combined Immunodeficiency T−B+NK− IL2RG, JAK3
Adenosine Deaminase and Purine Nucleoside Phosphory- −
T B NK+ +
CD3D, CD3E, CD3G,† CD3Z,
lase Deficiencies.  Figure 24-2 shows the salvage pathway IL7R, PTPRC
of purine nucleotide synthesis. Deficiencies of the enzymes *B-cell development is variably affected in nucleoside phosphorylase
adenosine deaminase (ADA) and purine nucleoside phos- (NP) deficiency.
phorylase (PNP) are associated with immunodeficiency.9,10 †
CD3G mutations are rarely associated with a severe T-cell deficiency.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 889

dAdenosine/Adenosine dGuanosine/Guanosine


dInosine/Inosine nucleoside

↑dATP Hypoxanthine Guanine ↑dGTP

Toxicity Xanthine Toxicity

Uric acid

Figure 24-2 Salvage pathway of purine nucleotide biosynthesis. d, Deoxy; dATP, deoxyadenosine triphosphatase; dGTP, deoxyguanosine triphos-

discussed here because of similarities in their biochemical [q22;q13]) resulting in the COL1A1-platelet-derived
pathophysiology with ADA deficiency. The absence of growth factor β (PDGFB) fusion gene.22 Between 10%
ADA or PNP leads to intracellular accumulation of deoxy­ and 15% of patients with ADA deficiency may have a
adenosine and deoxyguanosine, respectively. These mol- delayed or late-onset form that may be manifested in late
ecules are not themselves toxic to lymphocytes. However, infancy or early childhood. These patients initially may
when they are converted to their 5′-triphosphates (dATP have variable numbers of circulating lymphocytes and
and dGTP), they inhibit ribonucleotide reductase and some humoral immunity that quickly wanes. The severity
prevent de novo synthesis of deoxynucleotides. Without of the phenotype appears to correlate to some degree with
building blocks for the replication and repair of DNA, the amount of residual ADA activity.23 Autoimmunity is
the cells cease to divide. Lymphocytes die to a much particularly common in patients with residual ADA enzy-
greater extent than other cell types do. In both ADA and matic activity.24
PNP deficiency, T-cell precursors in the thymus appear to Patients with PNP deficiency are very susceptible to
be especially sensitive to death by apoptosis (programmed viral and fungal infections. They have decreased numbers
cell death).12 B cells are more often depleted in ADA of circulating T cells, often initially with normal numbers
deficiency than in PNP deficiency. In the latter the B-cell of B cells and normal serum immunoglobulin (Ig) levels.
phenotype is more variable. With time, humoral immunity usually deteriorates.
Approximately 85% of individuals with ADA defi- Approximately 50% of children with PNP deficiency
ciency will display a SCID phenotype with markedly have neurologic complications such as spasticity, diplegia,
reduced numbers of both T and B cells and low serum paresis, and other motor disorders, as well as cognitive
antibody levels. NK cells are only rarely found in patients impairment.25 Autoimmune manifestations, especially
with ADA deficiency. Additional clinical manifestations cytopenias, are also very common.26
may include radiographic alterations of the ribs, vertebral After clinical suspicion is aroused, diagnosis of ADA
bodies, and iliac crests9 as well as sensorineural deaf- or PNP deficiency is not difficult. Both ADA and PNP
ness,13 liver dysfunction,14 lung disease resembling alveo- activity is readily measurable in red blood cell or leuko-
lar proteinosis,15 and cognitive impairment and other cyte lysates. In symptomatic patients, activity is usually
neurologic abnormalities.16,17 Immune dysregulation is 1% or less of that in normal subjects. These methods may
common in patients with ADA deficiency18; it may mani- be applied also for prenatal diagnosis on cultured amni-
fest with allergy (eczema, asthma) and autoimmunity otic or chorionic villus cells or on fetal blood sampling.
(cytopenias, hypothyroidism, diabetes) and is associated PNP is required for the production of hypoxanthine, a
with loss of regulatory T-cell function.19 Rarely, ADA precursor of uric acid (see Fig. 24-2). Thus individuals
deficiency may present with generalized erythroderma with PNP deficiency will have reduced serum and urine
and infiltration of skin by activated autologous T cells, urate levels.
resembling Omenn syndrome (OS).20 Bone marrow hypo- Several therapeutic options are available to patients
cellularity is frequently observed in ADA deficiency; with ADA deficiency, including hematopoietic stem cell
myelodysplasia also has been reported.21 Finally, patients transplantation (HSCT), enzyme replacement therapy
with ADA deficiency are at increased risk for multicentric (ERT) and gene therapy. Excellent results (survival >85%)
dermatofibrosarcoma protuberans, a very rare tumor have been reported after HSCT from matched sibling
with a characteristic chromosomal translocation (t[17;22] donors, but results of HSCT from haploidentical or

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

unrelated donors are much less satisfactory (43% and NK cell differentiation is usually preserved. Therefore,
66% survival, respectively).27 Moreover, patients with these patients most often exhibit a phenotype other than
ADA deficiency surviving after HSCT remain at high risk T- B- NK- SCID; however, we describe this disorder here
of neurologic complications.28 ERT with weekly intra- because it also affects purine metabolism, similar to
muscular injections of polyethylene glycol–conjugated ADA and PNP deficiencies. OS with oligoclonal expan-
bovine ADA (PEG-ADA) is usually well tolerated and is sion of T cells has been described in a patient with AK2
effective to normalize levels of toxic phosphorylated hypomorphic (partially functional) mutations.36 Patients
(deoxy)adenosine derivatives and to improve immune are at increased risk of myelodysplasia.37 Sensorineural
function.29 However, immune reconstitution is often deafness reflects a role of AK2 in the stria vascularis
incomplete.30 Encouraging results have been obtained of the inner ear.34 Treatment is based on HSCT, but
with gene therapy, associated with nonmyeloablative results are less satisfactory than in other forms of SCID,
cytoreduction.31,32 This represents a very important option and use of myeloablative conditioning is required for
for patients who lack a human leukocyte antigen (HLA)- engraftment.38
identical related donor. HSCT is the only curative thera-
peutic option for patients with PNP deficiency. T−B−NK+ Severe Combined Immunodeficiency
Defects of Recombinase-Activating Genes (RAG) 1 and
Reticular Dysgenesis Caused by Adenylate Kinase 2 Defi- 2.  RAG1 and RAG2 encode for DNA-binding proteins
ciency.  Reticular dysgenesis caused by adenylate kinase that bind to specific recognition sequences flanking coding
2 (AK2) deficiency is a very rare autosomal recessive gene elements of the Ig and T cell receptor (TCR) loci.
form of SCID, associated with agranulocytosis (with a RAG1 and RAG2 initiate the VDJ recombination process
block at the promyelocyte stage of differentiation in the by inducing DNA double-strand breaks at these loci.
bone marrow) and sensorineural deafness.33 AK2 regu- Proteins of the nonhomologous end-joining (NHEJ)
lates levels of ADP in mitochondria. Deficiency of this complex ultimately join coding Ig and TCR elements,
enzyme is associated with abnormalities of energy metab- allowing expression of Ig and TCR molecules (Fig.
olism in granulocytes and lymphocytes (especially T 24-3).39 In patients with RAG defects, B- and T-cell dif-
cells), resulting in apoptosis.34,35 The number of circulat- ferentiation is arrested at an early stage of development.
ing B and NK lymphocytes can be variably affected, and Therefore patients with functionally null mutations of the






NHEJ Artemis, Cernunnos, Ligase IV


Figure 24-3  Gene defects affecting lymphocyte antigen receptor gene rearrangement and causing T−B−NK+ severe combined immunodeficiency.
The genes that encode immunoglobulin and T-cell antigen receptors are assembled from subunit segments that are separated in the germline and
undergo assembly or somatic rearrangement during lymphocyte development. In the figure, a TCR or Ig heavy-chain locus is shown. The heavy
chains are composed of four distinct segments: V, variable; D, diversity; J, joining; and C, constant. Some of the segments are flanked by recombi-
nation signal sequences (RSS). RAG1 and RAG2 initiate the process that leads to double-strand breaks (DSB) in DNA. The DNA between coding
segments is looped out and forms circles, with the coding sequences joining to one another. In the case of T cells, the larger DNA circle is referred
to as a T-cell receptor excision circle. All these DNA joins are made by a group of molecules that together subserve the function of nonhomologous
end joining (NHEJ).

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 891

RAG1 and RAG2 genes have very low numbers of T and an associated feature of general radiation sensitivity not
B lymphocytes, but NK cell differentiation is preserved.40 seen with RAG1 or RAG2 mutations and is caused by
Some patients with hypomorphic RAG1 or RAG2 muta- mutations in the gene DCLRE1C (DNA cross-link repair
tions may sustain differentiation of a limited number of enzyme 1C), whose protein product is called Artemis.53
T and (less frequently) B lymphocytes, a condition that Artemis has a critical role in the function of NHEJ, or
is also referred to as “leaky” or “atypical” SCID.41,42 In the repair of double-stranded DNA breaks (see Fig. 24-3).
these patients, T lymphocytes often undergo homeostatic During VDJ recombination, it opens the hairpins sealing
proliferation in the periphery and acquire an activated the coding ends at V, D, and J elements that have been
(CD45RO+) phenotype. Oligoclonal expansion of T lym- targeted by the RAG proteins.39 Absence or impaired
phocytes that infiltrate target tissues causing damage is function of Artemis blocks T and B lymphocyte develop-
observed in patients with OS.43 Patients with OS present ment at an early stage, similar to RAG1 and RAG2
with clinical features suggestive of acute graft-versus-host mutations. Artemis is ubiquitously expressed, and loss of
disease. Symptoms include recurrent severe infections, its function in nonhemopoietic tissues may account for
failure to thrive, chronic severe diarrhea, and erythro- nonimmunologic problems (oral and genital ulcers, dental
derma with exfoliation and exudation. Examination may abnormalities, and malabsorption) and for the increased
reveal hepatosplenomegaly and lymphadenopathy. Labo- cellular radiation sensitivity that these patients exhibit.
ratory studies show anemia, hypogammaglobulinemia OS has been observed in some patients with Artemis
with an elevated IgE level, a decrease in the number of defects.54 A partial form of the disease, with residual
peripheral B cells, and presence of activated (CD45RO+) expression and function of the protein, is characterized
circulating T lymphocytes with a restricted (oligoclonal) by reduced number of circulating T and B lymphocytes
T cell repertoire. In vitro proliferation of T lymphocytes and increased risk of lymphoma.55
to antigens and to anti-CD3 is abrogated, whereas pro-
liferation to phytohemagglutinin (PHA) may be variably DNA Ligase IV Deficiency.  DNA ligase IV (LIG4) is also
affected.44 Although hypomorphic RAG1 and RAG2 required for NHEJ. Mutations in the LIG4 gene are
mutations are the most common form of OS, the same associated with microcephaly, cognitive impairment,
phenotype may be observed in patients with hypomorphic bone marrow failure, and cellular immunodeficiency that
mutations in other SCID-causing genes. Some evidence may manifest as T−B−NK+ SCID, “leaky” SCID, or OS.
suggests that expansion of oligoclonal, tissue-infiltrating There is profound cellular radiosensitivity. Patients are at
T lymphocytes in patients with OS may reflect defects of increased risk of myelodysplasia and leukemia.56-59
T-cell tolerance. The study of thymic biopsies from
patients with OS has shown abnormalities of medullary Cernunnos Deficiency.  Cernunnos (also known as XLF)
epithelial cells, with impaired expression of AIRE (auto- is another component of the NHEJ pathway39 and is
immune regulator, discussed later),45 a transcription encoded by the NHEJ1 (nonhomologous end-joining 1)
factor that promotes expression of self-antigens, thereby gene. Mutations of this gene cause lymphopenia, radia-
permitting intrathymic deletion of autoreactive T cells or tion sensitivity, growth retardation, microcephaly and
their diversion to FOXP3+ regulatory T (Treg) cells. Con- developmental delay, bone marrow failure, and an
sistent with this, absence of FOXP3+ cells has also been increased risk of myelodysplasia.60 The T-and B-cell
demonstrated in thymic biopsies from patients with OS.45 immunodeficiency of Cernunnos deficiency is less severe
Environmental triggers may modify the disease pheno- than in patients with RAG or LIG4 defects; however,
type in patients with RAG gene defects. In at least one there are quantitative and qualitative alterations of the
case, progression to OS was observed in a patient with a T-cell repertoire, a severe reduction in the number of
RAG2 mutation after infection with parainfluenza virus invariant NK T cells and mucosa-associated invariant T
type 3.46 Cytomegalovirus (CMV) infection has been lymphocytes,61 and abnormalities of class-switch recom-
associated with in vivo expansion of TCRγδ+ T cells and bination in B lymphocytes (see section on class-switch
autoimmune manifestations.47,48 Finally, somatic muta- defects).62
tions may become superimposed on null or “amorphic”
mutations and yield mosaicism with revertant or hypo- DNA Protein Kinase Catalytic Subunit (DNA-PKcs) Defi-
morphic populations of lymphocytes and resultant OS.49 ciency.  A homozygous missense mutation in the PRKDC
Hypomorphic RAG mutations that result in produc- (protein kinase, DNA-activated, catalytic polypeptide)
tion of mutated proteins with more robust (although gene, encoding for DNA-PKcs was identified in a patient
subnormal) recombination activity have been identified in with T− B−NK+ SCID and cellular radiosensitivity, but
patients with delayed presentation characterized by gran- without microcephaly or mental retardation.63
ulomatous lesions and autoimmunity.50,51 Occasionally,
autoimmunity in patients with RAG defects is associated T−B+NK− Severe Combined Immunodeficiency
with preserved number of circulating B cells and normal X-Linked Severe Combined Immunodeficiency, Muta-
or increased Ig serum levels. One patient with compound tions of the Cytokine Receptor Common γ Chain.  In
heterozygous missense RAG1 mutations presented with Western countries, approximately 40% of all patients
idiopathic CD4 lymphopenia.52 with SCID are males with an X-linked form of the disease,
(XSCID), caused by mutations of the IL2RG (interleukin-
Mutations of DCLRE1C (Artemis).  A form of autosomal 2 receptor γ) gene, that encodes for the common γ chain
recessive SCID with the classic T−B−NK+ phenotype has (γc), shared by cytokine receptors for interleukin-2 (IL-2),

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

T-/NK cell B cell

development, differentiation, T cell NK cell Stimulate
activation lg class switch development Hemopoiesis development CD8 T, B, NK

IL-2 IL-4 IL-7 IL-9 IL-15 IL-21

α β γc α γc α γc α γc α β γc α γc
Figure 24-4 Cytokine receptors and signaling
via γc and Jak3. The γc chain participates in
Jak1 Jak1 Jak1 Jak1 Jak1 Jak1 signaling by way of all these cytokine receptors;
it associates with the Jak3 kinase in every case.
Jak3 Jak3 Jak3 Jak3 Jak3 Jak3 The α chains of each receptor are distinct;
receptors for IL-2 and IL-15 also share a β
chain. The α or β chains or both associate with
Jak1. After cytokine binding, Jak kinases
recruit STAT (signal transducer and activator
STAT5 STAT3 STAT5 STAT3 of transcription) proteins. These molecules
dimerize and then translocate to the nucleus,
STAT5 where they associate with other transcriptional
regulators and alter gene expression.

IL-4, IL-7, IL-9, IL-15, and IL-21 (Fig. 24-4).64,65 Thus a tions of the IL7R gene in humans cause T−B+NK+
defect in a single molecule interrupts several cytokine SCID.75 One case of OS caused by a homozygous mis-
pathways, thereby severely disrupting immune function. sense mutation, permissive for IL-7Rα expression, has
Typically, patients with XSCID lack T and NK lympho- been reported.76
cytes; these defects reflect defective signaling via IL-7R
and IL-15R, respectively. However, some patients with Mutations Affecting Components of the T-Cell Antigen
XSCID may have variable numbers of their own T or NK Receptor Complex
cells and may retain partial immune function, reflecting The TCR/CD3 complex is made up of the TCRα and
some preservation of γc expression and of cytokine- TCRβ (or TCRγ and TCRδ) chains of the receptor
mediated signaling.66 B lymphocytes are typically present, making contact with major histocompatibility antigen-
but they are nonfunctional as a result of impaired IL-21– peptide complexes, as well as components of the CD3
mediated signaling.67 Patients with γc deficiency have signal-transducing complex: CD3γ, CD3δ, CD3ε, and
typical clinical features of SCID. In addition, they are CD3ζ (Fig. 24-5).
unusually susceptible to chronic and severe human papil- Defects in the CD3δ (gene CD3D) lead to a T−B+NK+
lomavirus (HPV) infections, and this phenotype may not SCID phenotype.77,78 Patients have varying degrees of
be corrected after HSCT.68 Delayed presentations have panhypogammaglobulinemia and are susceptible to dis-
been reported in association with hypomorphic muta- seminated viral infections. In some cases, a normal-sized
tions or with somatic mutations in T-cell progenitor cells, thymus was visualized, in marked contrast to almost all
allowing generation of a diversified pool of functional T other forms of SCID, in which the thymus is absent or
lymphocytes that may persist for years.69-71 Gene rever- extremely hypoplastic.77 In one case, CD3δ deficiency was
tant T cells undergoing in vivo expansion may also cause associated with OS.79 A multicenter study of 13 patients
a phenotype resembling OS.72 with CD3δ deficiency treated by HSCT has shown supe-
rior immune reconstitution after transplantation from
JAK3 Deficiency.  A form of T−B+NK+ SCID phenotypi- HLA-matched donors: use of conditioning chemotherapy
cally very similar to XSCID is associated with defects in may be needed to achieve engraftment.79
the tyrosine kinase JAK3.73 The similarity with XSCID is Deficiency of CD3ε (gene CD3E)78 and of CD3ζ (gene
easily understood because JAK3 is a critical signal- CD3Z)80,81 are associated with a similar phenotype and
transducing molecule associated with the γc chain (see Fig. markedly reduced levels of the TCR/CD3 complex on the
24-4). Hypomorphic mutations that allow residual JAK3 surface of circulating T lymphocytes. In one patient with
protein expression and function may associate with CD3ζ deficiency, some of the circulating T cells were
partial preservation of circulating T cells and delayed found to express normal levels of the TCR/CD3 complex
clinical onset, with lymphoproliferation and susceptibil- as the result of somatic mutations on one of the CD3Z
ity to warts and other viral infections.74 alleles, allowing expression of poorly functioning TCR/
CD3 complexes.80
T−B+NK+ Severe Combined Immunodeficiency In contrast, the phenotype of CD3γ (gene CD3G) defi-
Defects of the Interleukin-7 Receptor α Chain.  Signaling ciency is heterogeneous. One of two genotypically affected
through the IL-7 receptor (IL-7R) is required for prolif- siblings presented with clinical features of SCID and
eration of early T-cell progenitors and survival of T lym- autoimmunity associated with severe T-cell lymphopenia,
phocytes. The IL-7R is composed of an α chain (IL-7Rα), whereas the other one had a milder immunologic pheno-
encoded by the IL7R gene, and γc (see Fig. 24-4). Muta- type and remained asymptomatic until 12 years of age,

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 893

CD3 complex
α(γ) β(δ)

ζ ζ γ ε δ ε

Figure 24-5 Components of the T-cell antigen receptor. The ZAP-70 Fyn

actual receptor making contact with a major histocompatibil-
ity complex (MHC)-peptide complex is a heterodimer of α and
β (or γ and δ) chains. This heterodimer sits in the cell mem-
brane in association with the signal-transducing CD3 complex. Lck
This complex contains two heterodimers, one γε and one δε,
and one ζ2 homodimer. Also shown is the MHC class II core-
ceptor molecule CD4. Tyrosine kinases Lck, Fyn, and ZAP-70
associate with components of the receptor complex via immu-
noreceptor tyrosine-based activating motifs (ITAMs) and
transduce signals after interaction of the receptor with peptide/

when he developed autoimmunity and recurrent infec- Proliferative responses to anti-CD3 were profoundly
tions.82,83 This variability of clinical and immunologic impaired.89
phenotype has been confirmed in other patients.84
A homozygous splice-site mutation in the TCRα RhoH Deficiency.  The Ras homology family member H
constant region gene has been identified in two patients (RhoH) is a small GTPase that is phosphorylated in
with a history of recurrent infections and autoimmunity. response to TCR stimulation, allowing recruitment of
Development of T cells expressing TCRγδ was not affected. Lck and ZAP-70 to the TCR-associated signaling
In vitro proliferative responses to mitogens and antigens complex. Mutations of the RHOH gene have been identi-
were decreased, but specific antibody production was fied in two siblings with warts, variably associated with
preserved.85 granulomatous lung disease, psoriasiform skin changes,
and molluscum contagiosum.90 One of the affected indi-
CD45 Deficiency viduals developed Burkitt lymphoma in childhood.
A few patients have been found to have a form of SCID Immunologic abnormalities included reduced number of
resulting from mutations in the gene encoding the protein naïve CD4+ lymphocytes and oligoclonal T cell reper-
tyrosine phosphatase CD45 (gene PTPRC), which plays toire, with accumulation of CD8+ effector memory
an important role in T-cell activation.86-88 These patients CD45RA+ lymphocytes (TEMRA cells) with an
have a SCID phenotype with diminished numbers of “exhausted” (CD45RA+CCR7−) phenotype. The reduced
poorly functional T cells, normal or increased numbers number of lymphocytes expressing skin-homing receptors
of B cells, and variable number of NK cells. (cutaneous lymphocyte antigen, CCR4, CCR6, CCR10,
Other Combined Immunodeficiencies (with T Cells Present)
Table 24-3 lists disorders of combined immunodeficiency
with variable lymphocyte phenotypes. TABLE 24-3  Combined Immunodeficiencies with
T Cells Present and Associated Gene Defects
Relative Deficiency of CD4+ T Cells
Lck Deficiency.  The lymphocyte-specific protein tyrosine Syndrome Gene
kinase (Lck) associates with CD4 and CD8 molecules and Variable T cell lymphopenia CORO1A, MST1
plays a critical role in T-cell signaling by mediating phos-
Relative CD4+ T cell deficiency LCK, MHCIITA, RFX5,
phorylation of immunoreceptor tyrosine activation motifs RFXANK, RFXAP, RHOH
in the intracytoplasmic domains of CD3 subunits and
of the ζ chain–associated protein of 70 kDa (ZAP70). Relative CD8+ T cell deficiency CD8A, TAP1, TAP2, TAPBP,
Homozygosity for a missense LCK mutation was identi-
fied in a child with recurrent respiratory infections, pro- Hyper IgE syndrome type 2 DOCK8
tracted diarrhea, failure to thrive, skin nodules, vasculitis, Veno-occlusive disease with SP110
arthritis, and autoimmune thrombocytopenia. There was immunodeficiency
a severe defect in the number of circulating CD4+ lym- Ion (Ca++ and Mg++) transport MAGT1, ORAI1, STIM1
phocytes, and the density of both CD4 and CD8 mole- defects
cules on the surface of CD3+ cells was markedly reduced.
Other CARD11, IL21R
T lymphocytes showed a restricted TCR repertoire.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

β7-integrin) may impair defense against cutaneous viral shuttling of cytosolic peptides across the endoplasmic
infections and contribute to development of warts. reticulum to load onto nascent HLA class I molecules for
eventual expression at the cell surface and presentation
Major Histocompatibility Complex Class II Deficiency.  to TCRs (Fig. 24-6). HLA class I molecules are highly
The major histocompatibility complex (MHC) in humans unstable without a peptide in their binding cleft, and
is called the HLA complex. The class I and class II HLA they are not transported to the cell surface. Patients
molecules expressed on cell surfaces are critical for practi- with defective expression of HLA class I molecules suffer
cally all mechanisms of specific immune activation. Class mainly from upper and lower respiratory tract bacterial
I molecules are present on most cells of the body. They infections, bronchiectasis, and granulomatous skin inflam-
present antigenic peptides derived principally from intra- mation. Occasional asymptomatic individuals have also
cellular sources to the antigen receptors of T cells express- been described. The main immunologic abnormality is
ing CD8. HLA class II molecules are generally restricted low peripheral blood CD8+ T cells; antibody responses
to specialized antigen-presenting cells (APCs), including may be normal.
monocytes and macrophages, dendritic cells, and B cells,
but are also expressed by thymic epithelial cells. HLA ZAP-70 Deficiency.  The ZAP-70 tyrosine kinase has a
class II molecules mainly present peptides imported from critical role in TCR-mediated signaling by inducing phos-
outside the cell to antigen receptors of T cells bearing phorylation of the linker of activated T cells and SH2
CD4. Defects in the synthesis, expression, or function of domain-containing leukocyte phosphoprotein of 76 kDa
HLA molecules may be expected to have profound con- (SLP-76) (see Fig. 24-5). Mutations of the ZAP70 gene
sequences on lymphocyte development and on immune in humans are typically associated with severe, early
competence. In particular, defective expression of HLA onset infections. Patients have almost complete absence
class II molecules on the surface of thymic epithelial cells of CD8+ T cells. Although circulating CD4+ cells appear
impairs development of CD4+ lymphocytes by impairing normal, they fail to respond to signals delivered by way
their positive selection. of the TCR.94,95 In a few cases, hypomorphic ZAP70
Most patients with MHC class II deficiency present mutations have been associated with delayed onset of the
early in life with recurrent and severe infections, chronic disease and manifestations of immune dysregulation (skin
diarrhea, and failure to thrive.91 Chronic opportunistic rash, wheezing, eosinophilia).96,97 Treatment is based on
infections of the gastrointestinal tract caused by Crypto- HSCT.
sporidium or CMV organisms may lead to severe liver
disease with sclerosing cholangitis. The number of circu- CD8α Deficiency.  CD8 molecules are expressed on the
lating CD4+ cells is markedly decreased, and delayed cell surface as either a CD8α2 homodimer or a CD8αβ
hypersensitivity responses are impaired. All forms of heterodimer. CD8α (gene CD8A) deficiency is a rare
MHC class II molecules (DP, DQ, and DR) are not autosomal recessive disorder characterized by lack of cir-
expressed. Most patients have profound hypogamma- culating CD8+ lymphocytes and by an increased number
globulinemia; however, some patients have normal serum of CD3+CD4−CD8− cells that express markers of effec-
Ig levels, yet specific antibody responses are not elicited. tor cytotoxic T lymphocytes (CD11b, CD57). The disease
As a rule, these children do not survive without HSCT. is reported here because of some phenotypic similarities
However, bone marrow transplantation in these patients (reduced number of CD8+ cells) with ZAP-70 deficiency;
has not been consistently successful,91 probably reflecting however, clinical manifestations are distinct and more
inability to correct defective expression of MHC class II similar to MHC class I deficiency, with recurrent respira-
molecules on the surface of thymic epithelial cells. tory infections and delayed diagnosis.98
MHC class II deficiency results from defective regula-
tion of gene transcription as a result of mutations in any Other Forms of Combined Immunodeficiency with
of four different genes (CIITA, RFXANK, RFX5, RFXAP) Variable Presentation
encoding for components of HLA class II transcription A number of primary immunodeficiencies may have a
complex.91 Without a complete transcription complex, no variable clinical phenotype; in some cases, patients
HLA class II mRNA is produced, and class II proteins affected with these disorders may present with clinical
cannot be synthesized. The same complex activates tran- and laboratory features suggestive of a combined
scription at all HLA class II gene promoters. RFXANK immunodeficiency.
mutations are the main cause of the disease, which is
more common in Northern Africa and in the Middle Macrophage Stimulating 1 Deficiency
East.92 Macrophage stimulating 1 (MST1), also known as serine
threonine kinase 4 (STK4), is a molecule that controls
Relative Deficiency of CD8+ T Cells apoptosis and survival of naïve T lymphocytes by inducing
Defective Expression of HLA Class I.  Several patients expression of FOXO1, a transcription factor that induces
with defective expression of HLA class I molecules have expression of the IL-7R. MST1 deficiency is associated
been described.93 These patients have mutations in one of with recurrent infections, immune dysregulation, a moder-
two genes encoding either TAP1 or TAP2 (transporter ate degree of neutropenia, and congenital heart disease.
associated with antigen processing 1 or 2) or in the Viral infections are particularly common and include
gene encoding tapasin, a TAP-binding protein molecular warts, molluscum contagiosum, and EBV-driven lympho-
chaperone. The TAP1/TAP2 heterodimer is required for proliferative disease. The number of naïve T cells is

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 895

CD8+ T cell

Plasma membrane

Transport of peptide-
MHC complex to
cell surface



Assembly of intact
peptide/MHC class I (TAP 1 deficiency)
α transporter
β 2m
Nascent class I ER

Figure 24-6 Synthesis and assembly of major histocompatibility complex (MHC) class I molecules. ER, Endoplasmic reticulum; β2m, β2-
microglobulin; TAP, transporter associated with antigen processing.

markedly decreased, and there is an expansion of TEMRA lymphomas, leiomyosarcoma). The disease has a severe
cells, associated with a restricted T cell repertoire. T lym- prognosis with high mortality rate; treatment is based on
phocytes show increased apoptosis and reduced prolifera- HSCT.103
tion to mitogens. There is also an increased proportion of Immunologic abnormalities include T-cell lymphopenia
transitional B lymphocytes, with reduced number of with impaired thymopoiesis, a low number of naïve CD8+
memory B cells.99,100 cells, and accumulation of TEMRA lymphocytes. T cell
proliferation to mitogens and antigens is often reduced,
Dedicator of Cytokinesis 8 Deficiency especially within CD8+ lymphocytes. Ig abnormalities in-
Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleo- clude elevated serum IgE and low levels of IgM, and B cell
tide exchange factor that activates Cdc42 and participates responses to TLR agonists are compromised.104 Immuno-
at intracellular signaling in lymphoid and dendritic cells. logic memory is defective in both T- and B-cell compart-
DOCK8 mutations cause an autosomal recessive form of ments. In most cases, the genetic defect is represented by
combined immunodeficiency with hyper-IgE (this is also large intragenic deletions.102
known as hyper-IgE syndrome type 2).101,102 Patients
suffer from chronic viral cutaneous infections (warts, mol- Coronin-1A Deficiency
luscum contagiosum), recurrent skin abscesses and cel- The Coronin-1A protein inhibits F-actin formation in T
lulitis, respiratory tract infections, candidiasis, eczema lymphocytes and thereby modulates cytoskeleton rear-
and other manifestations of severe allergy, autoimmunity rangement and T-cell activation. Coronin-1A deficiency
(cytopenias, central nervous system [CNS] vasculitis), and causes a combined immunodeficiency with recurrent
an increased risk of malignancy (epithelial cell carcinoma, and severe infections, including severe varicella and

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

EBV-driven lymphoproliferation.105,106 Developmental CD4 lymphopenia and impaired T cell proliferation to

delay has also been observed, possibly reflecting a role CD3 stimulation. The MAGT1 gene encodes for a
for Coronin-1A in the CNS.105 There is profound T-cell membrane-associated Mg++ transporter. Female carriers
lymphopenia, with reduced survival of T lymphocytes have a skewed pattern of X chromosome inactivation in
and impaired in vitro proliferation to mitogens and anti- circulating T lymphocytes, suggesting that Mg++ signaling
gens. HSCT can cure the immunologic abnormalities and plays an important role in T lymphocyte development
the increased susceptibility to infections.105 and survival.
Veno-Occlusive Disease with Immunodeficiency Syndrome Caspase Recruitment Domain Family Member 11 Deficiency
Veno-occlusive disease with immunodeficiency (VODI) Caspase recruitment domain family member 11 (CARD11)
syndrome is an autosomal recessive condition character- is a scaffold protein that interacts with B-cell lymphoma
ized by severe infections (often including Pneumocystis 10 and mucosa-associated lymphoid tissue lymphoma
jiroveci and CMV infection) and hepatomegaly with translocation gene 1 proteins, thereby inducing activation
abnormalities of liver function and evidence of veno- of the canonical nuclear factor κB (NF-κB) pathway in
occlusive disease on liver biopsy.107 Cerebrospinal leuko- lymphocytes. Biallelic loss of function mutations of
dystrophy has been reported in several patients.108 CARD11 are associated with a combined immunodefi-
Immunologic abnormalities include T- and B-cell lympho- ciency, marked by increased susceptibility to opportunis-
penia, poor T-cell function, severe hypogammaglobu- tic infections and hypogammaglobulinemia.114 The
linemia, and lack of memory B lymphocytes.108 If number and distribution of T lymphocytes are preserved,
untreated, the disease is often fatal within the first years other than for a reduced number of Treg cells; by con-
of life. Administration of intravenous immunoglobulin trast, there is expansion of transitional B lymphocytes
(IVIG) and antimicrobial prophylaxis may prolong sur- and reduction of mature naïve and memory B lympho-
vival, but the only curative approach is represented by cytes. Moreover, in vitro activation of T and B cells with
HSCT.109 Recurrence of veno-occlusive disease after phorbol myristate acetate is severely impaired, and pro-
HSCT has been reported.108 VODI was initially described liferation of T lymphocytes in response to stimulation by
in patients of Lebanese descent, but the disease has been way of CD3/CD28 is abrogated. On in vitro activation,
reported in other ethnic groups as well. The disease is production of IL-2 by T cells and of interferon IFN-γ by
caused by mutations of SP110 encoding for a nuclear NK cells is decreased.114
body protein that is thought to have a role in regulation
of gene transcription.107 IL-21 Receptor Deficiency
IL-21 regulates proliferation of lymphocytes, differentia-
Immunodeficiencies Caused by Defects of Calcium-Release tion of T helper 17 (Th17) cells, maturation of B cells
Activated Channels into plasmablasts, and induction of NK cell cytotoxicity.
On TCR-mediated signaling, Ca++ is mobilized from IL-21 receptor (IL-21R) defects have been identified in
endoplasmic reticulum (ER) stores. This depletion is four patients from two kindreds whose clinical phenotype
sensed by stromal interacting molecule 1 (STIM1), which included respiratory infections, chronic diarrhea, failure
oligomerizes and binds to the ORAI proteins that form to thrive, and severe liver and biliary tract disease caused
the calcium-release activated channels (CRACs) on by infection with Cryptosporidium organisms.115 The
the cell surface, thereby permitting influx of Ca++, activa- number of T, B, and NK lymphocytes is normal, but the
tion of transcription factors (e.g., nuclear factor of acti- proportion of switched memory B cells is reduced. Serum
vated T cells), cytokine production, T-cell proliferation, IgG levels are low or slightly subnormal, but IgE is ele-
and induction of effector T cell responses. Mutations vated. Antibody responses to T-dependent and
of STIM1 and ORAI1 genes in humans account for T-independent antigens are decreased. On in vitro activa-
autosomal recessive combined immunodeficiencies with tion with CD40 ligand (CD40L) and IL-21, B lympho-
recurrent infections, signs of ectodermal dystrophy, non- cytes from the patients show reduced proliferation and
progressive myopathy (reflecting a role of CRACs in defective class switch recombination. NK cytotoxic activ-
muscle cells).110,111 Autoimmune manifestations (cytope- ity is markedly decreased. T cells proliferate normally in
nias, lymphadenopathy, and splenomegaly) may also be response to stimulation by CD3 and CD28 but fail to
observed, especially in patients with STIM1 deficiency.111 produce IL-17 and IL-22. Proliferation to antigens in
Kaposi sarcoma due to human herpesvirus 8 (HHV-8) vitro is impaired.115
infection has been reported.112 The absolute lymphocyte
count is normal, with preserved distribution of major
lymphocyte subsets. However, in vitro proliferation to MANAGEMENT OF COMBINED
mitogens and antigens is impaired, and cell-mediated IMMUNODEFICIENCY
cytotoxicity and cytokine production are also affected.
Diagnostic Approach
Magnesium Transporter Protein 1 Deficiency Suspicion of SCID or other forms of combined immuno-
Magnesium transporter protein 1 (MAGT1) is an deficiency is prompted by clinical symptoms, family
X-linked disease characterized by severe chronic viral history, or positive results of screening assays. In particu-
infections, chronic diarrhea, and EBV-driven lymphopro- lar, newborn screening for SCID can be performed by
liferative disease.113 Immunologic abnormalities include quantifying levels of TCR excision circles (TRECs; see

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 897

Fig. 24-3 legend) in dried blood spots collected at birth.116 one of their haploidentical parents, most often the mother.
TRECs are a by-product of rearrangement of TCR genes In this case, mature T lymphocytes must be removed from
during intrathymic T-cell development. In patients with the graft to prevent graft-versus-host disease. T cell–
SCID, TREC levels are extremely low or absent as a result depleted HSCT from a haploidentical donor for SCID
of lack of significant thymic T-cell output.117 Indeed, since may be performed without or with pretransplant chemo-
newborn screening for SCID has been started in various therapy. Unconditioned T cell–depleted haploidentical
parts of the United States, several cases of SCID have transplantation leads to long-term T-cell engraftment124;
been identified at birth in otherwise healthy-looking new- however, B- and NK-cell engraftment is rarely achieved,
borns.118 However, it is not clear yet whether determina- and lifelong use of IVIG may be needed, especially in
tion of TREC levels at birth may also reliably identify patients who lack B cells (e.g., defects of VDJ recombina-
other forms (and which ones) of combined immunodefi- tion) or those whose genetic defects compromise B-cell
ciency with residual T-cell development. Tandem mass function (γc, JAK3 defects).125 Use of chemotherapy may
spectrometry can also be used for newborn screening of allow stem cell engraftment (and hence also permit recon-
ADA deficiency119 and may also identify subjects with stitution of B- and NK-cell immunity); however, it is also
residual levels of ADA activity, who could otherwise be associated with toxicity. In a large series, overall survival
missed by the TREC-based assay.120 in SCID patients transplanted after the year 2000 was
Quantification of TRECs represents an important, yet 90% when HLA-matched siblings served as donors and
nonspecific, indicator of a possible severe T-cell immuno- 66% after haploidentical HSCT.123 However, when trans-
deficiency, the diagnosis of which must be confirmed by plantation is performed in infants younger than 3.5
appropriate immunophenotypic, functional, and molecu- months of age, survival is greater than 95%, even after
lar tests. Flow cytometry, looking at the distribution and haploidentical donors,126 thus justifying newborn screen-
absolute number of the major T-cell subsets, B and NK ing for SCID based on quantification of TRECs at birth.118
lymphocytes, may provide important information. Deter- HSCT is also the mainstay of treatment for other
mination of naïve (CD45RA+CD62L+) and activated/ forms of combined immunodeficiency with presence of
memory (CD45RO+ CD62L−) T lymphocytes should be residual or normal number of autologous T lymphocytes.
included in the diagnostic panel to correctly identify In such cases, however, pretransplant conditioning must
patients with maternal T-cell engraftment or with leaky be used to achieve engraftment. Overall survival after
SCID and expansion of in vivo activated, activated T HSCT for these conditions is less satisfactory than in
cells. Functional tests include in vitro proliferation to patients with SCID, being approximately 80% from
mitogens (PHA, anti-CD3 monoclonal antibody) and matched siblings and 50% from haploidentical donors.123
antigens (provided that the patient has been exposed to
these through immunization or natural infection). Ulti- Gene Therapy
mately, identification of the specific disease-causing Gene therapy for the treatment of human disease was first
mutation(s) may permit molecular diagnosis of the attempted in patients with ADA deficiency.127,128 A func-
disease. tional copy of the ADA gene in a retroviral vector was
transduced into populations of mature T cells or bone
Hematopoietic Stem Cell Transplantation marrow cells. Transduced cells expressed normal levels
Identification of a patient with SCID should be consid- of ADA and showed normal function in vitro. However,
ered a pediatric emergency.121 Children with this disorder clinical efficacy was difficult to assess in these early
are so prone to infections that extreme measures must be attempts because adjunctive therapy with PEG-ADA was
taken to protect them from microbial invasion. Before mandated on ethical grounds, even after the re-introduction
newborn screening for SCID became a reality, most of transduced cells into patients. More recently, gene
patients were already infected when initially evaluated therapy for ADA deficiency has been performed by trans-
and required aggressive interventions to keep their clini- ducing hematopoietic stem cells without concurrent in
cal course from running inexorably downhill. After full vivo administration of PEG-ADA31,129; use of submye-
immunologic evaluation has been performed (as expedi- loablative doses of busulfan has permitted robust engraft-
tiously as possible), these patients should begin receiving ment and long-term immune reconstitution in the vast
IVIG infusions. Prophylaxis for P. jiroveci pneumonia is majority of the patients.31,32,129 However, the absolute
indicated for all patients. T-cell count remains suboptimal in many patients, pos-
Although alternative therapies may work for some sibly reflecting irreversible thymic damage caused by
patients (e.g., PEG-ADA for ADA deficiency), the defini- toxic adenosine derivatives.
tive treatment for the great majority of patients with The earliest “complete” success of gene therapy is
SCID and other combined immunodeficiencies is HSCT. considered to have occurred with XSCID.130,131 Hemato-
A variety of sources have been used for stem cells, includ- poietic stem cells were transduced ex vivo with a retro-
ing HLA-identical sibling donors, haploidentical related viral vector carrying a functional copy of the γc gene and
donors (usually parents), unrelated donors, and umbilical then infused into patients without any conditioning che-
cord blood.122,123 Transplantation from a matched sibling motherapy. Twenty patients have been treated in this
donor in patients with SCID does not require condition- manner. Most patients have exhibited rapid and persis-
ing and is associated with excellent survival and long- tent reconstitution of T cell–mediated immunity. Recon-
term immune reconstitution. Patients with SCID who stitution of B-cell immunity has been achieved only in
lack a matched sibling donor may receive HSCT from some patients. The therapy appears to be less effective if

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

performed later in life, probably because of deterioration TABLE 24-4  Cellular Immunodeficiency
of the thymic rudiment over time.132 Syndromes and Their Associated Gene Defects.
Unfortunately, 5 of the 20 infants with XSCID treated
by gene therapy have developed leukemia, which was Syndrome Gene
fatal in one. Leukemias were caused by insertional muta-
Wiskott-Aldrich syndrome WAS
genesis. The vector integrated within or near oncogenes
(in particular, LMO2) and the strong enhancers con- DiGeorge syndrome del22q11, TBX1
tained in the viral long terminal repeats (LTRs) caused DNA repair defects:
oncogene transactivation and uncontrolled cell prolifera-  Ataxia-telangiectasia ATM
tion.133,134 Novel clinical trials, based on self-inactivating  Nijmegen breakage syndrome ATLD, NBS1, PMS2
retroviral and lentiviral vectors in which expression of and others
the γc gene is driven by weaker cellular promoters (instead Disorders of chromosome
of the strong viral LTRs), are currently under way in instability:
Europe and in the United States.   Bloom syndrome BLM
  ICF syndrome DNMT3B, ZBTB24
Disorders of pigmentary dilution:
  Griscelli syndrome type 2 RAB27A
The term syndromic immunodeficiencies has been coined   Hermansky-Pudlak syndromes AP3B1, PLDN
to describe the occurrence of abnormal development or types 2 and 9
function of the immune system leading to susceptibility
Defects of the NF-κB pathway IKBKG, IKBA
to infection, autoimmunity, or malignancy in the setting
of a genetically determined disorder with characteristic Defect in Toll-like receptor IRAK4, MYD88
features of altered development or function of other signaling
organ systems or the body as a whole. Here we will WHIM syndrome CXCR4
review several disorders with prominent immune dys- Hyper IgE syndromes STAT3, TYK2
function. These diseases and their associated genes are
listed in Table 24-4. Space does not permit a detailed Chronic mucocutaneous candidiasis CARD9, IL17RA, IL17F,
description of the tremendous variety of syndromes that
have been associated with immunodeficiency. Interested Immunodeficiencies with skeletal
readers are referred to an excellent review on this abnormalities:
 Cartilage-hair hypoplasia RMRP
topic.135  Schimke immuno-osseous SMARCAL1
Wiskott-Aldrich Syndrome
Disorders of vitamin metabolism TCN2, MTHFD1
Wiskott-Aldrich syndrome (WAS) is an X-linked disease
characterized by eczema, immunodeficiency, and throm- ICF, Instability facial anomalies; WHIM, warts,
bocytopenia.136 Bloody diarrhea is often seen and may be hypogammaglobulinemia, infec­tions, and myelokathexis.
the initial feature. Eczema may be mild or exuberant;
staphylococcal superinfection is common. Recurrent otitis
media and sinopulmonary infections occur frequently, Platelets are small, do not function normally, and are
and opportunistic infections are also seen. In addition, also cleared more rapidly (although the number of bone
autoimmune hemolytic anemia, vasculitis, inflammatory marrow megakaryocytes is normal or even increased).136
bowel disease, glomerulonephritis, and other autoim- In the appropriate clinical context, measurement of plate-
mune processes have been frequently observed in WAS. let size confirms the diagnosis. In normal individuals
Patients most often die as a result of overwhelming infec- platelet volume is 7.1 to 10.5 fL, with a diameter of 2.3
tion or massive hemorrhage. Those who avoid these com- ± 0.12 µm, whereas platelets from patients with WAS
plications have a greatly increased risk for lymphoma, have volumes ranging from 3.8 to 5.0 fL with diameters
many of which are EBV positive. There is also an increased of 1.82 ± 0.12 µm. The low platelet volume distinguishes
risk of aortic aneurysms.136,137 the thrombocytopenia of WAS from immune thrombocy-
Variability of the clinical phenotype has been reported, topenic purpura (ITP), in which platelets are often large.
and a clinical score has been developed to reflect this However, ITP may develop in as many as 20% of patients
phenotypic heterogeneity.136 A milder form of the disease, with WAS.
characterized by thrombocytopenia with mild eczema and The mainstay of treatment for WAS is HSCT.141
lack of severe infections, is also referred to as isolated Without HSCT, survival beyond adolescence is uncom-
X-linked thrombocytopenia (XLT).138 Although XLT mon. The rates for 5-year survival after HSCT for WAS
patients have better survival rates compared with patients approximates 90% for transplants performed after year
who have classical WAS, nonetheless they have a signifi- 2000. Optimal results (survival >95%) are obtained after
cant risk of complications (e.g., autoimmunity, hemor- HSCT from matched siblings, but significantly improved
rhage). In some cases, the thrombocytopenia may even be outcome has been also achieved after HSCT from unre-
intermittent.139 On the other hand, patients who present lated donors and even mismatched related donors.141
early in life with very profound (<10 × 109/L) and persis- Mixed chimerism is associated with increased risk of
tent thrombocytopenia have very poor outcomes.140 autoimmunity after transplant.141

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 899

Pretransplant morbidity and mortality rates may be frequently reported in WAS.151 However, the impact of this
reduced with regular infusions of IVIG and antibiotic phenomenon on clinical phenotype remains unclear.
prophylaxis.136 Blood products, when needed, should be The diagnosis of WAS is facilitated by analysis of
irradiated and tested for CMV. Splenectomy often WASP expression by flow cytometry or Western-blotting;
increases the platelet count, although immune thrombo- however, this approach may miss patients who express a
cytopenia may later supervene. Moreover, splenectomy mutant form of the protein. Ultimately, mutation analysis
markedly increases the risk of overwhelming infections. is required to confirm the diagnosis.136 Female carriers of
Immunosuppressive agents may be needed to treat auto- WAS are generally asymptomatic and have normal plate-
immune complications of the disease.136 let counts but show nonrandom X-chromosome inactiva-
The immune defects in WAS are variable.136,142 Immune tion in lymphocytes and granulocytes.152 Occasionally,
function may be normal in early infancy, but it gradually occurrence of WAS or XLT in females has been reported
wanes. T cell numbers may be decreased, and T cells have as the result of various mechanisms, including extreme
diminished, but not absent, responses to mitogens and lyonization favoring the mutant X chromosome,153,154
antigens in vitro. T cells in WAS will also proliferate in random X-chromosome inactivation,155,156 or WAS gene
response to nonspecific activating stimuli such as phorbol mutation on both X chromosomes.157
esters and calcium ionophores but show a striking absence
of reactivity to immobilized antibodies directed against WAS Protein-interacting Protein Deficiency
the CD3 complex of the TCR. The diversity of the T-cell A single case of a female patient with mutations of the
repertoire appears normal throughout childhood, but it WIPF1 gene, encoding WIP, has been reported. The phe-
may become more restricted with consequent worsening notype included recurrent infections, thrombocytopenia,
immunodeficiency in adulthood.143 defective T-cell proliferation and chemotaxis, and
Serum levels of IgA and IgE are often elevated, whereas impaired NK cell function. No expression of the WIP and
IgM may be low; however, increased serum IgM is associ- WASP proteins was detected in circulating cells.158
ated with an increased risk of autoimmunity and worse
outcome.144 Isohemagglutinins and specific antibody DiGeorge Syndrome
responses to polysaccharide antigens are also diminished. DiGeorge syndrome (DGS) arises as a result of a failure
Although the frequency of class-switched B cells (i.e., of migration of neural crest cells into the third and fourth
those not expressing IgM) appears to be normal, there pharyngeal pouches. Patients display a characteristic
are fewer memory B cells expressing CD27, thus indicat- facies, cardiac defects, parathyroid hormone deficiency,
ing some alteration in B-cell activation in germinal centers and varied immune defects.159,160 The facies consists of
that could underlie or contribute to the humoral immu- hypertelorism; micrognathia; short philtrum; and low-set,
nodeficiency.145 Finally, dendritic cells and monocytes posteriorly rotated ears with small pinnae. Cardiac defects
show impaired formation of podosomes and defective are varied. Type B interrupted aortic arch is the most
directional migration in response to chemotactic signals.142 common and is associated with DGS in 50% of patients
The gene defective in WAS has been identified; its with this defect. Truncus arteriosus and other conotruncal
official name is WAS, and its product is designated the anomalies are also common. Structural anomalies of the
WAS protein (WASP). The same gene is defective in airways have likewise been found in some patients, as well
XLT,146 as well as in X-linked congenital severe neutro- as dysphagia secondary to laryngoesophageal dysmotility.
penia.147 The latter disease is due to activating WAS The bilateral paired parathyroid glands are normally
mutations; its phenotype is very different from WAS adherent to the thymus. Thus these organs are affected
and includes chronic neutropenia with a differentiation together in this disease. The parathyroid deficiency is
block in the bone marrow and an increased risk of often more pronounced than the thymic defect; hypocal-
myelodysplasia.147,148 cemic tetany is one of the more common initial symptoms
WASP interacts with several intracellular partners, of DGS. Even small islands of ectopic thymus tissue may
including the WASP-interacting protein (WIP), Rho permit the development of sufficient T cells for immune
family guanosine triphosphatases, and the Arp2/3 competence. Neuropsychiatric problems and some degree
complex, which leads to reorganization of the actin cyto- of cognitive impairment are seen in many patients and
skeleton in response to activating stimuli in lymphoid and become more prominent during adulthood.161
myeloid cells.142 Partial and complete forms of DGS have been distin-
There is a good, yet imperfect, genotype-phenotype cor- guished on the basis of clinical and immunologic charac-
relation in WAS.149 In particular, XLT is more often associ- teristics.159,160 In the complete form the thymus is absent
ated with residual expression of WASP and with missense or severely hypoplastic.162 These patients have absent or
mutations in exons 1 and 2 of the WAS gene that corre- markedly decreased numbers of T lymphocytes. B cells
spond to a domain of WASP that interacts with WIP. This are present, but specific antibody production is impaired.
interaction stabilizes WASP, thereby explaining reduced Some patients may have erythroderma, similar to that
levels of WASP detected in cells from patients with XLT.150 seen in OS. In this condition, also referred to as atypical
In contrast, the more severe phenotypes are associated complete DGS, oligoclonal, activated (CD45RO+) tissue-
with complete absence of protein or with expression of infiltrating T lymphocytes are detected.162 If untreated,
truncated, nonfunctional forms of WASP. Somatic muta- complete DGS is most often fatal in early childhood;
tions allowing expression of WASP in some cell popula- patients die as a result of hypocalcemia, cardiac compli-
tions (more often, in CD8+ T lymphocytes) have been cations, infection, or a combination of these causes.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

The occurrence of partial forms of DGS outnumbers 41% and the count of naïve CD4+ cells remained very
that of the complete form by about 100 : 1. T-cell number low.175
and function in most patients are varied and presumably
correlate with the amount of ectopic thymus tissue FOXN1 Deficiency
present. Immune function in patients with complete DGS The transcription factor FOXN1 plays a critical role in
does not improve; patients with partial DGS may have development of the thymus and eccrine glands. FOXN1
less immunodeficiency as they get older. In some cases, mutations in humans cause athymia, profound T-cell lym-
the diagnosis has been made in adults being evaluated phopenia, alopecia totalis, and nail dystrophy, fully
for hypoparathyroidism and hypocalcemia.163 Humoral resembling the “nude” phenotype observed in Foxn1-
immunity is generally intact in patients with partial mutated mice.176 There is complete lack of CD4+ lym-
DGS; however, IgA deficiency and defective antibody phocytes, whereas a low number of oligoclonal CD8+
production have been reported.160 An increase in atopic cells may be present.177 Similar to DGS, reconstitution of
dermatitis and asthma has been reported in individuals T-cell immunity can be achieved with thymic transplanta-
with 22q11 deletion.164 Autoimmunity (especially ITP, tion.178 Alternatively, HSCT from HLA-identical siblings
other cytopenias, juvenile arthritis, and celiac disease) is may provide some immune reconstitution through
observed in 10% of the patients.165 homeostatic proliferation of T lymphocytes contained in
In various series, between 55% and 90% of patients the graft.179
with DGS have 2 to 3 megabase deletions involving chro-
mosome 22q11.2.166,167 Deletions in the same region are Ataxia-Telangiectasia
found in patients with a spectrum of phenotypically over- Ataxia-telangiectasia (AT) is an autosomal recessive dis-
lapping conditions, including velocardiofacial syndrome order with an estimated incidence of 1 in 20,000 U.S.
and conotruncal anomaly face syndrome, and in some Caucasian births (95% confidence interval, 1 in 2500 to
patients with isolated cardiac defects. There is heteroge- 700,000).180 AT is characterized by progressive cerebellar
neity in expression of the DGS phenotype, even in mono- ataxia, oculocutaneous telangiectasia, and immunodefi-
zygotic twins. Approximately 40 genes are present in the ciency.181 Associated features are an increased incidence
deleted regions in DGS, and the contributions of each to of lymphoma and sensitivity to radiation. Impairment in
the phenotype are only beginning to be understood.168 motor development may be noted early in the disease
TBX1 encodes a member of a family (T-box) of transcrip- course and is progressive. Walking may be delayed until
tion factors. Mice that are heterozygous for deletion of 16 to 18 months of age or later. Telangiectases of con-
this gene have a phenotype that is variable but often very junctival and cutaneous vessels do not appear until chil-
similar to that of humans with DGS, including thymic dren are 3 to 5 years of age. The cutaneous lesions are
and parathyroid hypoplasia, cardiac outflow tract abnor- found mainly on the pinnae and in skin creases. Immu-
malities, and abnormal facial structure.169 Two truncating nodeficiency will occur in approximately 70% of patients.
and three missense mutations in TBX1 have been found Manifestation of the immunodeficiency is quite varied,
in a few patients with DGS or velocardiofacial syndrome but it is often seen as recurrent sinopulmonary bacterial
and no detectable 22q11.2 deletion.170-172 Interestingly, infections. Granulomatous lesions are frequently seen
the missense mutations were found to result in gain of and may reflect immune dysregulation.182 Growth retar-
function, suggesting that increased TBX1 activity may dation is a prominent feature in many patients and has
phenocopy TBX1 loss of function or haploinsufficiency.172 been associated with decreases in insulin-like growth
Some patients with DGS have deletions on chromosome factor I and its binding protein.183
10p13-p14.173 The median age at death in patients with AT is approx-
Although recurrent infections can be observed in up to imately 19 to 25 years.184,185 Many patients die as a result
25% to 30% of patients with DGS, severe viral and of progressive pulmonary disease caused by repeated
opportunistic infections are very rare, other than in infection. Possibly, noninfectious and ultimately fatal
patients with complete DGS. Live viral vaccines may be interstitial lung disease may also occur in approximately
administered safely to the great majority of patients.160 By 25% of patients.186 The lifetime risk for malignancies in
contrast, complete DGS has a severe prognosis, but it can AT is 30% to 40%; 85% of the cancers are acute leuke-
be treated successfully by thymus transplantation. Immu- mias or lymphomas.187 Elevated serum levels of
nosuppression is needed to control severe immune dys- α-fetoprotein (AFP) are found in more than 95% of
regulation in patients with complete atypical DGS while patients with AT and have diagnostic value in the appro-
preparing for thymus transplantation.174 In a recent study priate clinical context; however, levels of AFP are physi-
43 of 60 patients (72%) treated with this procedure were ologically higher at birth and for the first two years.188
reported to be alive at a median of 4.7 years after trans- T and B cell lymphopenia is a well-recognized, though
plantation, and they attained an increase in T-cell count variable, feature of AT in adulthood but may also be
with improved function, although absolute naïve CD4+ present at birth and be detected by abnormal TREC levels
and CD8+ counts remained below the 10th percentile in at newborn screening for SCID.189 T cells bearing the
most of them.174 HSCT from matched donors may also TCRγδ constitute up to 50% or more of the total number
provide some immune reconstitution through homeostatic of T cells in patients with AT.190 These cells make up
proliferation of mature T lymphocytes contained in the fewer than 10% of peripheral T cells in normal individu-
graft; however, in a series of 17 patients with complete als. Cutaneous delayed hypersensitivity responses, as well
DGS treated by HSCT, overall survival rate was only as results of in vitro assays of T-cell function, are often

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 901

depressed. Varying degrees of humoral immunodeficiency repair pathway. PMS2 deficiency is associated with
are common. IgA deficiency occurs in two thirds of increased occurrence of malignancies, café-au-lait spots,
patients. Decreased levels of IgG2, IgG4, and IgE are also and defective CSR.202 MSH6 deficiency is also associated
common, yet approximately 10% to 30% of the patients with increased risk of cancer and defective maturation of
have increased IgM.191,192 Impaired specific antibody antibody responses, with impairment of CSR and a
responses, particularly to pneumococcal polysaccharide skewed pattern (higher rate of transitions) of somatic
antigens, have also been noted in AT patients.193 hypermutation.203
The gene that is defective in AT is designated ATM (AT
mutated). ATM has critical roles in regulation of the cell IMMUNODEFICIENCIES WITH
cycle: It is involved in the detection of DNA damage and CHROMOSOMAL INSTABILITY
in the initiation of repair.194 There is a marked delay in
induction of the tumor suppressors p53 and BRCA1 after Bloom syndrome is characterized by chromosomal insta-
exposure of AT cells to radiation. Even low-dose radia- bility with increased sister chromatid exchange and ho-
tion leads to significantly greater DNA damage in AT mologous chromosome translocations and is associated
fibroblasts and lymphoblasts than in normal individu- with increased frequency of infections, low levels of IgM,
als.195 ATM mutations are associated with impaired lym- and impaired delayed-type hypersensitivity responses.
phocyte proliferation.196 Lymphocytes of patients with The disease is caused by mutations of the BLM gene,
AT also show a remarkable number of chromosomal encoding for a helicase.204
translocations and inversions. These changes predomi- The immunodeficiency-centromeric instability facial
nantly involve the loci that rearrange to generate mature anomalies syndrome is characterized by hypogam­
Ig (2p12, 22q12, and 14q32) and TCR (7p15, 7q35, and maglobulinemia, facial dysmorphisms, and branching
14q11) genes and reflect defective repair of the double- of chromosomes 1, 9, and 16. The disease may be
stranded breaks produced as part of the physiologic gene caused by mutations in the DNA methyl transferase 3B
rearrangement process during lymphocyte development. (DNMT3B)205 or in the zinc-finger- and-BTB (bric-a-
ATM is also involved in class-switch recombination brac, tramtrack, broad complex)-domain-containing 24
(CSR), and this may explain reduced levels of IgG, IgA, (ZBTB24) genes.206
and IgE seen in patients.197 Mutations of the mini-chromosome maintenance-
No definitive cure is available for AT. Medical man­ deficient 4 (MCM4) gene have been identified in patients
agement aimed at preventing and treating infections with recurrent and severe viral infections (in particular,
(antibiotics, Ig), tumor surveillance, and neurorehabilita- caused by herpes simplex virus 1 [HSV-1], varicella zoster
tion represent the mainstays of treatment.188 Very recently, virus [VZV] and CMV), growth retardation, adrenal
some improvement of neurologic signs has been observed insufficiency, and selective NK cell deficiency with lack of
on administration of betamethasone, possibly reflecting the CD56dim NK subset.207,208 The disease is inherited as
antiinflammatory and antioxidant activity of glucocorti- autosomal recessive trait. MCM4 is a component of a
coids in the CNS.198 multiprotein complex required for both initiation and
Whether pathologic changes result from the heterozy- elongation of eukaryotic DNA replication.209 MCM4
gous carrier state of AT remains a subject of controversy. mutations were shown to cause abnormalities of cell
Carriers heterozygous for ATM mutations have none of cycle, with increased proportion of fibroblasts in G2/M
the classic clinical manifestations of AT; however, the sen- and S phases of cell cycle and an aberrant (>4n) DNA
sitivity of their DNA to radiation is increased, and several content, and genomic instability.207
reports suggest that AT heterozygotes have an increased
rate of a variety of malignancies, such as breast cancer.199 PIGMENTARY DILUTION DISORDERS
OTHER IMMUNODEFICIENCIES ASSOCIATED WITH Pigmentary dilution disorders include diseases in which
DEFECTIVE MECHANISMS OF DNA REPAIR abnormalities in melanosome trafficking within cells
lead to characteristic pale skin and silvery-gray or ashen
The Nijmegen breakage syndrome is a disorder of chro- hair. Several forms of pigmentary dilution disorders are
mosome fragility with autosomal recessive inheritance.200 also characterized by a variable degree of immune defi-
The phenotype is similar to that of AT and consists of ciency, in particular impaired cell-mediated cytotoxicity.
growth retardation, microcephaly, immunodeficiency, In these conditions inability to clear virus-infected cells
sensitivity to radiation, and a high rate of lymphoma. The leads to persistent and exaggerated inflammatory
affected gene is designated NBS1. Nibrin, its protein responses with macrophage activation, release of proin-
product, is another substrate of ATM in the cellular flammatory cytokines, and continuous activation of infil-
response to ionizing radiation. Absence of nibrin function trating CD8+ T cells that secrete high amounts of IFN-γ
leads to disruption of mechanisms of DNA repair, but it and cause tissue damage. Fever, hepatosplenomegaly,
does not appear to result in abnormal function of cell lymphadenopathy, and cytopenia caused by impaired
cycle checkpoints. Another similar syndrome, AT-like dis- hematopoiesis in the bone marrow and hemophagocyto-
order, results from mutations of the gene MRE11A, sis are typical manifestations of immune activation during
which encodes another ATM substrate.201 the so-called accelerated phase of the disease. Impaired
Postmeiotic segregation 2 (PMS2) and MutS homo- cytotoxicity of virus-infected cells reflects defective traf-
logue 6 (MSH6) are components of the DNA mismatch ficking, docking or release of cytolytic granules in NK

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

cells, and cytotoxic T cells. This defect parallels defects vivo.221 However, whether this may affect the disease
of melanosome trafficking. phenotype is not clear.
Chédiak-Higashi syndrome is characterized by partial Patients may suffer opportunistic-type disseminated
albinism, peripheral neuropathy, and increased risk of viral infections and P. jiroveci pneumonia and are also
viral infections. Neutropenia is often present and may highly susceptible to atypical mycobacterial infections.
facilitate bacterial infections. Recognition of “giant” Inflammatory bowel disease is also frequently seen,
lysosomes in leukocytes facilitates the diagnosis.210 The reflecting a role of NF-κB in controlling epithelial integrity
disease is caused by mutation of the lysosomal trafficking and the interaction between the mucosal immune system
regulator (LYST) gene.211 The precise mechanism by and gut microflora.222 Finally, lymphedema and osteope-
which the LYST protein works is not known, although it trosis may also be part of the disease phenotype.220
is thought to regulate trafficking of intracellular vesicles. Most patients are hypogammaglobulinemic and have
HSCT is the only definitive treatment, but it does not impaired vaccine responses (especially to polysaccharide
prevent possible progression of neurologic complications. antigens). Peripheral blood lymphocyte subsets and in
Griscelli syndrome (GS) type 2 also associates partial vitro measures of lymphocyte function may be unremark-
albinism and immunodeficiency with increased suscepti- able or variably diminished; NK cell cytotoxicity may be
bility to infections, fever, and cytopenia. The disease is impaired. Signaling by way of TLRs is also affected.
caused by mutations of the RAB27A gene, which encodes Therapy with gamma globulin and antibiotic prophylaxis
for a protein that permits docking of the cytolytic gran- is essential. Despite these measures, infections may still
ules to the cell membrane.212 In contrast, GS type 1 occur. HSCT may cure the immunologic abnormalities
(caused by mutations of the MYO5A gene, encoding for and resolve increased susceptibility to infections, but
the myosin Va protein) and GS type 3 (due to mutations inflammatory bowel disease may persist, along with
of the gene encoding for the melanin chaperone mela- extra-immune manifestations of the disease.223
nophilin) are characterized by hypopigmentation without A few patients have been found to have a similar phe-
immunodeficiency. notype as a result of a so-called hypermorphic (gain of
Hermansky-Pudlak syndrome type 2 (HPS2) is char- function) mutation of the IκBα chain.224,225 In this situa-
acterized by oculocutaneous albinism, bleeding diathesis, tion the IκBα is resistant to phosphorylation by IKK and
neutropenia, interstitial lung disease, and recurrent infec- cannot be dissociated, degraded, and induced to release
tions.213 Patients are at increased risk of hemophagocyto- NF-κB so that it may translocate to the nucleus to acti-
sis. The disease is caused by mutations of the β subunit vate transcription.
of the adaptor-related protein complex 3 (gene AP3B1)
involved in sorting of proteins to the lysosomes.214 Patients DEFECTS OF TOLL-LIKE RECEPTOR SIGNALING
with HPS9, which is caused by mutations of the pallidin
(PLDN) gene,215 present with hypopigmentation and nys- IRAK-4 and Myd88 are components of a complex mediat-
tagmus; recurrent cutaneous infections also have been ing signaling downstream of all TLRs (except TLR3).226
reported.216 Patients with IRAK4 or MYD88 mutations have severe,
invasive bacterial infections such as meningitis, bacteremia,
MUTATIONS OF THE NUCLEAR FACTOR septic arthritis, deep-tissue abscesses, and osteomyelitis
κ-B PATHWAY with gram-positive organisms (pre­dominantly Staphylococ-
cus aureus and Staphylococcus pneumoniae.227-229 Less
NF-κB is a transcription factor that is critical for the severe skin and respiratory infections also occur frequently.
activation of numerous genes on leukocyte stimulation.217 Most patients begin to exhibit infections in early childhood,
Activity of this factor is regulated by an inhibitor known but these wane significantly in frequency and intensity in
as IκB. Phosphorylation of IκB by IκB kinase (IKK) leads the second decade of life. Most patients have impaired
to IκB degradation and liberates active NF-κB. IKK is antibody responses to pneumococcal polysaccharides, but
composed of three subunits, α, β, and γ; the latter is also other routine tests of immune function are normal. Many
known as the NF-κB essential modulator (NEMO). The patients have high levels of all Ig isotypes, possibly owing
gene encoding NEMO is on the X chromosome. Null to immune stimulation by repeated bacterial infections.
mutations in this gene are incompatible with life for male Signaling is impaired through all TLRs other than TLR3.
subjects and lead to the X-linked dominant disease incon- Management is mainly with antibiotic prophylaxis and IgG
tinentia pigmenti in females. Certain mutations that therapy.
allow partial NEMO function are associated with an
immunologic phenotype that may have some similarities THE SYNDROME OF WARTS,
to hyper-IgM. Along with a combined immunodeficiency, HYPOGAMMAGLOBULINEMIA, INFECTIONS,
these patients may exhibit hypohidrotic ectodermal dys- AND MYELOKATHEXIS
plasia and lymphedema with osteopetrosis.217-220 Distinct
hypomorphic mutations define specific disease character- The syndrome of warts, hypogammaglobulinemia, infec-
istics, thus establishing genotype-phenotype correlation, tions, and myelokathexis (WHIM syndrome) is an auto-
albeit imperfectly.218 Somatic mosaicism in T lympho- somal dominant disorder of leukocyte trafficking caused
cytes has been detected in a significant proportion of by mutations of the chemokine receptor CXCR4.230
males with NEMO deficiency, providing evidence for Patients carry heterozygous mutations in the intracellular
selective advantage for NEMO-expressing T cells in tail of CXCR4 that prevent interaction with β-arrestin,

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 903

thus allowing continuous signaling induced by CXCR4 tion, medical history, and imaging studies are needed to
ligand, CXCL12. This signal retains mature neutrophils evaluate, diagnose, and treat any infections. Controver-
in the bone marrow (myelokathexis) and alters trafficking sial results have been obtained after HSCT.243,244
of B and T lymphocytes, causing lymphopenia.231
Impairment of cellular immunity and defective number AUTOSOMAL RECESSIVE HYPER-
of plasmacytoid dendritic cells (which are the major IMMUNOGLOBULIN E SYNDROME CAUSED
source of IFN-γ) cause warts, and neutropenia and hypo- BY TYK2 MUTATIONS
gammaglobulinemia account for recurrent bacterial infec-
tions that mostly affect the respiratory tract.231,232 The Two distinct forms of autosomal recessive HIES are
number of switched memory B cells is reduced, and there known. Of these, DOCK8 deficiency has been discussed
is oligoclonality of the antibody repertoire.233 Gamma in the preceding section “Other Combined Immunodefi-
globulin replacement therapy generally reduces the rate ciencies with Variable Presentation.” Two patients with
of infection. The CXCR4 antagonist AMD3100 (plerixa- autosomal recessive HIES caused by mutations of TYK2,
for) corrects neutropenia and lymphopenia.234 a member of the JAK family of tyrosine kinases involved
in intracellular signaling, have been reported. The first
HYPERIMMUNOGLOBULIN E SYNDROME CAUSED patient presented with atopy, elevated serum IgE, and
BY STAT3 MUTATIONS susceptibility to infections sustained by S. aureus, BCG,
Salmonella organisms, and viruses.245 The second patient
Hyper-IgE syndrome (HIES, often designated type 1) suffered from disseminated BCG infection, neurobrucel-
was initially described in 1972 in patients with severe losis, and cutaneous herpes zoster but had normal serum
sinopulmonary bacterial infections, severe skin superin- IgE and did not develop atopy.246
fections with S. aureus on a chronic eczematous eruption
(for which the disease is also known as Job syndrome), CHRONIC MUCOCUTANEOUS CANDIDIASIS
and susceptibility to Aspergillus fumigatus pneumonitis
with pneumatocele formation.235 Additional manifesta- CMC affecting the nails, skin, and mucosa is the clinical
tions include asymmetric or coarse facial features, hallmark of three distinct genetic disorders that affect
delayed shedding of primary teeth, bone fragility and IL-17–dependent immunity.247 These include complete,
fractures, scoliosis, and keratoconjunctivitis.236 Patients autosomal recessive deficiency of IL-17 receptor α chain
show increased susceptibility to nonfilamentous molds, (IL17RA),248 partial autosomal dominant IL-17F defi-
such as P. jiroveci pneumonia and in particular chronic ciency,248 and heterozygous gain-of-function mutations
mucocutaneous candidiasis (CMC). There is an increased of signal transducer and activator of transcription 1
rate of malignancies, especially non-Hodgkin lym- (STAT1).249,250 The latter represents the most common
phoma.236 Cardiovascular anomalies have been described cause of isolated CMC. Mutations of caspase recruitment
in recent years and include aneurysms, in particular of domain-containing protein 9 (CARD9) gene, encoding a
the carotids, cerebral arteries, and coronary arteries, and cytosolic adaptor molecule involved in intracellular sig-
may lead to additional complications such as myocardial naling in cells recognizing fungi, also affect development
infarction.237 Inheritance of this form of HIES is autoso- of Th17 cells and cause CMC; however, CARD9-deficient
mal dominant, but many cases represent sporadic pre- patients are also at increased risk of disseminated Candida
sentations. The disease is caused by heterozygous infections as well as of other fungal infections.251 Defi-
dominant-negative mutations of the STAT3 gene that ciency of Th17 cells accounts for CMC also in other
encodes for a transcription factor involved in signaling forms of primary immunodeficiency, including T-cell defi-
from a multitude of receptors.238,239 In particular, STAT3 ciencies, HIES, and autoimmune polyendocrinopathy-
is required for the development of Th17 cells, which candidiasis-ectodermal dystrophy (APECED).
secrete IL-17 and IL-22, two cytokines that play an
important role in defense against candida and in pro- IMMUNODEFICIENCIES WITH SKELETAL
moting secretion of antimicrobial peptides by bronchial ABNORMALITIES
epithelial cells.240
The major immunologic findings are elevated serum Cartilage-hair hypoplasia (CHH) is an autosomal reces-
levels of IgE (3000 to >50,000 IU/mL) and eosinophilia. sive disease characterized by short-limbed dwarfism with
Along with a deficiency of Th17 cells, a reduced number metaphyseal dysplasia, sparse and fair hair, and joint
of memory (CD27+) B lymphocytes also have been hypermotility. Dyserythropoietic anemia and a variable
reported. The diagnosis is established on clinical and degree of immunodeficiency are present in 80% of the
laboratory grounds; a scoring system241 has been devel- patients. A minority of subjects also present with
oped that may be helpful, especially if used in combina- Hirschsprung disease. There is a 6% to 10% rate of
tion with demonstration of lack of Th17 cells.242 malignancies, especially lymphoma and basal cell carci-
Management of HIES caused by STAT3 mutations is noma. The disease has a higher prevalence among Finnish
mainly by skin care and antimicrobial prophylaxis against and Amish populations252 and is caused by mutations
S. aureus. The role of antifungal prophylaxis is contro- in the RMRP gene that encodes for the untranslated
versial, but it may be helpful in patients with CMC. HIES RNA component of the mitochondrial RNA-processing
patients may lack classical signs and symptoms of infec- endoribonuclease253 that is involved in multiple functions,
tion, such as fever. Therefore careful physical examina- including ribosomal and messenger RNA processing,

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

mitochondrial DNA replication, and negative regulation recurrent and severe viral infections (especially those
of target RNA transcripts on interaction with TERT caused by papillomavirus and herpesviruses), and fungal
(telomerase reverse transcriptase).252 infections. There is increased risk of myelodysplasia and
The immunodeficiency of CHH is characterized by malignancies, including acute myeloid leukemia, squa-
increased frequency of infections. Severe and persistent mous cell carcinoma, and EBV-positive leiomyosarcoma.
viral infections (EBV, CMV, HSV, and VZV) and fungal Pulmonary alveolar proteinosis and primary lymphedema
infections may occur, in addition to recurrent respiratory have been observed in several patients.266-269
infections. Granulomatous lesions affecting the skin and Typical laboratory features include profound monocy-
other tissues have been described in several patients.254 topenia, severe reduction in the number of B and NK
Laboratory tests reveal a variable degree of immune dys- lymphocytes (in particular, of the CD56bright subset) and
function that predominantly affects T cells. In rare cases, dendritic cells and elevated levels of fms-like tyrosine
immunodeficiency is very severe and may resemble SCID, kinase ligand (Flt3L).266,267,270 Depletion of regulatory T
“leaky” SCID with reduced number of CD8+ lympho- cells also has been reported.267 Examination of the bone
cytes, or OS.255,256 Irrespective of the severity of the clini- marrow reveals hypocellularity, often associated with
cal phenotype, thymopoiesis is reduced, and there is multilineage dysplasia and cytogenetic abnormalities,
T-cell lymphopenia. Moreover, T lymphocytes show including monosomy 7 and trisomy 8. In vitro IL-12 and
abnormalities of cell cycle progression and an increased IFN-γ production in response to stimulation with LPS is
rate of apoptosis.257 HSCT is an effective form of treat- markedly reduced,267,268 suggesting that disruption of the
ment for patients with a severe clinical phenotype.258 IL-12/IFN-γ axis may contribute to the increased occur-
Schimke immuno-osseous dysplasia is an autosomal rence of mycobacterial disease.
recessive disease characterized by spondyloepiphyseal The disease has been referred to as MonoMAC syn-
dysplasia, focal glomerulosclerosis leading to progressive drome (to indicate the monocytopenia and susceptibility
renal failure, and T-cell immunodeficiency.259 There is T to nontuberculous mycobacterial infections)266,268 or
cell lymphopenia, with an increased proportion of DCML (dendritic cells, monocytes, B and NK lympho-
activated/memory T cells and of TCRγδ-expressing T cytes) deficiency267 and has been shown to be caused by
lymphocytes. The disease is caused by mutations of the heterozygous, loss-of-function mutations of the GATA2
SMARCAL1 gene, which encodes for a chromatin remod- gene.271-273 GATA-2 is a transcription factor that contains
eling protein.260 two highly conserved zinc finger domains that mediate
protein-DNA and protein-protein interactions and is
IMMUNODEFICIENCIES ASSOCIATED required for stem cell homeostasis,274 lymphatic vessel
WITH DISORDERS OF FOLATE AND development,273 and the maturation and homeostasis of
COBALAMIN METABOLISM NK lymphocytes.270 Disease-causing mutations also
include intronic deletions and point mutations in regula-
Inborn errors of folate and cobalamin metabolism may tory regions of the gene that affect GATA2 transcript
associate with varying degrees of immunodeficiency. In levels.275 Both autosomal dominant inheritance and spo-
particular, genetically determined defects in vitamin B12 radic presentation have been reported. If untreated, the
metabolism are associated with megaloblastic anemia, disease has a severe prognosis, with death occurring in
neutropenia, and neurologic symptoms with seizures and adulthood as a result of infections or malignancies. Non-
developmental delay.261 Transcobalamin II (gene TCN2) myeloablative HSCT has been successfully performed in
deficiency causes neutropenia leading to recurrent bacte- several patients, with reconstitution of the number of
rial infections.262 Severe lymphopenia is observed in monocyte, B-cell, and NK-cell populations and reversal
patients with deficiency of methionine synthase, causing of the clinical phenotype.276
a SCID-like phenotype with severe viral and bacterial
infections.263 Mutations of proton-coupled folate trans- IMMUNODEFICIENCIES WITH IMMUNE
porter that impede folate absorption through the gastro- DYSREGULATION
intestinal mucosa are also associated with extreme
lymphopenia and clinical features of SCID.264 Mutations Although autoimmune and inflammatory manifestations
of the MTHFD1 gene that encodes for a trifunctional may be seen in a large number of primary immunodefi-
protein essential for processing of single-carbon folate ciencies, they represent the main feature in some. The
derivatives cause SCID with decreased number of T, B, pathophysiology of these disorders may reflect a variety
and NK lymphocytes, which is associated with megalo- of mechanisms, including impairment of central and
blastic anemia, leukopenia, atypical hemolytic uremic peripheral tolerance and chronic immune activation asso-
syndrome, and neurologic abnormalities. Parenteral sup- ciated with the inability to clear infections. These disor-
plementation therapy is beneficial.265 ders and their associated genes are listed in Table 24-5.


In 2010 Vinh and coworkers266 reported on a series of DYSTROPHY SYNDROME
patients with a distinct clinical phenotype characterized
by onset in late childhood or adulthood, susceptibility APECED syndrome represents the prototypic disorder
to disseminated nontuberculous mycobacterial disease, associated with impairment of central T-cell tolerance.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 905

TABLE 24-5  Immunodeficiency Syndromes with IPEX require immune suppression, but the only
Associated with Dysregulation definitive treatment currently available is allogeneic
Syndrome Gene
candidiasis ectodermal IL-2–mediated signaling is important to maintain immune
dystrophy (APECED) homeostasis and support the function of Treg lympho-
Immune dysregulation FOXP3 cytes. Mutations in the IL2RA gene, which encodes
polyendocrinopathy X-linked CD25, the α chain of the IL-2R, cause immunodeficiency
(IPEX) with IPEX-like immune dysregulation.290,291 The clinical
Defects of IL-2 signaling IL2RA, STAT5B phenotype is marked by severe diarrhea, failure to thrive,
CMV infection, chronic lung disease, lymphadenopathy,
Autoimmune CASP8, CASP10, FAS, FASLG, splenomegaly, and autoimmunity (diabetes mellitus,
lymphoproliferative KRAS, NRAS
syndrome (ALPS) autoimmune hepatitis). Poor in vitro T-cell function that
could not be corrected with exogenous IL-2 was demon-
Other ITCH
strated. The number of FOXP3+ cells was preserved in
patients with CD25 deficiency; however, secretion of
IL-10, a cytokine with immunosuppressive activity, was
impaired,290 possibly accounting for the autoimmune
manifestations of the disease.
APECED is inherited as an autosomal recessive trait and Mutations of the signal transduced and activator of
is characterized by autoimmune hypoparathyroidism, transcription 5B (STAT5B) gene, which encodes a tran-
Addison disease, and CMC. Patients are also prone to scription factor activated by IL-2 signaling, cause an
other autoimmune manifestations, such as hepatitis, alo- autosomal recessive form of immunodeficiency with
pecia, ovarian failure, and hypothyroidism. There is an immune dysregulation. Because STAT5B is also activated
increased incidence of oral squamous cell carcinoma, in response to growth hormone receptor stimulation,
and fulminant autoimmune hepatitis. The disease is patients with STAT5B deficiency also show growth failure
caused by mutations in the gene AIRE (autoimmune with growth hormone insensitivity.292,293
regulator) encoding a transcription factor expressed by
medullary thymic epithelial cells (mTECs).277,278 AIRE AUTOIMMUNE LYMPHOPROLIFERATIVE
promotes expression of tissue-specific antigens that are SYNDROME
presented by mTECs and thymic dendritic cells to
nascent T lymphocytes.279 High-affinity recognition of Apoptosis of self-reactive lymphocytes is another impor-
self peptides leads to deletion of self-reactive T cells. tant mechanism to prevent autoimmunity in the periph-
Therefore mutations of the AIRE gene compromise the ery and may be induced either through the extrinsic,
mechanism of central tolerance and result in APECED, Fas-dependent pathway or through induction of the mito-
which is associated with production of multiple autoan- chondrial pathway in response to cell damage and cyto-
tibody specificities.280 Interestingly, autoantibody pro- kine (e.g., IL-2) starvation. Both pathways converge on
duction in patients with APECED is not restricted to caspase 9 and downstream effector caspases 3 and 7,
AIRE-dependent self-antigens but also includes antibod- causing apoptosis. Autoimmune lymphoproliferative syn-
ies to interferon-α and β281 as well as IL-17 and drome (ALPS) is characterized by lymphadenopathy, sple-
IL-22.282,283 Defective Th17-dependent immune responses nomegaly, and autoimmune cytopenias and an increased
may account for chronic mucocutaneous candidiasis in risk of developing lymphoma. Infiltrative lymphoprolif-
this disease. erative disease may also cause organ-specific complica-
tions (glomerulonephritis, hepatitis, encephalitis, uveitis,
IMMUNE DYSREGULATION interstitial pulmonary disease). There is a characteristic
POLYENDOCRINOPATHY ENTEROPATHY expansion of CD3+TCRαβ+CD4−CD8− double-negative
Most patients are heterozygous for a mutation in the
Treg cells maintain peripheral T cell tolerance by sup- FAS gene; in such families the disease is inherited as an
pressing self-reactive T lymphocytes that have escaped autosomal dominant trait with variable penetrance.
central tolerance.284 Generation of Treg cells is controlled Somatic mutations in FAS are another common cause of
by the transcription factor FOXP3.285 Mutations of the the disease.295,296 More rarely, patients may show biallelic
FOXP3 gene cause immune dysregulation, polyendocri- mutations.
nopathy, enteropathy, X-linked (IPEX) syndrome.286,287 Other rare causes of ALPS are represented by muta-
IPEX is characterized by severe early-onset autoimmune tions of genes encoding Fas ligand (FasL),297 FADD,298
manifestations that involve the gut (causing intractable caspase 8,299 and caspase 10,300 all of which are involved
diarrhea), pancreas (diabetes), the skin, and other organs. in the Fas-mediated signaling pathway leading to apop-
Lymphoproliferation and cytopenias are also very common. tosis. The number of DNTs is only marginally elevated
Delayed presentations have been also observed.288 Patients in patients with caspase 8 deficiency.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

In addition to an increased proportion of DNTs, other TABLE 24-6  Immunodeficiency Syndromes with
biomarkers that may facilitate the diagnosis of ALPS and Impaired Cytotoxicity
that are associated especially with FAS mutations include
elevated serum levels of vitamin B12, soluble FasL, IL-10, Syndrome Gene
and IL-18. Hypergammaglobulinemia is common. More-
Familial hemophagocytic PRF1, STX11,
over, patients with ALPS caused by FAS mutation fre- lymphohistiocytosis STXBP2, UNC13D
quently have a reduced number of memory (CD27+) B
lymphocytes.301 X-linked lymphoproliferative syndromes BIRC4, SH2D1A
Defects of the “intrinsic” (mitochondrial) pathway of Other CD16, CD27, ITK
apoptosis leading to ALPS include gain-of-function muta-
tions of NRAS302 and somatic mutations of KRAS,303,304
but these variants do not result in an increased number FAMILIAL HEMOPHAGOCYTIC
Management of ALPS includes use of immunosuppres-
sive drugs (steroids, mycophenolate mofetil, sirolimus) to Familial hemophagocytic lymphohistiocytosis (FHL)
control autoimmune manifestations and regular monitor- includes a heterogeneous group of monogenic disorders
ing of lymphoproliferation by computed tomography characterized by impaired cell-mediated cytotoxicity. In
scanning or positron emission tomography for surveil- patients with FHL, the inability to clear viral infections
lance of lymphoma. Splenectomy may improve the cyto- causes persistent activation of CD8+ and NK lympho-
penias but is associated with a marked increase of sepsis. cytes, with production of high amounts of IFN-α and -β
Chronic cytopenias tend to improve over time; HSCT and of proinflammatory cytokines (tumor necrosis factor-
should be reserved for very severe clinical presentations alpha [TNF-α], IL-6).309 Clinical features of FHL include
with autoimmune disease refractory to treatment.305 recurrent episodes of high fever, pancytopenia, liver and
spleen enlargement, and signs of neurologic involvement.
The diagnostic criteria were revised in 2007.310 Elevated
ITCH DEFICIENCY serum levels of triglycerides, ferritin, and soluble CD25
Mutations of the E3 ubiquitin ligase ITCH have been and decreased levels of fibrinogen and poor NK function
shown to cause multisystem autoimmune disease in are typical laboratory findings. If left untreated, FHL is
affected individuals from a large Amish kindred.306 Char- rapidly fatal. Severe bacterial and fungal infections and
acteristic clinical features include failure to thrive, hepa- multiple organ failure are the main causes of death. Treat-
tosplenomegaly, multiorgan autoimmune manifestations ment should be aimed at eradicating the underlying infec-
(hypothyroidism, hepatitis, diabetes, enteropathy), tion while suppressing immune activation at the same
chronic lung disease, developmental delay, dysmorphic time. Corticosteroids, cyclosporine A, etoposide, and
features, and hypotonia. Dysfunction of E3 ubiquitin antithymocyte globulin are often effective in tempering
ligases have been shown to lead to indiscriminate T cell immune activation.311 However, relapses are common,
activation, loss of tolerance to self-antigens and accumu- and the only curative treatment is represented by HSCT.
lation of autoreactive B lymphocytes.307 In particular, reduced intensity conditioning has shown
excellent efficacy and limited toxicity.312
IMMUNODEFICIENCIES WITH IMPAIRED CELL- The genetic defect has been identified for four forms
MEDIATED CYTOTOXICITY of FHL so far, and all of them are inherited as autosomal
recessive traits. Perforin deficiency accounts for approxi-
CD8+ cytotoxic T lymphocytes (CTLs) and NK cells play mately 30% of all cases of FHL. It is caused by mutations
a critical role in antiviral immune defense through two of the PRF1 gene that prevent expression or correct
mechanisms: Fas-mediated apoptosis of virus-infected cells assembly of perforin multimers that form pores through
and release of cytolytic granules. In resting CTLs and NK which cytolytic enzymes are released into target cells.313
lymphocytes, cytotoxic proteins are contained in endo- Mutations of the UNC13D gene, encoding for Munc13-
somal secretory granules. On activation of CTLs and NK 4, impair priming of the cytolytic granules, which is nec-
lymphocytes, lytic granules polarize toward the immune essary for their fusion with the cell membrane. UNC13D
synapse, dock, and fuse with the cell membrane of the effec- mutations represent the most common form of FHL
tor cell. Multimers of perforin form pores through which (30% to 40% of all cases).314 Defects of the Syntaxin 11
CTLs and NK cells release cytotoxic proteins (granzyme B, (STX11) gene affect granule exocytosis.315 Finally, FHL
granulolysin) into virus-infected target cells, causing activa- may also be caused by defects of Munc18-2, a protein
tion of caspases and apoptosis of target cells.308 partner of STX11 encoded by the Syntaxin binding
Defects in this process are responsible for various protein 2 (STXBP2) gene.316
forms of familial hemophagocytic lymphohistiocytosis.309
Defective cell-mediated cytotoxicity is also observed in X-LINKED LYMPHOPROLIFERATIVE DISEASE
several forms of pigmentary dilution disorders (discussed
previously). Finally, selective susceptibility to EBV infec- X-linked lymphoproliferative (XLP) disease is character-
tion is at the basis of various forms of lymphoprolifera- ized by unique susceptibility to severe complications after
tive syndrome. These diseases and their associated genes EBV infection in male subjects. Two genetically distinct
are listed in Table 24-6. forms are known. In XLP1 the disease is caused by

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 907

mutations of the SH2 domain containing protein 1 A subsets. By interacting with CD70, it promotes genera-
(SH2D1A) gene, encoding for a small adapter protein tion and maintenance of T-cell memory. It is also com-
(SLAM-associated protein, or SAP) involved in intracel- monly used as a marker of memory B lymphocytes. CD27
lular signaling in T and NK lymphocytes.317,318 In particu- deficiency has been identified in some patients presenting
lar, SAP binds to CD244 (a SLAM family member) with severe EBV infection. Lymphoma and secondary
expressed by NK lymphocytes. EBV-infected B cells hypogammaglobulinemia have been reported in some of
express high levels of CD48, the CD244 ligand. On these patients. HSCT represents a curative form of
CD244/CD48 binding, SAP participates at intracellular treatment.327,328
signaling and promotes NK cytolytic activity against
EBV-infected target cells. In the absence of SAP, NK cyto- CD16 DEFICIENCY
lytic activity is impaired.319 SAP is also important for the
function of follicular helper T cells that promote matura- One of the mechanisms by which NK lymphocytes
tion of antibody responses.320 XLP2 is caused by muta- mediate killing of target cells is antibody-dependent cel-
tions of the BIRC4 gene, which encodes for the X-linked lular cytotoxicity (ADCC), whereby antibody-bound
inhibitor of apoptosis (XIAP) protein.321 target cells come in contact with NK lymphocytes through
XLP1 and XLP2 have partially overlapping clinical binding of the Fc region of IgG molecules to a specific
features. Hemophagocytic lymphohistiocytosis (HLH) receptor (FcγRIIIa, also known as CD16) expressed on
subsequent to primary EBV infection is a prominent sign the surface of NK lymphocytes. Homozygosity for the
at clinical presentation in both diseases. XLP1 may mani- Leu66His amino acid substitution in CD16 causes defi-
fest with fatal infectious mononucleosis, aplastic anemia, cient spontaneous NK cell-mediated cytotoxicity but sur-
pulmonary lymphoid granulomatosis with vasculitis, and prisingly leaves ADCC intact. Expression of CD2, a
lymphoma.322 A proportion of XLP1 patients who survive co-activating NK cell receptor, is decreased, affecting
primary EBV infection will develop hypogammaglobu- intracellular signaling in NK lymphocytes. Recurrent and
linemia, which in some cases is associated with elevated severe herpesvirus infections are the clinical hallmark of
levels of IgM or IgA. Some patients may have a clinical this condition.329
and laboratory phenotype consistent with common vari-
able immunodeficiency (CVID, discussed later). Func- IMMUNODEFICIENCIES WITH SELECTIVE
tional activity of NK and CTLs is impaired. Finally, PREDISPOSITION TO PATHOGENS
patients with XLP1 lack NKT lymphocytes.323 Without
HSCT, 62.5% of the patients survive (and most of them Most forms of primary immunodeficiencies are charac-
require Ig replacement); however, poor survival rates (less terized by susceptibility to a broad range of pathogens,
than 20%) have been observed in patients without trans- whose nature (bacteria, viruses, fungi, protozoa) reflects
plants who have features of HLH. HSCT may cure the underlying immune defect. However, in the last two
approximately 80% of XLP1 patients, but poorer decades it has become clear that certain gene defects
outcome (50% survival) has been observed if HLH is that affect the immune system may lead to selective pre-
present.322 disposition to a narrow group of pathogens. These find-
In contrast, XLP2 causes recurrent episodes of HLH, ings have supported the genetic theory of infectious
with or without EBV infection.323 Patients with XLP2 are diseases, whereby life-threatening infections early in life
not at increased risk of lymphoma; on the other hand, may in fact be caused by inborn errors of immunity.330
inflammatory bowel disease is frequently observed.324 These disorders and their associated genes are listed in
Definitive treatment of XLP2 is also based on HSCT; Table 24-7.
however, use of a myeloablative conditioning regimen is
associated with high mortality.325 Mendelian Susceptibility to Mycobacterial Diseases
The designation Mendelian susceptibility to mycobacte-
rial diseases (MSMD) refers to a group of PIDDs char-
IL-2 INDUCIBLE TYROSINE KINASE DEFICIENCY acterized mainly by selective susceptibility to infection
Interleukin-2 inducible tyrosine kinase (ITK) is a nonre- with mycobacteria including both Mycobacterium
ceptor tyrosine kinase that modulates the strength of tuberculosis and many atypical species.331-334 Patients
intracellular signaling in T lymphocytes on TCR-induced
activation. Patients with ITK deficiency are susceptible to
EBV-driven lymphoproliferative disease (often involving
the lungs as well), Hodgkin lymphoma, hypogamma-
globulinemia, autoimmunity, and HLH.326 The disease is TABLE 24-7  Immunodeficiencies with Selective
inherited as an autosomal recessive trait. There is a Predisposition to Pathogens
reduced number of naïve CD4+ lymphocytes and of NKT
cells. Allogeneic HSCT may cure the disease. Syndrome Gene
Mendelian susceptibility to IFNGR1, IFNGR2, IL12B,
mycobacterial disease IL12RB1, STAT1
Epidermodysplasia verruciformis TMC6, TMC8
CD27 is a member of the TNF receptor family and is
Trypanosomiasis APOL1
broadly expressed on the surface of various lymphocyte

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

are also susceptible to disseminated infections with Sal- Inheritance varies according to the genes and the spe-
monella species. There are no other consistent clinical cific mutations involved. Thus far, mutations in
manifestations, and all routine screening tests of UNC93B1 have shown exclusively autosomal recessive
humoral and cellular immunity are normal. The vast inheritance, whereas mutations of TRAF3 and TBK1
majority of these patients harbor mutations in one of have exhibited exclusively autosomal dominant inheri-
five genes that encode elements in a signaling cascade tance. Mutations of TLR3 and TICAM1 have shown
involving IFN-γ and IL-12. IL-12 is produced by mono- either dominant or recessive inheritance depending on
nuclear cells in response to stimulation by way of TLRs the specific lesion.
and other pattern recognition receptors. IL-12 stimu-
lates Th1 differentiation, and mature Th1 cells and NK Susceptibility to Trypanosomiasis
cells produce IFN-γ. IFN-γ then acts on mononuclear Trypanosomes are single-cell (protozoan) organisms
cells to promote intracellular killing of phagocytosed causing endemic infections in many parts of the world.
organisms. In the absence of the normal operation of Trypanosoma cruzi is the causative agent of Chagas
this sequence, macrophages are not able to kill ingested disease, and it is estimated that approximately 10
mycobacteria or Salmonella organisms, and severe million people in South America harbor this parasite,
infection results. Thus far, mutations have been found most being asymptomatic. Subspecies of Trypanosoma
in the genes encoding the IL-12 p40 subunit (IL12B), brucei are responsible for sleeping sickness, and it is
the β1 chain of the IL-12 receptor (IL12RB1), both estimated that more than 60 million individuals in
chains of the IFN-γ receptor (IFNGR1, IFNGR2), and Africa harbor this organism. Most individuals are pro-
the STAT1 signal transducing molecule which mediates tected from progression of disease by apolipoprotein
signaling of the IFN-γ receptor.331-334 Most cases show L1 (APOL1), which can lyse the T. brucei plasma
autosomal recessive inheritance, but a few specific membrane and kill the organism. Some strains of try-
mutations of IFNGR1 may exhibit autosomal dominant panosomes have become more pathogenic by virtue
inheritance. Acquired forms of susceptibility to myco- of their resistance to APOL1 lysis.344-348 Conversely,
bacterial infection have been ascribed to autoantibodies individuals who have mutations in their APOL1 genes
to IFN-γ. are more susceptible to trypanosome infection and
Therapy for MSMD is mainly through aggressive severe disease. There are no known clinical conse-
treatment of infections when they occur and prophy- quences of deleterious APOL1 mutations beyond sus-
laxis for selected individuals who may relapse frequently. ceptibility to T. brucei. However, isoforms of APOL1
For patients with hypomorphic (partly functional) muta- selected through evolution for higher trypanosome lytic
tions of IFNGR1, IFN-γ supplementation may be activity are risk factors for nondiabetic kidney disease
beneficial. in African-Americans.349
Epidermodysplasia Verruciformis
Mutations in the genes TMC6 (transmembrane channel-
like 6) and TMC8 give rise to epidermodysplasia verru- The humoral immunodeficiencies and their associated
ciformis (EV). These genes were previously called gene defects are listed in Table 24-8. These disorders are
EVER1 and EVER2, respectively. EV exhibits autoso- characterized by hypogammaglobulinemia or dysgamma-
mal recessive inheritance, and affected individuals are globulinemia, often together with relative deficiency of
susceptible to persistent skin infection only by HPV.335,336 antibody responses to various forms of antigenic chal-
There is a high rate of malignant transformation in the lenge.3,4 Cellular immunity is generally intact. Humoral
skin, but there are no other infectious susceptibilities or immunodeficiency is most commonly manifested by
clinical manifestations of the disease. Acquired EV has recurrent bacterial and viral infections of the upper and
been associated with human immunodeficiency virus lower respiratory tract. Pyogenic skin infections, as well
(HIV) infection.337,338 as meningitis, osteomyelitis, and other foci of infection,
are also seen frequently. These infections are generally
Herpes Simplex Encephalitis caused by the same organisms that are virulent in immu-
HSVs are prevalent in the general population and are nocompetent hosts, predominantly encapsulated bacteria
capable of causing disseminated severe and even fatal such as Streptococcus pneumoniae, Hemophilus influen-
infections in patients with profound T-cell defects (dis- zae, S. aureus, and Neisseria meningitidis. Viral infections
cussed earlier). However, in rare cases individuals are usually resolve normally in these patients, although a
susceptible specifically to encephalitis caused by HSV, in higher rate of recurrence with the same agent may be seen
the absence of any other organ or system involve- because there is impaired production of neutralizing anti-
ment.339-343 To date, mutations in five distinct genes have bodies or B-cell memory. The results of physical examina-
been associated with this clinical entity: TLR3 (TLR3), tion are not specific and show only the presence or
UNC93B1, TRAF3, TICAM1 (previously known as sequelae of microbial infections. A relative paucity of
TRIF), and TBK1. All of the proteins encoded by these peripheral lymphoid tissue may be noted in some patients,
pathways interact in transducing responses by way of especially areas rich in B cells (e.g., tonsils). Studies of
TLR3 (and in some cases also TLR4) with the common peripheral blood lymphocyte subsets are often normal;
result of a failure to produce sufficient amounts of type the number of B cells may be reduced in certain
1 interferons in response to HSV infection in the brain. syndromes.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 909

TABLE 24-8  Humoral Immunodeficiencies and erythroid cells. A variety of BTK gene defects such as
Associated Gene Defects point mutations, deletions, and insertions have been
described in patients with XLA. In most patients B-cell
Syndrome Gene development is impeded at an early stage (the pro–B-cell
to pre–B-cell transition).
X-linked (Bruton) BTK
agammaglobulinemia BTK mutations account for approximately 85% of all
cases of agammaglobulinemia.354 BTK mutations have
Autosomal recessive CD79A, CD79B, BLNK, also been described in patients with “atypical” XLA who
agammaglobulinemias IGHM, IGLL1, LRRC8,
PIK3R2 have low numbers of B cells and low-level antibody
production.351-353 In some patients with atypical XLA,
Monogenic common variable BAFFR, CD19, CD21, CVID was misdiagnosed (discussed later) before discov-
immunodeficiency CD81, ICOS
ery of the BTK defect.355 In general, BTK mutations that
Common variable Undefined permit the expression of small amounts of functional or
immunodeficiency partially functional Btk protein are associated with milder
Good syndrome Undefined clinical phenotypes and slightly higher numbers of B cells
Selective IgA deficiency Undefined in the circulation. 351-353 However, even siblings with iden-
tical mutations may show quite divergent phenotypes.
IgG subclass deficiency Undefined Female carriers of XLA show nonrandom X-chromosome
Specific antibody deficiency with Undefined inactivation in their B cells.
normal immunoglobulins
Autosomal Recessive Agammaglobulinemias
Transient Undefined
hypogammaglobulinemia of Female patients with agammaglobulinemia and no B cells
infancy and males with a similar phenotype lacking BTK muta-
Class-switch defects: tions have been described. These patients have forms of
 CD40 ligand deficiency TNFSF5 agammaglobulinemia with autosomal recessive inheri-
(X-linked HIM) tance that result from several distinct molecular defects,354
 CD40 deficiency TNFRSF5 including mutations of the Igµ heavy-chain locus, which
  B-cell–specific defects AICDA, UNG
prevents formation of the IgM heavy chain required for
formation of the Ig receptors on pre-B cells and mature
B cells (see Fig. 24-7). Defects of λ5 (a component of the
The Agammaglobulinemias
X-Linked Agammaglobulinemia
X-Linked agammaglobulinemia (XLA) is also known as Pre-BCR
Bruton agammaglobulinemia because Bruton provided Surrogate light chain
the classic description of the disease in 1952.350 Affected
IgM heavy chain
male subjects are often asymptomatic during the first
months of life while they are protected by transplacen- Igα
tally acquired maternal antibodies. These antibodies fall α β α β
to low levels by 6 to 9 months of age, and patients begin
to experience recurrent bacterial infections.351-353 Physical
examination at any age often reveals a striking absence
of tonsils and palpable lymphoid tissue. Serum Ig is ITAMs
absent or the level is extremely low; in addition, no B Lyn Btk PLC-γ 2 IP3
cells are found or their numbers are extremely low. Cel-
lular immunity is completely intact. However, these Ca++
patients are prone to the development of chronic entero-
viral meningoencephalitis and vaccine-associated para-
lytic poliomyelitis, which suggests an important role for PKC
humoral immunity in the control of these infections.
Moreover, patients may have arthropathy resembling Syk BLNK Vav MAPK
rheumatic disease, which may be due to infection with
Mycoplasma or Ureaplasma organisms. Other opportu- Figure 24-7 Signaling via the pre–B-cell receptor (Pre-BCR). The
nistic infections, such as P. jiroveci pneumonia, are seen Pre-BCR is composed of an IgM heavy chain with a surrogate light-
chain heterodimer (VpreB and λ5), along with a signaling heterodimer
only rarely. of Igα and Igβ. The immunoreceptor tyrosine-based activating motifs
XLA is another example of an immunodeficiency (ITAMs, see Fig. 24-5) recruit tyrosine kinases (Lyn, Syk, Btk) that initi-
caused by a defect in a signal transduction molecule. In ate downstream signaling. The adapter proteins BLNK and Vav recruit
fact, this protein tyrosine kinase is now known as Bruton additional signaling intermediates. Defects in components shown in
blue lead to agammaglobulinemia by blocking pre-BCR signaling and
tyrosine kinase ([Btk], Fig. 24-7).351-353 It is expressed in interrupting B-cell development. DAG, Diacylglycerol; IP3, inositol
B cells at all stages of development, as well as in cell lines triphosphate; PKC, protein kinase C; PLC, phospholipase C; MAPK,
derived from monocytes, macrophages, mast cells, and mitogen-activated protein kinase.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

surrogate light chain) also prevent formation of the pre– of patients and has been linked in some patients to HHV-8
B-cell Ig receptor required for B-cell development. Igα infection.365,366 More diffuse noncaseating granulomatous
(CD79a) and Igβ are transmembrane molecules required disease resembling sarcoidosis may be encountered in the
for signal transduction by way of the pre–B-cell and skin or viscera. Additional manifestations include lung
mature B-cell Ig receptors. Lesions in these genes prevent disease resembling asthma, chronic rhinitis, chronic giar-
Ig receptor signaling and B-cell development.356 Defects diasis, and recurrent or chronic arthropathy. The appar-
in the signal transduction proteins BLNK (B-cell linker ent “atopic” symptoms usually occur in the absence of
protein) and the p85 (β-regulatory) subunit of phos- allergen-specific IgE.367 Malabsorptive inflammatory
phoinositide 3′ (PI3) kinase (gene PIK3R2) have also bowel disease may occur.368 A broad spectrum of autoim-
been found.354,357 Mutations in these molecules prevent mune diseases may be associated, including a variety of
intracellular signaling after ligation of the B-cell receptor. cytopenias, arthritides, and vasculitides.369,370 Widespread
All these mutations arrest B-cell development at early lymphoproliferation may cause splenomegaly, adenopa-
stages in bone marrow. thy, and intestinal lymphonodular hyperplasia.371-373
One patient has been described with an apparent dom- Patients with CVID also have a higher incidence of gas-
inantly expressed translocation abrogating the function trointestinal and lymphoid malignancies.364 The relative
of the LRRC8) gene.358 The function of the LRRC8 risk for lymphoma has been estimated to be as much
protein is not yet known; it is a member of a growing as 30- to 400-fold greater than that in the general
family of proteins of unknown function called the LRRC8 population.
family, within the much larger and very diverse superfam- Memory B-cell subpopulations may be useful diagnos-
ily of leucine-rich repeat proteins. The female patient has tic and potentially prognostic markers in CVID.363,374-379
agammaglobulinemia with arrest of B-cell development Memory B cells express the CD27 (TNFRSF7) molecule.
in bone marrow. Naïve B cells express IgM and IgD but not CD27.
Unswitched memory B cells (also called marginal zone
cells) express IgM, IgD, and CD27. After class-switching
Other Predominantly Antibody Deficiency Syndromes
in germinal centers, B cells cease expressing IgM and IgD
Common Variable Immunodeficiency and subsequently express “downstream” Ig isotypes such
The diagnostic label of CVID encompasses an unknown as IgG, IgA, and IgE (Fig. 24-8). Memory B cells after
number of conditions that are genetically and etiologi- class-switching (switched memory B cells) are
cally distinct but have in common late-onset humoral IgM−IgD−CD27+. Additional subsets of B cells include
immunodeficiency, most often in the first or third decades transitional B cells (IgMhighCD38high) and CD21low B cells.
of life.359-363 Hypogammaglobulinemia and impaired spe- Proportions of these peripheral B cell subtypes enumer-
cific antibody production are universal, by definition. ated by flow cytometry correlate with clinical pheno-
Deficiency of IgA is very common in CVID.364 IgM is types. A more severe clinical phenotype with lower Ig and
also frequently affected; the pattern varies from one worse infections and increased granulomatous disease
individual to another. The levels of particular isotypes in correlates with a decreased number of marginal zone and
any patient are often static over time, but fluctuations class-switched B cells. Granulomatous disease and sple-
may occur. nomegaly also correlate with an expansion of CD21low B
Patients with CVID resemble individuals with XLA cells. Increase in transitional B cells is associated with
(and other humoral immunodeficiencies) because they lymphadenopathy. Specific B cell subsets are developmen-
also have recurrent sinopulmonary bacterial infections. tally regulated, and age-adjusted values should be used in
Chronic enteroviral infections, including meningoenceph- these instances.380-382
alitis, may also be seen in CVID. A form of granulocytic/ Although cellular immune function is grossly preserved
lymphocytic interstitial lung disease occurs in a subset in the majority of patients with CVID, a variety of

– M – – D – – G3 – – G1 – – psE – – A1 – – psG – – G2 – – G4 – – E – – A2

x x I
x x II
x x III
x x IV
x x V
x x VI

Figure 24-8  Immunoglobulin (Ig) heavy-chain gene deletion haplotypes. The top line shows the order of the Ig constant region genes (e.g., M =
IgM, etc.). The letters ps designate a pseudogene that is not expressed; numbers indicate subclasses. Six haplotypes have been defined (Roman
numerals). In each haplotype the entire region indicated by the Xs is missing. (Data from Lefranc MP, Hammarstrom L, Smith CI, Lefranc G:
Gene deletions in the human immunoglobulin heavy chain constant region locus: molecular and immunological analysis. Immunodefic Rev 2:265–
281, 1991.)

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 911

functional and phenotypic T-cell abnormalities are found

in some.359,382-385 These include reductions in peripheral CD19, CD21, and CD81 Deficiencies
blood T-cell populations, as well as functional defects CD19 is expressed on B cells and is a component of a
such as reduced in vitro proliferative responses, defects receptor complex that contains CD21, a receptor for the
in cytokine production, decreased T-helper cell function, complement fragment C3dg (it is also called complement
abnormalities in T-cell signaling, diminished expression receptor 2, or CR2, and it is the cellular receptor for EBV)
of the costimulatory molecule CD40L, decreased numbers along with a tetraspan molecule called TAPA1 (also
of naïve T cells, increased suppressor T-cell function, and CD81). Simultaneous cross-linking of the CD19/CD21/
decreased numbers of regulatory T cells. CD81 complex and the B-cell Ig receptor lowers the
The genetic heterogeneity of CVID is beginning to threshold for B-cell activation. Patients with defects of
yield to molecular biologic analysis. Several single-gene the CD19,396,397 CD21,398,399 or CD81400 genes exhibit
defects have been found in varying (small) proportions recurrent infections, hypogammaglobulinemia, and low
of patients with CVID (discussed later). It may also levels of switched memory B cells. Autoimmunity and
happen that individuals classified as having CVID (or lymphoproliferation do not appear to be elements of the
a phenotype consistent with CVID) on clinical and labo- clinical presentations of these disorders.
ratory grounds may be found to have mutations in
genes characteristically associated with other primary BAFF Receptor Deficiency
immunodeficiencies. Such has been the case with Two siblings have been described with homozygous dele-
some individuals with mutations in BTK (causative in tions in the BAFFR gene encoding the BAFF (B cell acti-
XLA),355 SH2D1A or XIAP (XLP disease),386,387 and vating factor) receptor.401 Both had low IgG, poor
TNFSF5 (CD40L, X-linked hyper-IgM syndrome).388 polysaccharide antibody response, and low memory B
Functionally relevant polymporphisms in TNFRSF13B cells. However, only one sibling had recurrent infections.
(encoding TACI) occur in approximately 1% of the It is not clear why only one sibling was affected clinically,
general population. The most common are Cys104Arg but variable penetrance is frequently observed in all forms
(cysteine 104 replaced by arginine) and Ala181Glu. of immunodeficiency.4
Approximately 10% of patients with CVID are heterozy-
gous, and 1% are homozygous for these.389-392 TACI is Good Syndrome
expressed on B cells and interacts with the ligands BAFF The occurrence of thymoma in the context of a clinical
and APRIL expressed on macrophages and dendritic and immunologic picture very similar to that of CVID
cells. These interactions have important roles in B-cell with low numbers of B cells and generally more severely
activation and Ig class switching. TACI polymorphisms impaired T-cell function has been designated Good
are not entirely disease causing by themselves, but the syndrome.402-406 The spectrum of bacterial sinopulmonary
presence of one of these TACI polymorphisms does infections and pathogens is similar to those associated
appear to confer increased risk of lymphoproliferation with the more prevalent forms of CVID. However, Good
and autoimmunity.393 syndrome is associated more frequently with opportunis-
The genetic determinants of CVID in the majority of tic infections, including mucocutaneous candidiasis,
patients may be more complex. A recent genome-wide severe varicella-zoster virus infection, P. jiroveci, CMV,
association study revealed complex patterns.394 The and recurrent HSV. Lymphadenopathy and splenomegaly,
strongest associations were with the MHC locus and a commonly seen in CVID, are not characteristic features
family of disintegrin/metalloproteinase genes. However, of Good syndrome. Autoimmune disease is a frequent
there were at least 16 associated gene duplications or complication of Good syndrome, most notably pure red
deletions together with many (≈100) unique intraexonic cell aplasia and neutropenia. Patients with Good syn-
duplications or deletions. Furthermore, a complex genetic drome also often suffer from chronic diarrhea of unclear
signature composed of more than 1000 single nucleotide etiology.
polymorphisms was highly predictive of the CVID phe- Panhypogammaglobulinemia is a consistent finding in
notype. How this heterogeneous genetic picture relates to Good syndrome.402-406 Unlike the majority of patients
the clinic manifestations of CVID is unknown. with CVID, immunophenotypic analysis of peripheral
blood lymphocytes frequently shows absent or very low
Deficiency of Inducible T-Cell Costimulator numbers of B cells, reduced CD4+ T cells, absent cutane-
The inducible T-cell costimulator (ICOS) is expressed on ous delayed hypersensitivity responses, and reduced in
T cells after stimulation. It interacts with a member of vitro T-cell response to mitogen. It is not clear whether
the B7 family of molecules known as ICOS ligand. Fewer patients with Good syndrome exhibit as yet undiscovered
than 20 patients worldwide have been found to have specific genetic or immunologic abnormalities that clearly
CVID associated with ICOS deficiency.395 These patients distinguish them from CVID.
may manifest recurrent respiratory and gastrointestinal
infections in adulthood, panhypogammaglobulinemia Selective IgA Deficiency
and impaired vaccine responses, autoimmune disease There are two subclasses of human IgA: IgA1 and IgA2.
(neutropenia), lymphoproliferation, and cancer (carci- They are encoded by separate genes on the heavy-chain
noma of the vulva). Lymphoid tissues exhibit poorly C region locus on chromosome 14 (see Fig. 24-8). IgA1
formed germinal centers, and circulating switched predominates in serum (80% to 90%), whereas IgA1 and
memory B cells are markedly reduced. IgA2 are equally prevalent in secretions. Both subclasses

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

are equally affected in selective IgA deficiency (SIGAD). SIGAD may occur as a drug side effect and has been
SIGAD is defined as a serum IgA level of less than 0.07 g/L reported with phenytoin, carbamazepine, valproic acid,
with normal serum IgG and IgM in a child older than 4 zonisamide, sulfasalazine, gold, penicillamine, hydroxy-
years of age in whom other causes of hypogammaglobu- chloroquine, and nonsteroidal antiinflammatory drugs.418
linemia have been excluded.4 Note that this definition is The IgA level may normalize after cessation of the drug.
restricted to the absence of serum IgA. There is no known
clinical association with IgA levels between the lower Immunoglobulin G Subclass Deficiency
limit of detection and the lower limit of the normal range. Four subclasses of IgG exist in humans: IgG1, IgG2,
It is not appropriate to refer to patients with these nonzero IgG3, and IgG4. Their designations order their preva-
low IgA values as being IgA-deficient. lence in serum, with each constituting roughly 67%,
SIGAD is seen in approximately 1 in 700 Caucasians 23%, 7%, and 3% of the total, respectively. A different
in the United States.407 In contrast, its incidence among gene encodes the heavy-chain constant region of each
Japanese is only 1 in 18,500. This presumably reflects subclass (see Fig. 24-8). Each subclass has unique struc-
population genetic differences, possibly related to the tural properties and plays a different role in immune
HLA complex. SIGAD has been associated with extended responses as a result of different interactions with the
HLA haplotypes similar to those observed in CVID.408,409 complement system and with receptors for IgG on phago-
The majority of individuals with SIGAD are completely cytic cells and lymphocytes. In addition, IgG subclasses
asymptomatic. Some may have a clinical course similar are produced in different relative amounts depending on
to that seen in CVID or in IgG subclass deficiency (dis- the antigenic stimulus.422 Mainly IgG1 is produced in
cussed later). The proportion of patients with SIGAD is response to soluble protein antigens. Viral antigens also
increased in a population of people with chronic lung elicit predominantly IgG1 responses and often significant
disease, and 20 years’ observation of blood donors with amounts of IgG3 as well. Particular viruses (e.g., hepati-
SIGAD has documented an increased incidence of respi- tis, herpes simplex, and varicella) also elicit IgG4. The
ratory infections and autoimmune disease.410-413 pneumococcal capsular polysaccharide response is almost
The spectrum of autoimmune syndromes associated exclusively of the IgG2 subclass, whereas H. influenzae
with SIGAD is similar to CVID.410-413 In addition, atopic type B (HIB) polysaccharide elicits mainly IgG2, with
diseases appear to be more prevalent among those with some IgG1 (the latter is found in younger children par-
SIGAD, and some have also noted an increased incidence ticularly). Note that the current HIB and pneumococcal
of the type of malignancies encountered in CVID. In rare (Prevnar) vaccines are protein conjugates and elicit
cases, SIGAD has evolved into CVID, or levels of IgA responses characteristic of protein antigens.
have increased over time.414,415 Treatment of SIGAD has IgG subclass deficiency (IGGSD) is defined as a level
generally focused on management of complications as of one or more IgG subclasses greater than 2 SD below
they occur. In some instances, gamma globulin infusions the age-adjusted mean with a normal total level of IgG.
may be helpful, especially if an associated IgG subclass Precise criteria for diagnosis are difficult to establish
or specific antibody deficiency is present (discussed later). because of variability in Ig measurements by various
However, researchers in one study did not find an associa- techniques (e.g., nephelometry and radial immunodiffu-
tion between a history of infections and lower antibody sion) and the wide variability in normal ranges with
responses to pneumococcal polysaccharides.411 Some respect to age and ethnicity. The significance of decreased
studies do show an association of increased infections if levels of IgG subclasses in patients with recurrent infec-
there is an IgG subclass deficiency or mannose-binding tions is further clouded by the fact that the majority of
lectin (MBL) deficiency together with SIGAD.416 individuals with isolated subclass deficiencies are asymp-
Apart from the absence of IgA itself and its occasional tomatic. These factors make the diagnosis of IGGSD
association with abnormalities of IgG subclasses, there controversial.423
are few other characteristic immunologic abnormalities. Patients with IGGSD commonly present with recur-
Some researchers have found low levels of switched rent sinopulmonary infections of varying severity caused
memory B cells in some patients and observed correla- by common respiratory bacterial pathogens.424-428 Some
tions with disease severity and autoimmune complica- may also have recurrent diarrhea, often of infectious
tions similar to those in CVID.417 origin. Furthermore, atopic diseases such as asthma and
Molecular genetic defects have not been described in allergic rhinitis are more prevalent in patients with
SIGAD. Lesions in IgA C region genes are not found, IGGSD. Deficiency of the IgG2 subclass is detected most
except in rare instances associated with other deletions commonly in symptomatic patients. It may occur in isola-
(discussed later). SIGAD and CVID have been associated tion but is also usually associated with deficiency of
with the HLA haplotype A1, B8, DR3 in Caucasians.409,418 IgG4, IgA, or both. Selective deficiency of IgG3 alone is
A SIGAD susceptibility locus (IGAD1) has been mapped likewise observed (most often in adult women) and is
to the boundary region between HLA class II and class associated with the same clinical picture described
III.419,420 A more detailed analysis identified a positive earlier.424,425 The lowest IgG4 levels are usually associated
association of SIGAD with HLA-DRB1*0301, DQB1*02 with IgG2 deficiency. Recurrent infections have been
and a negative association with DRB1*1501, DQB1*0602. described in some patients with only IgG4 deficiency,
Another study identified an association of SIGAD with although a diagnosis of isolated IgG4 deficiency is con-
DRB1*0102, DQB1*0501.421 The significance of these sidered most controversial because normal ranges for
associations requires clarification. IgG4 are poorly defined.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 913

Several studies have shown an increased proportion deficiency is usually slow spontaneous resolution.415 Most
of individuals with subclass deficiencies among patients children have a greatly reduced incidence of infections by
with recurrent infections.4 Not all of these patients have late childhood.
demonstrably impaired responses to vaccines, however.
Thus the relationship between lack of an antibody Transient Hypogammaglobulinemia of Infancy
isotype and susceptibility to infection is far from straight- Transient hypogammaglobulinemia of infancy (THI) is,
forward. Assessing the response to antigen challenge as its name suggests, an antibody deficiency beginning in
is an important element in the evaluation of these infancy that resolves spontaneously, usually by 4 to 5
patients. Assessment of memory B-cell subsets may years of age.443-447 It is defined as the occurrence of an
become a useful diagnostic tool for IGGSD; some studies IgG level more than 2 SD below the age-adjusted mean.
suggest that reduced switched memory B cells have Many patients also have low IgA, and some also have
better a correlation with risk for infection than antibody low IgM. Vaccine antibody responses are usually intact,
responses do.429 but this is not always the case. Peripheral lymphoid tissue
The C region genes determining antibody classes and is sparsely populated with small or no germinal centers
subclasses are arranged in the same transcriptional ori- and markedly reduced plasma cell contents. Numbers of
entation on chromosome 14 (see Fig. 24-8). As with circulating B and T cells are generally normal, as are in
SIGAD, only rarely is clinically significant IGGSD asso- vitro assays of lymphocyte function (e.g., mitogen
ciated with genetic lesions of IgG C region genes. This response). One recent study documented higher B-cell
has been observed in a single reported patient with IgG2 counts than in an age-matched group.448
deficiency, in whom mutation prevented expression of Ig levels in THI gradually increase over time, and the
cell surface IgG2.430 In fact, large deletions of Ig C region majority of patients have normal levels by the age of 4
genes are surprisingly common; six multigene deletion or 5, rarely later.443-447 Thus the diagnosis can be con-
haplotypes have been identified (see Fig. 24-8).431 In one firmed only after Ig levels normalize. Prospective studies
population with a high degree of consanguinity, individ- show a preponderance of the diagnosis in male subjects
uals were found to be homozygous for one haplotype or and normalization of Ig levels at a median of approxi-
heterozygous for two different haplotypes. Fifteen of 16 mately 2 years, with an upper limit of approximately 5
people with deletions on both chromosomes were years. Female subjects and patients with lower IgG levels
entirely healthy despite a complete lack of one or more tend to take longer to normalize.
IgG subclasses or IgA1; one person had recurrent infec-
tions.432 Similarly, two healthy siblings have been Immunoglobulin Class-switch Defects
described, each having homozygous deletions of IgA1, As mentioned previously, naïve B cells express IgM and
IgG2, IgG4, and IgE.433 Another group described a IgD on the cell surface. These different isotypes are gener-
healthy 50-year-old man who had deletions encompass- ated by way of differential splicing of mRNA transcripts.
ing the heavy-chain genes encoding IgG1, IgG2, IgG4, When B cells are activated by antigen and interaction
and IgA1.434 This individual did not produce polysac- with helper T cells in germinal centers, they initiate a
charide antibody but did produce IgG3 to protein anti- process of class-switching whereby the DNA intervening
gens, including pneumococcal surface proteins. Finally, between the variable region gene and a downstream
an analysis of the Ig heavy-chain loci of 33 patients with isotype is excised. In this manner, B cells begin to express
CVID revealed only two patients who were heterozy- IgG, IgA, or IgE. When this process is impeded, the
gous for C gene deletions.435 amount of these isotypes produced is very low, while the
amount of IgM may be normal or very high. These dis-
Specific Antibody Deficiency with Normal Immunoglobulins orders are often referred to as hyper-IgM syndromes.
A population of patients with recurrent infections and However, there are many important differences among
poor antibody responses (mainly to polysaccharide anti- the disorders often placed in this group.449
gens) have completely normal levels of antibody classes
and subclasses. This condition has been called specific X-Linked Immunodeficiency with Normal or Elevated IgM
antibody deficiency with normal immunoglobulins As its name implies, X-linked immunodeficiency with
(SADNI) or functional antibody deficiency.436-438,439-441 In normal or elevated IgM (XHIM, also HIM1) denotes a
one retrospective compilation of 90 patients in a tertiary- form of selective hypogammaglobulinemia G and A,
care institution with newly diagnosed immunodeficiency, together with normal or elevated amounts of IgM.450-454,455
specific antibody deficiency with normal Igs was the most These patients are seen in the first 1 or 2 years of life with
common diagnosis, made in 23% of patients.442 Repeated the recurrent sinopulmonary bacterial infections often
immunization may lead to measurable antibody responses, found in those with hypogammaglobulinemia, together
although even protein conjugate pneumococcal polysac- with opportunistic infections by organisms such as P.
charide vaccines may not be as effective as in healthy jiroveci, Cryptosporidium, and Histoplasma. Affected
individuals.440 Measurement of memory B-cell popula- patients are also prone to the development of neutrope-
tions may correlate better with infection risk in these nia, anemia secondary to parvovirus, stomatitis, scleros-
patients, although further study is required.429 SIGAD, ing cholangitis, and liver and hematologic malignancies.
IGGSD, SADNI, and a subset of CVID may be entities in A variety of autoimmune manifestations may be seen,
a spectrum with similar pathophysiologic characteristics. including cytopenias, arthropathy, and inflammatory
The natural history of IGGSD and specific antibody bowel disease.456

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

The number of circulating B cells is normal, but they lack of which may underlie the predisposition to opportu-
express IgM exclusively (in association with IgD) on their nistic infection and malignancy seen in patients with CD40
surface. Immune responses are varied. Isohemagglutinins ligand deficiency.
are often present, and vaccination may elicit specific IgM Perhaps not too surprisingly, a clinically and immuno-
responses. No other isotypes are produced; there is no logically identical immunodeficiency syndrome arises
B-cell memory. Secondary lymphoid tissues are sparsely from mutations in the gene TNFRSF5, which encodes
populated and do not contain germinal centers. In spite CD40.451,454,457,458 Only a few patients with this defect
of the important defects in T-cell function for B-cell help, have been found so far.
screening studies such as flow cytometric measurement of These defects in CD40L and CD40 (TNFSF5 and
T-cell populations or in vitro proliferation tests are often TNFRSF5) are discussed here together with the humoral
normal.450-455 immunodeficiencies because of the prominence of the
The genetic lesion in XHIM is in TNFSF5 (tumor class-switch defect in the clinical expression. However,
necrosis factor superfamily member 5), also known as they are truly combined immunodeficiencies with impor-
CD40 ligand (CD40L) or CD154. 450-455 This is an inte- tant defects of T-cell function. In addition to IgG therapy
gral membrane protein that is mainly expressed on T cells and infection prophylaxis, these patients are candidates
after an activating stimulus, such as interaction of the for HSCT.
TCR with an MHC-peptide complex on the surface of a
B cell or APC (Fig. 24-9). The signal delivered by T-cell Mutations in Activation-Induced Cytidine Deaminase and Uracil
CD40L to CD40 is critical for Ig class switching, the Nucleoside Glycosylase
development of B-cell memory, affinity maturation of the Activation-induced cytidine deaminase (AID) and uracil
antibody response (somatic hypermutation of Ig V nucleoside glycosylase (UNG) defects exclusively affect
regions), and the expression of important costimulatory B-cell function while T-cell number and function are com-
molecules such as those of the B7 family by B cells and pletely normal. They were originally defined in the
APCs (see Fig. 24-9). medical literature as forms of hyper-IgM (HIM) syn-
The CD40 system has additional roles in the interaction drome, which leads to some confusion insofar as other
of T cells with monocytes. Several T-cell–derived cytokines forms of HIM are combined immunodeficiencies with
(granulocyte-macrophage colony-stimulating factor, IL-3, important T-cell dysfunction (discussed previously). AID
and IFN-γ) induce the expression of CD40 on monocytes. deficiency has been called HIM2454,459-461 and UNG defi-
Furthermore, engagement of monocyte CD40 induces ciency has been called HIM5454,462 (see Table 24-8). The
cytokine synthesis and activates tumoricidal mechanisms. AID and UNG enzymes are RNA modifiers expressed in
These phenomena suggest an important interaction, the B cells that act during class-switch recombination. In the

T-B Cell Interactions


Class II


CD40L CD40
Activation of
* switching

TCR + CD28 CD40 + IL4R

Proliferation Cytokine synthesis IgE isotype switching Proliferation

Figure 24-9 Signals required for T-cell activation by antigen-presenting cells (APCs), B-cell activation by the T cell, and B-cell immunoglobulin
class-switching. The T-cell receptor (TCR) interacts with MHC + peptide. Subsequent to this interaction, the T cell expresses CD40 ligand (CD40L)
and begins producing IL-2 and IL-4. CD40L interacts with CD40 on the APC (or B cell) inducing expression of B7-1 (also called CD80) and B7-2
(CD86). This interaction leads to full activation of APC function, macrophage killing capacity, or B-cell activation, depending on the cells involved.
Binding of B7 molecules to CD28 on the T-cell surface provides an important costimulatory signal leading to full T-cell activation and increased
cytokine production. IL-4 produced by the T cell interacts with its receptor on B cells to induce class-switching. Other cytokines act on other cell
types to modulate their activities in the immune response.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 915

absence of their activity, B cells cannot switch from pro- A high index of suspicion for antibody deficiency
duction of IgM and IgD to production of downstream Ig should be maintained in patients with recurrent, refrac-
isotypes (see Fig. 24-8). Somatic hypermutation is also tory, or severe infections. One study of primary antibody
affected. These processes normally occur during B-cell deficiency in the United Kingdom found that the median
activation in germinal centers. delay in diagnosis after the onset of symptoms (infec-
Another form of HIM syndrome with an unknown tions) was 2 years (mean, 4.4 years), even after the intro-
gene defect leads to impaired Ig class-switching duction of a set of national guidelines intended to reduce
recombination.463-466 This has been called HIM4. All these this delay.471
disorders are very similar clinically and immunologically.
Patients suffer mainly from respiratory tract bacterial IgG Replacement Therapy
infections and lymphadenopathy, and cellular immuno- The mainstay of therapy for significantly impaired ability
deficiency is not seen. IgG, IgA, and IgE levels are all low to produce antibody is IgG replacement.4,472 As men-
or absent; IgM levels tend to be higher than in the tioned earlier, this therapy is also important for the treat-
X-linked HIM syndrome. Patients tend to do well with ment of any combined immunodeficiency in which
IgG replacement. defective antibody production may occur. Patients with
XLA were the first to receive human gamma globulin
therapy. The effect of intramuscular injections of gamma
Management of Humoral Immunodeficiency
globulin was prompt and dramatic, with a reduction in
Diagnostic Approach the occurrence of infections. With the advent of prepara-
Patients with recurrent infections, regardless of antibody tions suitable for intravenous administration in the 1970s,
class or subclass levels, should undergo thorough evalu- this became the most common route of administration
ation to rule out other potential predisposing factors worldwide. A retrospective study of bacterial infections
(e.g., anatomic defects or environmental allergies).4 The in patients with XLA showed a reduction in incidence
amounts of one or more antibody isotypes are reduced in from 0.4 to 0.06 per patient per year with IVIG therapy.473
many of these diseases.3,4 The severity of the phenotype At present, administration of IVIG provides these patients
often correlates with the degree of hypogammaglobu- with an almost normal lifestyle.474-479 Many immunolo-
linemia. The predisposition that patients have to particu- gists also apply chronic antibiotic prophylaxis in addition
lar types of infections may also depend on the affected to IgG for patients with XLA, but this practice is not
isotypes (discussed later). It is always of the utmost universal. All patients with CVID and with class-switch
importance to use age-adjusted reference ranges. Ig levels defects should also be treated with IgG infu-
are low in infancy and rise throughout childhood. Most sions.4,472,474,477,480-483 For these patients, as with XLA,
isotypes reach fully adult levels between the ages of 5 and many immunologists also apply chronic antibiotic
10 years. prophylaxis.
Antibody titers to specific antigens may be measured In most countries gamma globulin replacement is
before or after immunization (often both). The specific administered predominantly by the intravenous route
antibodies most commonly assayed for protein antigens every 3 to 4 weeks. However, IgG can also be adminis-
are tetanus and diphtheria toxoids. With respect to poly- tered by subcutaneous infusion.477,480,481,484 Smaller subcu-
saccharide antigens, measurement of antibodies to pneu- taneous doses are given weekly or twice weekly or even
mococcal serotypes is frequently undertaken. If a child has daily. Intravenous infusion is generally well tolerated but
had a particular illness (e.g., varicella), a specific viral requires intravenous access and is associated with fre-
antibody titer may be useful. Note that the HIB vaccines quent mild (10% to 20% of patients) or moderate (5%)
and newer pneumococcal vaccines (e.g., Prevnar-13) cur- side effects. Subcutaneous infusions may be administered
rently in use for primary immunization in children are by patients themselves at their own convenience with a
protein conjugates. Thus measuring a polyribosylribitol much lower rate of systemic effects at the cost of gener-
phosphate or pneumococcal serum antibody concentration ally mild and transient (24-hour) local irritation. The
in children who have received these vaccines does not general efficacy of intravenous versus subcutaneous
necessarily reflect a “pure” polysaccharide antibody administration appears to be equivalent. Subcutaneous
response. The adequacy of carbohydrate responses may be infusion is becoming increasingly popular.
tested by challenge with 24-valent pneumococcal polysac-
charide vaccines (e.g., Pneumovax).438,439,467-469 This vaccine Antibiotic Prophylaxis
produces reliable results in normal children as young as 1 For milder forms of antibody deficiency such as SIGAD,
year.470 An unconjugated meningococcal vaccine (Meno- IGGSD, SADNI and THI, antibiotic prophylaxis is the
mune) may also be used to assess ability to respond to more common first-line approach for infection prophy-
polysaccharides. In children who are not fully immunized laxis.4 However, regimens are not standardized. Com-
or who are too young to immunize, isohemagglutinins may monly used agents include amoxicillin and trimethoprim-
be measured as an indicator of the ability to generate sulfamethoxazole. Depending on specific circumstances,
polysaccharide antibody.4 other antibiotics may be chosen, such as clarithromycin
Most children have been immunized with tetanus or azithromycin, amoxicillin-clavulanate, or doxycycline.
toxoid, HIB, and Prevnar, and antibody titers may be Also depending on circumstances, therapeutic dose or
determined at the first visit. If titers are low, response to half-dose regimens may be applied. For any of these dis-
booster immunization may be assessed. orders (with the possible exception of SIGAD), IgG

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

therapy may ultimately be prescribed if the response Classical Lectin Alternative

to antibiotic prophylaxis is poor, or if intolerable side pathway pathway pathway
effects or hypersensitivity precludes their continued Extracellular
use.424,426,477,485,486 In these circumstances, there is usually IgG, IgM MBL, ficolins matrix
a clearly observable reduction in the frequency of infec- C2, C4
tions. IgG replacement for SIGAD is especially controver- C1qrs MASP1, 2, 3 C3b
sial because experience has not demonstrated consistent
fB, fD, P
benefit. C3
General Care C4b2a C3bBbP

Patients with antibody deficiency require regular moni- C3a

toring for occurrence or progression of complications and C3b
adequacy of therapy.4 Lung function should be measured
regularly along with periodic assessment of hematologic
parameters, liver and kidney function, and Ig levels. C4b2a3b C3b2BbP
Therapy for autoimmune inflammatory complications in C5a
CVID and other antibody deficiencies generally follows +
regimens applied in similar situations in the absence of C5b
the immunodeficiency.365,369,371,392,480 However, patients C6, C7, C8 C9 x n
with primary immunodeficiency who are treated with C5b6789n
immunosuppression for autoimmune or lymphoprolifera- MAC
tive disorders may be more susceptible to infectious
Figure 24-10 Complement activation pathways. The alternative
complications. pathway is initiated when the C3b fragment with factor B (fB) and
properdin (P) bind to the extracellular matrix or some microbial poly-
saccharides. Factor D (fD) cleaves fB to yield the C3 convertase BbC3b.
COMPLEMENT DEFICIENCIES Addition of C3b creates the C5 convertase BbC3b2. The classical
pathway begins when IgG or IgM bound to a surface forms a complex
The complement system is composed of some 20 serum with C1qrs. The lectin pathway is initiated when mannose-binding
proteins, 5 complement receptors with varied distribu- lectin (MBL) or other initiators such as the ficolins and MBL-associated
tion among leukocytes, and several integral membrane serine protease 2 (MASP2) bind to microbial polysaccharides. Activated
regu­lators found on most cells of the body.487,488 The C1qrs and MBL/MASP2 are both capable of cleaving C2 and C4 to
latter group of molecules limit cell damage as a result of yield the C3 convertase C4b2a. Addition of C3b to this complex yields
the C5 convertase C4b2a3b. The C5 convertases generate C5b, the
a low constitutive level of complement activation. There nucleus for the membrane attack complex (MAC), which is formed by
are three distinct modes of complement activation: the the addition of one each of C6, C7, and C8 and several molecules of
classical pathway, the alternative pathway, and the lectin C9.
pathway. These pathways are shown in Figure 24-10.
Soluble or surface-bound antigen-antibody complexes
initiate the classical pathway; the alternative pathway is
activated when complexes of C3b, factor B, and proper-
din are deposited on bacterial surfaces or extracellular TABLE 24-9  Clinical Associations with
matrix components. The lectin pathway is initiated by Complement Deficiencies
binding of MBL to mannose-containing microbial poly-
saccharides. The activation of the complement system Symptoms/Syndrome Associated with
by way of any of these pathways consists of sequential Component Deficiency
proteolytic interactions having a common outcome: C1q, C1r Systemic lupus erythematosus–like
cleavage (activation) of the C3 complement component syndrome
to yield the anaphylatoxin C3a and the C3b fragment. C2 Systemic lupus erythematosus–like
C3b attaches to cell membranes (e.g., bacteria) and is syndrome, vasculitis, polymyositis
the principal opsonin for phagocytosis. After cleavage of
C4 Systemic lupus erythematosus–like
the C5 component (yielding the anaphylatoxin C5a), syndrome
additional reactions are nonenzymatic aggregation of
C5b, C6, C7, C8, and C9 to form the macromolecular C3 Recurrent pyogenic infections
membrane attack complex (MAC). The MAC is an C5, C6, C7, C8, C9 Neisserial infection, systemic lupus
amphiphilic cylinder; its hydrophobic end inserts into erythematosus–like syndrome
target cell membranes and permits free flow of ions and C1-INH Hereditary angioedema
other solutes, which leads to metabolic derangement or
lysis.489 Genetic defects of almost all complement com- Factor I, Factor H Recurrent pyogenic infections, atypical
hemolytic uremic syndrome
ponents are known. The clinical manifestations of these
defects are categorized in Table 24-9. Complement defi- Factor D, Properdin Neisserial infections
ciencies are among the rarest of primary immunodefi- MBL, MASP-2 Recurrent pyogenic infections
ciencies, accounting for fewer than 1% of all patients
Ficolin 3 Atopy (possibly also infection)

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 917

Deficiency of Classical Complement genes encoding C4 are also located in the class III region
Pathway Components of the HLA complex. There are two copies on each chro-
mosome, C4A and C4B. Each encodes proteins that differ
C1 Deficiency in structure only minimally, although their biologic activi-
C1 is a large complex multimer consisting of three major ties are distinct. Null alleles at these loci occur frequently;
subunits: C1q, C1r, and C1s. C1q is itself a complex of 35% of people have one copy of either C4AQ0 or
18 separate polypeptides, 6 molecules each of C1qA, C4BQ0. Ten percent of the population have two null
C1qB, and C1qC. The C1 complex is completed by the alleles, and 1% have three. The presence of four null
addition of two molecules each of C1r and C1s, which alleles (complete C4 deficiency) is rare. All of these partial
brings the total to 22 polypeptides. Patients with defects deficiency states are often asymptomatic. One study has
in any of the major subunits of C1 have a syndrome found an association of C4B null alleles with Henoch-
resembling systemic lupus erythematosus (SLE) and sus- Schönlein purpura.507 Older studies have found HLA
ceptibility to recurrent infections.490-493 Deficiency of C1q haplotypes containing C4 null alleles frequently in
may be caused by antigenically normal nonfunctional patients with SLE.508 However, more recent studies
protein or complete absence of C1q. The C1QA, C1QB, suggest that this association arises by linkage disequilib-
and C1QC genes are closely linked on chromosome 1; rium of C4 with the MHC locus rather than by the C4
defects in the C1QB and C1QC genes have been genes themselves.509 The relatively high rate of occurrence
described. The genes encoding C1r and C1s are closely of C2 and C4 null alleles leads to combined heterozygous
linked on chromosome 12, and mutations of both C1r partial deficiencies of both in about 1 in 1000 Cauca-
and C1s have also been described. In addition to geneti- sians. Approximately one third of these patients have SLE
cally determined or primary C1q deficiency, autoantibody- and other autoimmune diseases.510 It is possible that this
mediated depletion of C1q has been associated with association also may be the result of linkage disequilib-
SLE.494-497 rium with MHC.
C2 Deficiency C3 Deficiency
The monomeric C2 component of complement is the The C3 component sits at the confluence of all three
substrate for the activated C1s component of the C1q pathways of complement activation. The various frag-
complex. Two fragments are generated in this reaction: ments of C3 generated through the action of C3 conver-
The C2a fragment associates with C4b on a cell surface tases (C4b2a and C3b2Bb), as well as other serum
and becomes an activator for C3 (“C3 convertase”); the proteases, have diverse influences within the immune
C2b fragment is a substrate for plasmin and releases a system. C3a is a potent anaphylatoxin, whereas C3b is
vasoactive peptide that may play a role in hereditary the principal opsonin for phagocytosis and is a compo-
angioedema (HAE, discussed later). Approximately 50% nent of enzyme complexes in the alternative pathway of
of individuals with C2 deficiency are asymptomatic. The complement activation. Additional C3 fragments influ-
rest have one or more of the following: various forms of ence lymphocyte function. For example, C3d is an impor-
vasculitis such as discoid lupus erythematosus or SLE, tant regulator of B-cell activation.511 Patients with C3
chronic Henoch-Schönlein purpura, polymyositis, or deficiency are susceptible to recurrent pyogenic infections
recurrent pyogenic infections.498-501 Only approximately affecting any organ system, and this condition is often
25% of C2-deficient patients are prone to infections. C2 clinically indistinguishable from hypogammaglobu-
deficiency is associated with low levels of IgG subclasses, linemia. These patients also may exhibit skin, kidney, and
and low levels of IgG4 and IgA may play a role in deter- joint inflammation caused by immune complex deposi-
mining susceptibility to infection. tion as well as a variety of autoimmune diseases.512-514
The gene encoding C2 resides in the class III region of
the HLA complex on chromosome 6. Between 1% and Deficiency of Alternative Complement
1.5% of Caucasians are heterozygous for a null C2 allele
Pathway Components
(C2Q0). Thus approximately 1 in 10,000 will be homo-
zygous for C2Q0 and have a complete deficiency of Properdin Deficiency
C2.498-501 Two forms of C2 deficiency independent of Properdin stabilizes the alternative pathway C3 conver-
C2Q0 have been identified. In type I, a mutation results tase. The properdin gene is located on the X chromo-
in loss of a mRNA splice site and C2 cannot be trans- some. Lack of properdin does not cause any changes in
lated. In type 2 deficiency C2 is not secreted, but the basis serum levels of complement components; activation
for this is unknown. through the alternative pathway is inefficient. Susceptibil-
ity to respiratory bacterial infections, Neisseria infec-
C4 Deficiency tions, and SLE has been associated with properdin
The C4 component is another substrate for activated C1s. deficiency.510,515-518
The C4a fragment is a very weak anaphylatoxin, and the
C4b fragment associates with C2a on a cell membrane to Factor D Deficiency
constitute C3 convertase. Complete deficiency of C4 is Factor D cleaves factor B after it associates with C3b.
rare. Virtually all such individuals with C4 deficiency Factor D deficiency is associated with recurrent respira-
have SLE and severe glomerulonephritis.502-506 Renal tory bacterial infections, pneumococcal sepsis, Neisseria
failure and infection are the leading causes of death. The infections, and glomerulonephritis.519-522

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

Deficiency of Lectin Pathway Complement Components MBL in this study. Similarly, low blood MBL levels may
also increase the severity of primary immunodeficiency,
Mannose-Binding Lectin Deficiency such as in CVID or with IgA/IgG subclass deficiencies or
MBL is a member of the collectin protein family, which properdin deficiency.416,536-538
also includes lung surfactant proteins A and D.523 MBL MBL levels may also impact certain inflammatory
has a structure similar to C1q and interacts with polysac- states. A low level of MBL has been associated with a
charides containing mannose, glucose, and fucose, as well lower rate of acute rejection after heart transplantation539
as acetylated derivatives of these sugars. Thus MBL may and smaller infarct size and better outcome after cerebral
interact with members of virtually all classes of infectious infarction.540 However, another study reported a higher
microbes. Three proteins called MBL-associated serine risk for myocardial infarction in adults with MBL defi-
proteases (MASPs) 1 to 3 are similar to C1r and C1s. ciency.541 MBL deficiency has also been reported to predis-
MASP-2 may have the most important role in catalyzing pose to or worsen autoimmune or inflammatory diseases
cleavage of C2 and C4 in a manner analogous to C1s. such as rheumatoid arthritis, SLE, and celiac disease.542
Once this is accomplished, the classical pathway C3 con- There are also examples of studies reporting negative
vertase has been created and further reactions are identi- findings regarding disease susceptibility and MBL levels.
cal to the classical pathway. There are polymorphisms of For example, a recent study in 105 HIV patients did not
the gene encoding MBL that affect both structure and find a significant association between low MBL levels and
expression. Structural polymorphisms may impair the the occurrence of infection.543 Another study did not find
ability of MBL to form functional oligomers that bind correlation of MBL levels with outcomes in cystic fibrosis
effectively to carbohydrates and may also impair the patients544 (whereas earlier studies had reached opposite
association with MASP-2 and subsequent activation of conclusions544-548). The situation may be even more
the remainder of the classical pathway. Promoter poly- complex because of discrepancies between studies based
morphisms lead to variation in blood MBL levels of on measuring MBL levels versus those based on genetics.
greater than 1000-fold from 5 ng up to 10 µg/mL. A For example, MBL genotypes generally thought to be
clinically relevant lower limit is not well established. predictive of serum level and function did not correlate
Many studies use values of approximately 100 to 200 ng/ with infection rates in patients with colorectal cancer, in
mL, although slightly different values are occasionally contrast to a prior study that had found significant asso-
used. MBL levels also vary among ethnic groups. The ciations with the serum levels of MBL.549
genotype or functional tests may be more informative In spite of the controversy surrounding the clinical
than the serum level alone because it is possible to have significance of MBL levels, recombinant human MBL is
normal serum levels of a nonfunctional protein. under development as a therapeutic agent; one phase I
The clinical significance of MBL measurement is con- trial has shown no adverse effects of administration to
troversial. Low blood MBL level or function does not by healthy MBL-deficient individuals.550
itself clearly predispose to disease, except possibly during The ficolins 1-3 are also members of the collectin
infancy, when it may be associated with a higher rate of family of molecules and can interact with MASPs 1 to 3
bacterial respiratory tract infections.523 One study sug- and initiate the lectin pathway of complement activation.
gests that the (possible) increased susceptibility to pneu- Deficiency of ficolin 2 (also called L-ficolin) has recently
mococcal infections in MBL deficiency may be serotype been associated with recurrent respiratory infections
specific.524 In other words, MBL-determined host defense and atopy in children.551 However, a more recent report
is more important for some serotypes than for others. A from the same group suggests that the main clinical asso-
variety of other types of conditions have been reported ciation of low ficolin levels is with atopy rather than with
to be associated with MBL-deficiency, including pertus- infection.552 The significance of these findings requires
sis,525 cryptococcal meningitis,526 cryptosporidiosis,527 clarification.
recurrent vulvovaginal candidiasis,528 and the occurrence
of septic shock in pyelonephritis as a result of E. coli529 MASP-2 Deficiency
or severe course and fatality in adults with community- Abrogation of MASP-2 function is expected to have the
acquired pneumonia.530 same consequence as the absence of MBL function: failure
Some reports also suggest that in the setting of other to activate complement by way of the lectin pathway.
disease processes or stresses on the immune system, MBL Patients homozygous for MASP2 mutations have been
deficiency predisposes to a higher rate of a variety of reported to have similar clinical associations as described
infectious complications. For example, one study reported for MBL deficiency.524,530,549,553-555 All of the controversy
a higher rate of invasive aspergillosis in MBL-deficient regarding the clinical importance of MBL levels and
patients with secondary immune compromise resulting genetics applies equally to a discussion of functional
from acquired immunodeficiency virus or treatment with MASP2 polymorphisms or mutations.
steroids or cancer chemotherapy.531 Another report found
a higher rate of bacterial infections in patients with low Deficiency of Terminal Complement Components
MBL and hepatic cirrhosis532 or patients who underwent Recurrent neisserial and pneumococcal infections and
liver transplantation533 or HSCT.534 Another group rheumatic disease have been reported in patients with
reported a higher rate of CMV reactivation in MBL- C5,556,557 C6,558,559 and C7560 deficiencies. C6 deficiency
deficient patients after lung transplantation.535 Interest- has been found in approximately 1 in 1600 African-
ingly, overall survival was superior in those with low Americans in the southeastern United States in

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 919

association with a higher incidence of meningococcal gene, patients have inadequate levels of C1-INH, well
meningitis.561 below the 50% one would expect to be due to a simple
The C8 molecule is a heterotrimer of chains designated gene dosage effect. The mechanism that leads to inhibi-
α, β, and γ. The C8A and C8B genes are on chromosome tion of transcription of the normal gene is unknown.
1, whereas the C8G gene resides on chromosome 9. C8 Although inheritance is autosomal dominant, as many as
deficiency is also associated with recurrent neisserial infec- 10% to 25% of patients may express new mutations.
tion; patients have been identified with lesions of C8A or Acquired forms of HAE have also been described. In
C8B.562-565 Patients with lesions in the C8A genes also lack acquired angioedema (AAE) type 1, C1-INH levels
C8 γ protein, even though the latter genes are normal, decrease by an unknown mechanism, usually as a
because C8 α and γ are normally covalently linked. C9 paraneoplastic process associated with lymphoma and
deficiency is usually asymptomatic566; a few patients with lymphoproliferative disorders.576-581 In AAE type 2, auto-
recurrent neisserial infections have been described.567,568 antibodies against C1-INH deplete it from serum.582-584
One patient with IgA nephropathy associated with C9 These antibodies may arise sporadically, in the context of
deficiency has been reported.569 C9 deficiency has also other autoimmune syndromes, or in association with
been found in one patient with dermatomyositis.570 Allo- lymphoproliferation.
typy at IgG Fc receptor gene loci may have an impact on There are three distinct problems in the management
the susceptibility to infection in patients with deficiencies of HAE or AAE. These are the control of acute attacks
of terminal complement components.571 when they occur and the short-term (i.e., preprocedure)
and long-term prophylaxis of acute attacks.585,586-588 For
management of acute attacks in patients with HAE, medi-
Deficiency of Complement Regulatory Factors
cations such as epinephrine, antihistamines, and cortico-
C1 Inhibitor Deficiency (Hereditary Angioedema) steroids, used to treat angioedema subsequent to
HAE exhibits autosomal dominant inheritance. The hypersensitivity reactions, are entirely useless because the
symptoms of this disease are unpredictable recurrences of mechanism of swelling in HAE is unrelated. Analgesia is
acute and profound subepithelial edema in a variety of indicated for painful abdominal crises. Airway protection
anatomic locations.572,573 Physical trauma may be a pre- is vital and may require a tracheostomy.
cipitating factor. The distal ends of the extremities, face, Recently, several new products have been approved by
intestines, and pharynx are often affected. Extremity the U.S. Food and Drug Administration (FDA) for the
edema is painless but impedes function. Intestinal edema treatment of acute attacks of angioedema. These include
causes excruciating pain and is associated with abdomi- the human plasma–derived purified C1 inhibitor Beri-
nal distention, vomiting, and diarrhea. Pharyngeal edema nert,589,590 a recombinant kallikrein inhibitor,591-594 and a
may lead to fatal airway obstruction.574 Attacks evolve peptidomimetic bradykinin receptor 2 inhibitor.595-597 All
over a period of approximately 12 hours and resolve in of these drugs have proved effective for the treatment of
24 to 48 hours. Attacks in childhood are not uncommon acute HAE attacks, reducing the intensity of angioedema
but occur less frequently than in adulthood. An increase and shortening the time to resolution. Other medications
in incidence and severity often occurs during puberty and may be used if these are not available. Fresh frozen
is sustained thereafter. Attacks may be associated with plasma has been used in attempts to replace C1-INH.
menses in females. Patients may become symptomatic or There are several anecdotal reports of efficacy of this
may have more frequent symptoms when receiving estro- therapy.598 However, this is not considered first-line
gen replacement or contraceptive therapy. therapy for acute attacks with the availability of newer
C1 esterase inhibitor (C1-INH) is a serum serine pro- agents. Tranexamic acid may also be effective, but this is
tease inhibitor (Serpin G1) that limits activities of the also a second-line agent.585-588
complement proteases C1r and C1s, as well as those of Several strategies are available for short- and long-
kallikrein, coagulation factors XIa and XIIa, and term prophylaxis of angioedema attacks. Short-term pro-
plasmin.572,573 In type I HAE (≈85% of patients), levels of phylaxis is indicated whenever a patient is to undergo a
C1-INH are less than 30% of normal. Patients with type procedure (e.g., invasive dental work or surgery) that has
II HAE have normal levels of a mutated (nonfunctional) the potential to precipitate an attack. Long-term prophy-
protein. There is at least one additional form of HAE laxis is used to reduce the frequency of spontaneous
with autosomal dominant inheritance and completely attacks. Impeded androgens such as danazol, stanozolol,
normal C1-INH function. It is designated HAE type III and oxandrolone are useful for short- and long-term
and arises from mutations in the gene encoding coagula- prophylaxis.585-588 These hormones act to increase expres-
tion factor XII.575 The mechanism of angioedema is not sion of the normal SERPING1 gene. Pediatric use is
known. In HAE I and II the unopposed activities of C1r, limited by the tendency of these hormones to promote
C1s, and kallikrein lead to consumption of C2, C4, and epiphyseal closure; use in female subjects is limited by
kininogen.572,573 Diminished levels of these proteins are their undesirable virilizing effects. Tranexamic acid is also
highly characteristic of HAE. Peptides derived from C2 useful as long-term prophylaxis. Recently, another puri-
and especially bradykinin cause the increase in vascular fied human plasma–derived C1 inhibitor product
permeability and edema. (Cinryze) has been FDA approved for prophylactic
The SERPING1 gene is located on chromosome 11. therapy.599-601 Rituximab has been used with mixed
A variety of genetic lesions have been identified in patients success in a small cohort of patients with AAE resulting
with HAE.575 Despite having one normal copy of the from autoantibodies to C1-INH.602

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

impact: an updated report from the Jeffrey Modell Foundation.

Factor I Deficiency Immunol Res 51:61–70, 2011.
A unique report with global scope using the resources of the
Also known as C3 inactivator, the disulfide-linked het- Jeffrey Modell Foundation international network of clinical
erodimeric complement regulatory molecule factor I centers caring for patients with immunodeficiency to provide a
cleaves C3b. Deficiency of factor I leads to increased worldwide assessment of the current status of diagnosis and treat-
degradation of C3 (and factor B), principally because of ment of PIDD.
2. Zebracki K, Palermo TM, Hostoffer R, et al: Health-related quality
the inability to control constitutive low-level activity of of life of children with primary immunodeficiency disease: a com-
the alternative pathway of activation. These patients have parison study. Ann Allergy Asthma Immunol 93:557–561, 2004.
manifestations of C3 deficiency such as recurrent infec- One of the earliest wide-ranging quality of life studies in PIDD.
tions, urticaria, and immune complex disease.603-607 Factor 3. Al-Herz W, Bousfiha A, Casanova JL, et al: Primary immunode-
I deficiency is also associated with atypical hemolytic ficiency diseases: an update on the classification from the interna-
tional union of immunological societies expert committee for
uremic syndrome. primary immunodeficiency. Front Immunol 2:54, 2011.
This is the most recent report of an international committee
Factor H Deficiency charged with the classification of immunodeficiency disorders and
Factor H cooperates with factor I in the inactivation of is a standard reference in the field. The report is updated
C3b; its absence leads to reduced C3 and factor B and a 4. Bonilla FA, Bernstein IL, Khan DA, et al: Practice parameter for
syndrome of recurrent infections with Neisseria meningiti- the diagnosis and management of primary immunodeficiency. Ann
dis and membranoproliferative glomerulonephritis.608-614 Allergy Asthma Immunol 94:S1–S63, 2005.
Both familial and sporadic relapsing hemolytic-uremic syn- A set of guidelines developed under the auspices of a task force
dromes have also been associated with mutations in factor of the Joint Council of Allergy, Asthma, and Immunology for the
diagnosis and management of all forms of PIDD.
H. Similar clinical complications result from autoantibody- 27. Hassan A, Booth C, Brightwell A, et al: Outcome of hematopoi-
mediated depletion of factor H.615-617 etic stem cell transplantation for adenosine deaminase-deficient
severe combined immunodeficiency. Blood 120:3615–3624, 2012.
Diagnosis and Management of Complement Disorders ADA deficiency is one of the more common forms of SCID. This
is an excellent recent review of the outcome of HSCT for this
Clinical tests are available to assess the function of each disorder.
of the three major pathways of complement activa- 32. Candotti F, Shaw KL, Muul L, et al: Gene therapy for adenosine
tion.4,487,488,516,618-620 The lectin pathway is not as frequently deaminase-deficient severe combined immune deficiency: clinical
evaluated because the definition of clinically significant comparison of retroviral vectors and treatment plans. Blood
deficiency is controversial. Activation of the classical 120:3635–3646, 2012.
Gene therapy is one of the most important recent advances in
pathway is measured by the CH50 assay (total classical immunology and medicine in general. This is an excellent review
pathway hemolytic assay), which can be performed by a of the state of the art in the context of ADA SCID.
variety of methods. The alternative pathway is assessed by 39. Alt FW, Zhang Y, Meng FL, et al: Mechanisms of programmed
a similar test called the AH50. If the CH50 is low and the DNA lesions and genomic instability in the immune system. Cell
152:417–429, 2013.
AH50 is normal, then there is likely to be a defect in C1, B and T lymphocytes are the only cells in the body that somati-
C2, or C4. If the AH50 is low and the CH50 is normal, cally rearrange their genomes. Study of this process has led to
there is likely to be a defect in properdin, or factor D. If important knowledge regarding mechanisms that maintain
both are low, it is likely that there is a defect in any of the genome integrity and how they fail and lead to mutation and
terminal pathway components (C3-C9). Complement malignancy, as discussed in this paper.
66. Roifman CM, Somech R, Kavadas F, et al: Defining combined
depletion caused by consumption in an inflammatory immunodeficiency. J Allergy Clin Immunol 130:177–183, 2012.
process will lead to depression of both CH50 and AH50. An important study of the ranges of T-cell function that occur
The same situation is seen in regulatory component defects in SCID, variant SCID, and other PIDDs with prominent T-cell
(factor H and factor I) because of consumption of C3. deficiency and relation to limits of detection in newborn screening
assays based on TRECs.
Antibiotic prophylaxis is the mainstay of long-term 102. Engelhardt KR, McGhee S, Winkler S, et al: Large deletions and
management of the infectious predisposition in comple- point mutations involving the dedicator of cytokinesis 8 (DOCK8)
ment deficiencies.4,489,618 Patients should also maintain in the autosomal-recessive form of hyper-IgE syndrome. J Allergy
fully protective levels of antibodies for common encapsu- Clin Immunol 124:1289–1302, 2009.
lated organisms such as HIB, pneumococcus, and menin- This is a good example of gene and disease discovery using a
modern technique of genome scanning using comparative genomic
gococcus. The autoimmune or inflammatory complications hybridization.
are managed according to standard regimens as they 112. Byun M, Abhyankar A, Lelarge V, et al: Whole-exome sequencing-
arise. It should be noted that experience is limited with based discovery of STIM1 deficiency in a child with fatal classic
newer biologic therapies in the inflammatory states asso- Kaposi sarcoma. J Exp Med 207:2307–2312, 2010.
This is a good example of an exome sequence strategy for defini-
ciated with complement deficiency. Eculizumab is an tive molecular diagnosis in a patient with PIDD.
anti-C5 monoclonal antibody that inhibits the terminal 116. Puck JM: Laboratory technology for population-based screening
pathway and is approved for the management of atypical for severe combined immunodeficiency in neonates: the winner is
hemolytic-uremic syndrome.621 T-cell receptor excision circles. J Allergy Clin Immunol 129:607–
616, 2012.
Newborn screening for SCID represents a very important
References available online at ExpertConsult. advance in immunology and in newborn screening. This study
discusses various methods that have been tested.
117. Morinishi Y, Imai K, Nakagawa N, et al: Identification of severe
KEY REFERENCES combined immunodeficiency by T-cell receptor excision circles
1. Modell V, Gee B, Lewis DB, et al: Global study of primary immu- quantification using neonatal guthrie cards. J Pediatr 155:829–
nodeficiency diseases (PI)—diagnosis, treatment, and economic 833, 2009.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases 921

Most states that are conducting SCID newborn screening use a This study culminates 40 years of searching for the molecular
polymerase chain reaction–based method to detect TRECs, as basis of one of the earliest described forms of PIDD.
described here. 247. Puel A, Cypowyj S, Marodi L, et al: Inborn errors of human IL-17
118. Buckley RH: The long quest for neonatal screening for severe immunity underlie chronic mucocutaneous candidiasis. Curr Opin
combined immunodeficiency. J Allergy Clin Immunol 129:597– Allergy Clin Immunol 12:616–622, 2012.
604, 2012. The recent description of the Th17 type of T cell has developed
A historical perspective on the quest to establish newborn largely in the context of study of patients with CMC.
screening for SCID, first proposed approximately 20 years ago. 280. Mathis D, Benoist C: Aire. Annu Rev Immunol 27:287–312, 2009.
122. Griffith LM, Cowan MJ, Notarangelo LD, et al: Improving cel- The discovery of AIRE led to an important breakthrough in the
lular therapy for primary immune deficiency diseases: recognition, understanding of the establishment of “central” tolerance in the
diagnosis, and management. J Allergy Clin Immunol 124:1152– thymus.
1160, 2009. 284. Josefowicz SZ, Lu LF, Rudensky AY: Regulatory T cells: mecha-
Guidelines for the diagnosis and management of disorders of nisms of differentiation and function. Annu Rev Immunol
severe T-cell dysfunction, including decision to undergo HSCT, 30:531–564, 2012.
technique, and pre-HSCT and post-HSCT therapy. The biology of the various forms of Tregs defines the immune
124. Railey MD, Lokhnygina Y, Buckley RH: Long-term clinical system self-nonself discrimination and the induction and mainte-
outcome of patients with severe combined immunodeficiency who nance of tolerance and how it is broken in autoimmune disease.
received related donor bone marrow transplants without pretrans- 298. Bolze A, Byun M, McDonald D, et al: Whole-exome-sequencing–
plant chemotherapy or post-transplant GVHD prophylaxis. J based discovery of human FADD deficiency. Am J Hum Genet
Pediatr 155:834–840, 2009. 87:873–881, 2010.
A single center experience with a large patient cohort applying A good example of disease and gene discovery by an exome-
a particular strategy of HSCT: predominantly haploidentical sequencing strategy in a patient with PIDD.
related donor transplant without conditioning. 330. Casanova JL, Abel L: Human genetics of infectious diseases: a
129. Gaspar HB, Cooray S, Gilmour KC, et al: Hematopoietic stem unified theory. EMBO J 26:915–922, 2007.
cell gene therapy for adenosine deaminase–deficient severe An important synthesis of evolutionary theory and host-
combined immunodeficiency leads to long-term immunological pathogen interactions.
recovery and metabolic correction. Sci Transl Med 3:97ra80, 331. Al-Muhsen S, Casanova JL: The genetic heterogeneity of mende-
2011. lian susceptibility to mycobacterial diseases. J Allergy Clin
The latest compendium of data relating to gene therapy for Immunol 122:1043–1051, 2008.
ADA SCID. A good review of an important group of PIDDs.
130. Hacein-Bey-Abina S, Hauer J, Lim A, et al: Efficacy of gene 350. Khan WN: Colonel Bruton’s kinase defined the molecular basis of
therapy for X-linked severe combined immunodeficiency. N Engl X-linked agammaglobulinemia, the first primary immunodefi-
J Med 363:355–364, 2010. ciency. J Immunol 188:2933–2935, 2012.
A recent compendium of data related to gene therapy for A perspective on one of the seminal reports in the field of PIDD.
X-linked SCID. 353. Winkelstein JA, Marino MC, Lederman HM, et al: X-linked
135. Ming JE, Stiehm ER, Graham JM, Jr: Syndromic immunodeficien- agammaglobulinemia: report on a United States registry of 201
cies: genetic syndromes associated with immune abnormalities. patients. Medicine (Baltimore) 85:193–202, 2006.
Crit Rev Clin Lab Sci 40:587–642, 2003. Perhaps the most comprehensive compendium of clinical and
A good review of many syndromes with variable associations laboratory data regarding XLA.
with immunologic dysfunction, many not covered in this chapter 359. Bonilla FA, Geha RS: Common variable immunodeficiency.
owing to space limitations. Pediatr Res 65:13R–19R, 2009.
136. Ochs HD, Filipovich AH, Veys P, et al: Wiskott-Aldrich syn- CVID is one of the most prevalent forms of immunodeficiency.
drome: diagnosis, clinical and laboratory manifestations, and This is a good review of clinical and laboratory features and
treatment. Biol Blood Marrow Transplant 15:84–90, 2009. principles of management.
WAS is one of the more important combined immunodeficien- 394. Orange JS, Glessner JT, Resnick E, et al: Genome-wide association
cies and has led to a wealth of knowledge of immune system identifies diverse causes of common variable immunodeficiency. J
function. This is an excellent general review. Allergy Clin Immunol 127:1360–1367, e6, 2011.
162. Markert ML, Devlin BH, Alexieff MJ, et al: Review of 54 patients This study highlights the complex nature of genetic aberrations
with complete DiGeorge anomaly enrolled in protocols for thymus associated with CVID.
transplantation: outcome of 44 consecutive transplants. Blood 438. Orange JS, Ballow M, Stiehm ER, et al: Use and interpretation of
109:4539–4547, 2007. diagnostic vaccination in primary immunodeficiency: a working
Thymus transplantation represents an important therapeutic group report of the Basic and Clinical Immunology Interest
advance for immune reconstitution in complete DGS and will Section of the American Academy of Allergy, Asthma & Immunol-
likely have increasing application in other situations as the tech- ogy. J Allergy Clin Immunol 130:S1–S24, 2012.
nique is further developed. A review and discussion of some important considerations
166. McDonald-McGinn DM, Kirschner R, Goldmuntz E, et al: The regarding the use of routine and special vaccines for the diagnosis
Philadelphia story: the 22q11.2 deletion: report on 250 patients. of PIDD.
Genet Couns 10:11–24, 1999. 454. Notarangelo LD, Lanzi G, Peron S, et al: Defects of class-switch
DGS is one of the most commonly diagnosed forms of PIDD. recombination. J Allergy Clin Immunol 117:855–864, 2006.
This is an excellent overview of the clinical presentation, of which A good review of an important category of PIDD.
every pediatric clinician should have some knowledge. 472. Orange JS, Hossny EM, Weiler CR, et al: Use of intravenous
178. Markert ML, Marques JG, Neven B, et al: First use of thymus immunoglobulin in human disease: a review of evidence by
transplantation therapy for FOXN1 deficiency (nude/SCID): a members of the Primary Immunodeficiency Committee of the
report of 2 cases. Blood 117:688–696, 2011. American Academy of Allergy, Asthma and Immunology. J Allergy
Another example of a PIDD that is amenable to therapy with Clin Immunol 117:S525–S553, 2006.
thymus transplantation. A comprehensive guideline for the application of IgG therapy
188. Perlman S, Becker-Catania S, Gatti RA: Ataxia-telangiectasia: diag- in all categories of disease, including PIDD.
nosis and treatment. Semin Pediatr Neurol 10:173–182, 2003. 489. Frank MM: Complement disorders and hereditary angioedema. J
AT is an important immune deficiency with cancer predisposi- Allergy Clin Immunol 125:S262–S271, 2010.
tion. Study of AT has led to important knowledge regarding cell A good recent review of complement disorders.
cycle control and mechanisms for sensing and repairing DNA 586. Craig T, Pursun EA, Bork K, et al: WAO guideline for the manage-
damage. ment of hereditary angioedema. WAO J 5:182–199, 2012.
239. Holland SM, DeLeo FR, Elloumi HZ, et al: STAT3 mutations in An international consensus document on the management of
the hyper-IgE syndrome. N Engl J Med 357:1608–1619, 2007. hereditary angioedema.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases  921.e1

deficient severe combined immune deficiency. J Allergy Clin

REFERENCES Immunol 129:762–769, e1, 2012.
1. Modell V, Gee B, Lewis DB, et al: Global study of primary immu- 23. Arredondo-Vega FX, Santisteban I, Daniels S, et al: Adenosine
nodeficiency diseases (PI)—diagnosis, treatment, and economic deaminase deficiency: genotype-phenotype correlations based on
impact: an updated report from the Jeffrey Modell Foundation. expressed activity of 29 mutant alleles. Am J Hum Genet 63:
Immunol Res 51:61–70, 2011. 1049–1059, 1998.
2. Zebracki K, Palermo TM, Hostoffer R, et al: Health-related 24. Speckmann C, Neumann C, Borte S, et al: Delayed-onset adenos-
quality of life of children with primary immunodeficiency disease: ine deaminase deficiency: strategies for an early diagnosis. J
a comparison study. Ann Allergy Asthma Immunol 93:557–561, Allergy Clin Immunol 130:991–994, 2012.
2004. 25. Micheli V, Camici M, Tozzi MG, et al: Neurological disorders of
3. Al-Herz W, Bousfiha A, Casanova JL, et al: Primary immunode- purine and pyrimidine metabolism. Curr Top Med Chem 11:923–
ficiency diseases: an update on the classification from the interna- 947, 2011.
tional union of immunological societies expert committee for 26. Markert ML: Purine nucleoside phosphorylase deficiency. Immu-
primary immunodeficiency. Front Immunol 2:54, 2011. nodefic Rev 3:45–81, 1991.
4. Bonilla FA, Bernstein IL, Khan DA, et al: Practice parameter for 27. Hassan A, Booth C, Brightwell A, et al: Outcome of hematopoi-
the diagnosis and management of primary immunodeficiency. Ann etic stem cell transplantation for adenosine deaminase-deficient
Allergy Asthma Immunol 94:S1–S63, 2005. severe combined immunodeficiency. Blood 120:3615–3624, 2012.
5. van der Burg M, Gennery AR: Educational paper. The expanding 28. Honig M, Albert MH, Schulz A, et al: Patients with adenosine
clinical and immunological spectrum of severe combined immu- deaminase deficiency surviving after hematopoietic stem cell trans-
nodeficiency. Eur J Pediatr 170:561–571, 2011. plantation are at high risk of CNS complications. Blood 109:3595–
6. Muller SM, Ege M, Pottharst A, et al: Transplacentally acquired 3602, 2007.
maternal T lymphocytes in severe combined immunodeficiency: a 29. Booth C, Gaspar HB: Pegademase bovine (PEG-ADA) for the
study of 121 patients. Blood 98:1847–1851, 2001. treatment of infants and children with severe combined immuno-
7. Palmer K, Green TD, Roberts JL, et al: Unusual clinical and deficiency (SCID). Biologics 3:349–358, 2009.
immunologic manifestations of transplacentally acquired mater- 30. Serana F, Sottini A, Chiarini M, et al: The different extent of B
nal T cells in severe combined immunodeficiency. J Allergy Clin and T cell immune reconstitution after hematopoietic stem cell
Immunol 120:423–428, 2007. transplantation and enzyme replacement therapies in SCID patients
8. Kobrynski LJ, Abramowsky C: Monoclonal IgA gammopathy due with adenosine deaminase deficiency. J Immunol 185:7713–7722,
to maternal B cells in an infant with severe combined immunode- 2010.
ficiency (SCID) prior to hematopoietic stem cell transplantation. 31. Aiuti A, Cattaneo F, Galimberti S, et al: Gene therapy for immu-
J Pediatr Hematol Oncol 28:53–56, 2006. nodeficiency due to adenosine deaminase deficiency. N Engl J Med
9. Hershfield MS: Adenosine deaminase deficiency: clinical expres- 360:447–458, 2009.
sion, molecular basis, and therapy. Semin Hematol 35:291–298, 32. Candotti F, Shaw KL, Muul L, et al: Gene therapy for adenosine
1998. deaminase-deficient severe combined immune deficiency: clinical
10. Somech R, Lev A, Grisaru-Soen G, et al: Purine nucleoside phos- comparison of retroviral vectors and treatment plans. Blood
phorylase deficiency presenting as severe combined immune defi- 120:3635–3646, 2012.
ciency. Immunol Res 2013. 33. Small TN, Wall DA, Kurtzberg J, et al: Association of reticular
11. Walker PL, Corrigan A, Arenas M, et al: Purine nucleoside phos- dysgenesis (thymic alymphoplasia and congenital aleukocytosis)
phorylase deficiency: a mutation update. Nucleosides Nucleotides with bilateral sensorineural deafness. J Pediatr 135:387–389,
30:1243–1247, 2011. 1999.
12. Malacarne F, Benicchi T, Notarangelo LD, et al: Reduced thymic 34. Lagresle-Peyrou C, Six EM, Picard C, et al: Human adenylate
output, increased spontaneous apoptosis and oligoclonal B cells kinase 2 deficiency causes a profound hematopoietic defect associ-
in polyethylene glycol-adenosine deaminase-treated patients. Eur ated with sensorineural deafness. Nat Genet 41:106–111, 2009.
J Immunol 35:3376–3386, 2005. 35. Pannicke U, Honig M, Hess I, et al: Reticular dysgenesis (aleuko-
13. Albuquerque W, Gaspar HB: Bilateral sensorineural deafness in cytosis) is caused by mutations in the gene encoding mitochondrial
adenosine deaminase-deficient severe combined immunodefi- adenylate kinase 2. Nat Genet 41:101–105, 2009.
ciency. J Pediatr 144:278–280, 2004. 36. Henderson LA, Frugoni F, Hopkins G, et al: First reported case
14. Kuhl JS, Schwarz K, Munch A, et al: Hyperbilirubinemia and of Omenn syndrome in a patient with reticular dysgenesis. J
rapid fatal hepatic failure in severe combined immunodeficiency Allergy Clin Immunol 131:1227–1230, 2012.
caused by adenosine deaminase deficiency (ADA-SCID). Klin 37. Lagresle-Peyrou C, Neven B, Six E, et al: Occurrence of myelo-
Padiatr 223:85–89, 2011. dysplastic syndrome in 2 patients with reticular dysgenesis. J
15. Grunebaum E, Cutz E, Roifman CM: Pulmonary alveolar pro- Allergy Clin Immunol 128:230–232, e2, 2011.
teinosis in patients with adenosine deaminase deficiency. J Allergy 38. Bertrand Y, Muller SM, Casanova JL, et al: Reticular dysgenesis:
Clin Immunol 129:1588–1593, 2012. HLA non-identical bone marrow transplants in a series of 10
16. Rogers MH, Lwin R, Fairbanks L, et al: Cognitive and behavioral patients. Bone Marrow Transplant 29:759–762, 2002.
abnormalities in adenosine deaminase deficient severe combined 39. Alt FW, Zhang Y, Meng FL, et al: Mechanisms of programmed
immunodeficiency. J Pediatr 139:44–50, 2001. DNA lesions and genomic instability in the immune system. Cell
17. Nofech-Mozes Y, Blaser SI, Kobayashi J, et al: Neurologic abnor- 152:417–429, 2013.
malities in patients with adenosine deaminase deficiency. Pediatr 40. Schwarz K, Gauss GH, Ludwig L, et al: RAG mutations in human
Neurol 37:218–221, 2007. B cell-negative SCID. Science 274:97–99, 1996.
18. Sauer AV, Brigida I, Carriglio N, et al: Autoimmune dysregulation 41. Villa A, Sobacchi C, Notarangelo LD, et al: V(D)J recombination
and purine metabolism in adenosine deaminase deficiency. Front defects in lymphocytes due to RAG mutations: severe immunode-
Immunol 3:265, 2012. ficiency with a spectrum of clinical presentations. Blood 97:81–
19. Sauer AV, Brigida I, Carriglio N, et al: Alterations in the adenosine 88, 2001.
metabolism and CD39/CD73 adenosinergic machinery cause loss 42. Felgentreff K, Perez-Becker R, Speckmann C, et al: Clinical
of Treg cell function and autoimmunity in ADA-deficient SCID. and immunological manifestations of patients with atypical
Blood 119:1428–1439, 2012. severe combined immunodeficiency. Clin Immunol 141:73–82,
20. Roifman CM, Zhang J, Atkinson A, et al: Adenosine deaminase 2011.
deficiency can present with features of Omenn syndrome. J Allergy 43. Villa A, Santagata S, Bozzi F, et al: Partial V(D)J recombination
Clin Immunol 121:1056–1058, 2008. activity leads to Omenn syndrome. Cell 93:885–896, 1998.
21. Sokolic R, Maric I, Kesserwan C, et al: Myeloid dysplasia and 44. Signorini S, Imberti L, Pirovano S, et al: Intrathymic restriction
bone marrow hypocellularity in adenosine deaminase-deficient and peripheral expansion of the T-cell repertoire in Omenn syn-
severe combined immune deficiency. Blood 118:2688–2694, 2011. drome. Blood 94:3468–3478, 1999.
22. Kesserwan C, Sokolic R, Cowen EW, et al: Multicentric dermato- 45. Poliani PL, Facchetti F, Ravanini M, et al: Early defects in human
fibrosarcoma protuberans in patients with adenosine deaminase- T-cell development severely affect distribution and maturation of

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

thymic stromal cells: possible implications for the pathophysiol- common gammac cytokine receptor subunit or JAK-3 deficiency.
ogy of Omenn syndrome. Blood 114:105–108, 2009. Lancet 363:2051–2054, 2004.
46. Dalal I, Tabori U, Bielorai B, et al: Evolution of a T-B- SCID into 69. Stephan V, Wahn V, Le Deist F, et al: Atypical X-linked severe
an Omenn syndrome phenotype following parainfluenza 3 virus combined immunodeficiency due to possible spontaneous rever-
infection. Clin Immunol 115:70–73, 2005. sion of the genetic defect in T cells. N Engl J Med 335:1563–1567,
47. de Villartay JP, Lim A, Al-Mousa H, et al: A novel immunodefi- 1996.
ciency associated with hypomorphic RAG1 mutations and CMV 70. Speckmann C, Pannicke U, Wiech E, et al: Clinical and immuno-
infection. J Clin Invest 115:3291–3299, 2005. logic consequences of a somatic reversion in a patient with
48. Ehl S, Schwarz K, Enders A, et al: A variant of SCID with specific X-linked severe combined immunodeficiency. Blood 112:4090–
immune responses and predominance of gamma delta T cells. J 4097, 2008.
Clin Invest 115:3140–3148, 2005. 71. Kawai T, Saito M, Nishikomori R, et al: Multiple reversions of
49. Wada T, Toma T, Okamoto H, et al: Oligoclonal expansion of T an IL2RG mutation restore T cell function in an X-linked severe
lymphocytes with multiple second-site mutations leads to Omenn combined immunodeficiency patient. J Clin Immunol 32:690–
syndrome in a patient with RAG1-deficient severe combined 697, 2012.
immunodeficiency. Blood 106:2099–2101, 2005. 72. Wada T, Yasui M, Toma T, et al: Detection of T lymphocytes with
50. Schuetz C, Huck K, Gudowius S, et al: An immunodeficiency a second-site mutation in skin lesions of atypical X-linked severe
disease with RAG mutations and granulomas. N Engl J Med combined immunodeficiency mimicking Omenn syndrome. Blood
358:2030–2038, 2008. 112:1872–1875, 2008.
51. De Ravin SS, Cowen EW, Zarember KA, et al: Hypomorphic Rag 73. Macchi P, Villa A, Giliani S, et al: Mutations of Jak-3 gene in
mutations can cause destructive midline granulomatous disease. patients with autosomal severe combined immune deficiency
Blood 116:1263–1271, 2010. (SCID). Nature 377:65–68, 1995.
52. Kuijpers TW, Ijspeert H, van Leeuwen EM, et al: Idiopathic CD4+ 74. Frucht DM, Gadina M, Jagadeesh GJ, et al: Unexpected and vari-
T lymphopenia without autoimmunity or granulomatous disease able phenotypes in a family with JAK3 deficiency. Genes Immun
in the slipstream of RAG mutations. Blood 117:5892–5896, 2:422–432, 2001.
2011. 75. Puel A, Ziegler SF, Buckley RH, et al: Defective IL7R expression
53. Moshous D, Callebaut I, de Chasseval R, et al: Artemis, a novel in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet
DNA double-strand break repair/V(D)J recombination protein, is 20:394–397, 1998.
mutated in human severe combined immune deficiency. Cell 76. Giliani S, Bonfim C, de Saint Basile G, et al: Omenn syndrome in
105:177–186, 2001. an infant with IL7RA gene mutation. J Pediatr 148:272–274,
54. Ege M, Ma Y, Manfras B, et al: Omenn syndrome due to 2006.
ARTEMIS mutations. Blood 105:4179–4186, 2005. 77. Dadi HK, Simon AJ, Roifman CM: Effect of CD3delta deficiency
55. Moshous D, Pannetier C, Chasseval Rd R, et al: Partial T and B on maturation of alpha/beta and gamma/delta T-cell lineages in
lymphocyte immunodeficiency and predisposition to lymphoma severe combined immunodeficiency. N Engl J Med 349:1821–
in patients with hypomorphic mutations in Artemis. J Clin Invest 1828, 2003.
111:381–387, 2003. 78. de Saint Basile G, Geissmann F, Flori E, et al: Severe combined
56. O’Driscoll M, Cerosaletti KM, Girard PM, et al: DNA ligase IV immunodeficiency caused by deficiency in either the delta or the
mutations identified in patients exhibiting developmental delay epsilon subunit of CD3. J Clin Invest 114:1512–1517, 2004.
and immunodeficiency. Mol Cell 8:1175–1185, 2001. 79. Marcus N, Takada H, Law J, et al: Hematopoietic stem cell trans-
57. van der Burg M, van Veelen LR, Verkaik NS, et al: A new type plantation for CD3delta deficiency. J Allergy Clin Immunol 128:
of radiosensitive T-B-NK+ severe combined immunodeficiency 1050–1057, 2011.
caused by a LIG4 mutation. J Clin Invest 116:137–145, 2006. 80. Rieux-Laucat F, Hivroz C, Lim A, et al: Inherited and somatic
58. Enders A, Fisch P, Schwarz K, et al: A severe form of human CD3zeta mutations in a patient with T-cell deficiency. N Engl J
combined immunodeficiency due to mutations in DNA ligase IV. Med 354:1913–1921, 2006.
J Immunol 176:5060–5068, 2006. 81. Roberts JL, Lauritsen JP, Cooney M, et al: T-B+NK+ severe com-
59. Buck D, Moshous D, de Chasseval R, et al: Severe combined bined immunodeficiency caused by complete deficiency of the
immunodeficiency and microcephaly in siblings with hypomorphic CD3zeta subunit of the T-cell antigen receptor complex. Blood
mutations in DNA ligase IV. Eur J Immunol 36:224–235, 2006. 109:3198–3206, 2007.
60. Buck D, Malivert L, de Chasseval R, et al: Cernunnos, a novel 82. Arnaiz-Villena A, Timon M, Corell A, et al: Brief report: primary
nonhomologous end-joining factor, is mutated in human immu- immunodeficiency caused by mutations in the gene encoding the
nodeficiency with microcephaly. Cell 124:287–299, 2006. CD3-gamma subunit of the T-lymphocyte receptor. N Engl J Med
61. Vera G, Rivera-Munoz P, Abramowski V, et al: Cernunnos defi- 327:529–533, 1992.
ciency reduces thymocyte life span and alters the T cell repertoire 83. Allende LM, Garcia-Perez MA, Moreno A, et al: Fourteen years’
in mice and humans. Mol Cell Biol 33:701–711, 2013. follow-up of an autoimmune patient lacking the CD3 gamma
62. Du L, Peng R, Bjorkman A, et al: Cernunnos influences human subunit of the T-lymphocyte receptor. Blood 96:4007–4008,
immunoglobulin class switch recombination and may be associ- 2000.
ated with B cell lymphomagenesis. J Exp Med 209:291–305, 84. Recio MJ, Moreno-Pelayo MA, Kilic SS, et al: Differential biologi-
2012. cal role of CD3 chains revealed by human immunodeficiencies. J
63. van der Burg M, Ijspeert H, Verkaik NS, et al: A DNA-PKcs Immunol 178:2556–2564, 2007.
mutation in a radiosensitive T-B- SCID patient inhibits Artemis 85. Morgan NV, Goddard S, Cardno TS, et al: Mutation in the
activation and nonhomologous end-joining. J Clin Invest 119:91– TCRalpha subunit constant gene (TRAC) leads to a human immu-
98, 2009. nodeficiency disorder characterized by a lack of TCRalphabeta+
64. Noguchi M, Yi H, Rosenblatt HM, et al: Interleukin-2 receptor T cells. J Clin Invest 121:695–702, 2011.
gamma chain mutation results in X-linked severe combined immu- 86. Kung C, Pingel JT, Heikinheimo M, et al: Mutations in the tyro-
nodeficiency in humans. Cell 73:147–157, 1993. sine phosphatase CD45 gene in a child with severe combined
65. Liao W, Lin JX, Leonard WJ: IL-2 family cytokines: new insights immunodeficiency disease. Nat Med 6:343–345, 2000.
into the complex roles of IL-2 as a broad regulator of T helper 87. Tchilian EZ, Wallace DL, Wells RS, et al: A deletion in the gene
cell differentiation. Curr Opin Immunol 23:598–604, 2011. encoding the CD45 antigen in a patient with SCID. J Immunol
66. Roifman CM, Somech R, Kavadas F, et al: Defining combined 166:1308–1313, 2001.
immunodeficiency. J Allergy Clin Immunol 130:177–183, 2012. 88. Roberts JL, Buckley RH, Luo B, et al: CD45-deficient severe com-
67. Recher M, Berglund LJ, Avery DT, et al: IL-21 is the primary bined immunodeficiency caused by uniparental disomy. Proc Natl
common gamma chain-binding cytokine required for human Acad Sci U S A 109:10456–10461, 2012.
B-cell differentiation in vivo. Blood 118:6824–6835, 2011. 89. Hauck F, Randriamampita C, Martin E, et al: Primary T-cell
68. Laffort C, Le Deist F, Favre M, et al: Severe cutaneous papilloma- immunodeficiency with immunodysregulation caused by autoso-
virus disease after haemopoietic stem-cell transplantation in mal recessive LCK deficiency. J Allergy Clin Immunol 130:1144–
patients with severe combined immune deficiency caused by 1152, e11, 2012.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases  921.e3

90. Crequer A, Troeger A, Patin E, et al: Human RHOH deficiency 113. Li FY, Chaigne-Delalande B, Kanellopoulou C, et al: Second mes-
causes T cell defects and susceptibility to EV-HPV infections. J senger role for Mg2+ revealed by human T-cell immunodeficiency.
Clin Invest 122:3239–3247, 2012. Nature 475:471–476, 2011.
91. Picard C, Fischer A: Hematopoietic stem cell transplantation and 114. Stepensky P, Keller B, Buchta M, et al: Deficiency of caspase
other management strategies for MHC class II deficiency. Immunol recruitment domain family, member 11 (CARD11), causes pro-
Allergy Clin North Am 30:173–178, 2010. found combined immunodeficiency in human subjects. J Allergy
92. Ouederni M, Vincent QB, Frange P, et al: Major histocompatibil- Clin Immunol 131:477–485, e1, 2013.
ity complex class II expression deficiency caused by a RFXANK 115. Kotlarz D, Zietara N, Uzel G, et al: Loss-of-function mutations
founder mutation: a survey of 35 patients. Blood 118:5108–5118, in the IL-21 receptor gene cause a primary immunodeficiency
2011. syndrome. J Exp Med 210:433–443, 2013.
93. Zimmer J, Andres E, Donato L, et al: Clinical and immunological 116. Puck JM: Laboratory technology for population-based screening
aspects of HLA class I deficiency. QJM 98:719–727, 2005. for severe combined immunodeficiency in neonates: the winner is
94. Arpaia E, Shahar M, Dadi H, et al: Defective T cell receptor T-cell receptor excision circles. J Allergy Clin Immunol 129:607–
signaling and CD8+ thymic selection in humans lacking zap-70 616, 2012.
kinase. Cell 76:947–958, 1994. 117. Morinishi Y, Imai K, Nakagawa N, et al: Identification of severe
95. Elder ME, Lin D, Clever J, et al: Human severe combined immu- combined immunodeficiency by T-cell receptor excision circles
nodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. quantification using neonatal guthrie cards. J Pediatr 155:829–
Science 264:1596–1599, 1994. 833, 2009.
96. Picard C, Dogniaux S, Chemin K, et al: Hypomorphic mutation 118. Buckley RH: The long quest for neonatal screening for severe
of ZAP70 in human results in a late onset immunodeficiency and combined immunodeficiency. J Allergy Clin Immunol 129:597–
no autoimmunity. Eur J Immunol 39:1966–1976, 2009. 604, 2012.
97. Turul T, Tezcan I, Artac H, et al: Clinical heterogeneity can 119. Azzari C, la Marca G, Resti M: Neonatal screening for severe
hamper the diagnosis of patients with ZAP70 deficiency. Eur J combined immunodeficiency caused by an adenosine deaminase
Pediatr 168:87–93, 2009. defect: a reliable and inexpensive method using tandem mass
98. de la Calle-Martin O, Hernandez M, Ordi J, et al: Familial CD8 spectrometry. J Allergy Clin Immunol 127:1394–1399, 2011.
deficiency due to a mutation in the CD8 alpha gene. J Clin Invest 120. la Marca G, Canessa C, Giocaliere E, et al: Tandem mass spec-
108:117–123, 2001. trometry, but not T-cell receptor excision circle analysis, identifies
99. Nehme NT, Pachlopnik Schmid J, Debeurme F, et al: MST1 muta- newborns with late-onset adenosine deaminase deficiency. J
tions in autosomal recessive primary immunodeficiency character- Allergy Clin Immunol 131:1604–1610, 2012.
ized by defective naive T-cell survival. Blood 119:3458–3468, 121. Rosen FS: Severe combined immunodeficiency: a pediatric emer-
2012. gency. J Pediatr 130:345–346, 1997.
100. Abdollahpour H, Appaswamy G, Kotlarz D, et al: The phenotype 122. Griffith LM, Cowan MJ, Notarangelo LD, et al: Improving cel-
of human STK4 deficiency. Blood 119:3450–3457, 2012. lular therapy for primary immune deficiency diseases: recognition,
101. Zhang Q, Davis JC, Lamborn IT, et al: Combined immunodefi- diagnosis, and management. J Allergy Clin Immunol 124:1152–
ciency associated with DOCK8 mutations. N Engl J Med 361: 1160, 2009.
2046–2055, 2009. 123. Gennery AR, Slatter MA, Grandin L, et al: Transplantation of
102. Engelhardt KR, McGhee S, Winkler S, et al: Large deletions and hematopoietic stem cells and long-term survival for primary
point mutations involving the dedicator of cytokinesis 8 (DOCK8) immunodeficiencies in Europe: entering a new century, do we do
in the autosomal-recessive form of hyper-IgE syndrome. J Allergy better? J Allergy Clin Immunol 126:602–610, e1–11, 2010.
Clin Immunol 124:1289–1302, 2009. 124. Railey MD, Lokhnygina Y, Buckley RH: Long-term clinical
103. Gatz SA, Benninghoff U, Schutz C, et al: Curative treatment of outcome of patients with severe combined immunodeficiency who
autosomal-recessive hyper-IgE syndrome by hematopoietic cell received related donor bone marrow transplants without pretrans-
transplantation. Bone Marrow Transplant 46:552–556, 2011. plant chemotherapy or post-transplant GVHD prophylaxis. J
104. Jabara HH, McDonald DR, Janssen E, et al: DOCK8 functions Pediatr 155:834–840, 2009.
as an adaptor that links TLR-MyD88 signaling to B cell activa- 125. Buckley RH, Win CM, Moser BK, et al: Post-transplantation B
tion. Nat Immunol 13:612–620, 2012. cell function in different molecular types of SCID. J Clin Immunol
105. Shiow LR, Paris K, Akana MC, et al: Severe combined immuno- 33:96–110, 2013.
deficiency (SCID) and attention deficit hyperactivity disorder 126. Buckley RH: Molecular defects in human severe combined immu-
(ADHD) associated with a Coronin-1A mutation and a chromo- nodeficiency and approaches to immune reconstitution. Annu Rev
some 16p11.2 deletion. Clin Immunol 131:24–30, 2009. Immunol 22:625–655, 2004.
106. Shiow LR, Roadcap DW, Paris K, et al: The actin regulator 127. Blaese RM, Culver KW, Miller AD, et al: T lymphocyte-directed
coronin 1A is mutant in a thymic egress-deficient mouse strain gene therapy for ADA- SCID: initial trial results after 4 years.
and in a patient with severe combined immunodeficiency. Nat Science 270:475–480, 1995.
Immunol 9:1307–1315, 2008. 128. Bordignon C, Notarangelo LD, Nobili N, et al: Gene therapy in
107. Roscioli T, Cliffe ST, Bloch DB, et al: Mutations in the gene encod- peripheral blood lymphocytes and bone marrow for ADA- immu-
ing the PML nuclear body protein Sp110 are associated with nodeficient patients. Science 270:470–475, 1995.
immunodeficiency and hepatic veno-occlusive disease. Nat Genet 129. Gaspar HB, Cooray S, Gilmour KC, et al: Hematopoietic
38:620–622, 2006. stem cell gene therapy for adenosine deaminase-deficient severe
108. Cliffe ST, Bloch DB, Suryani S, et al: Clinical, molecular, and cel- combined immunodeficiency leads to long-term immunological
lular immunologic findings in patients with SP110-associated recovery and metabolic correction. Sci Transl Med. 3:97ra80,
veno-occlusive disease with immunodeficiency syndrome. J Allergy 2011.
Clin Immunol 130:735–742, e6, 2012. 130. Hacein-Bey-Abina S, Hauer J, Lim A, et al: Efficacy of gene
109. Ganaiem H, Eisenstein EM, Tenenbaum A, et al: The role of therapy for X-linked severe combined immunodeficiency. N Engl
hematopoietic stem cell transplantation in SP110 associated veno- J Med 363:355–364, 2010.
occlusive disease with immunodeficiency syndrome. Pediatr 131. Gaspar HB, Parsley KL, Howe S, et al: Gene therapy of X-linked
Allergy Immunol 24:250–256, 2013. severe combined immunodeficiency by use of a pseudotyped gam-
110. Feske S, Gwack Y, Prakriya M, et al: A mutation in Orai1 causes maretroviral vector. Lancet 364:2181–2187, 2004.
immune deficiency by abrogating CRAC channel function. Nature 132. Thrasher AJ, Hacein-Bey-Abina S, Gaspar HB, et al: Failure of
441:179–185, 2006. SCID-X1 gene therapy in older patients. Blood 105:4255–4257,
111. Picard C, McCarl CA, Papolos A, et al: STIM1 mutation associ- 2005.
ated with a syndrome of immunodeficiency and autoimmunity. N 133. Hacein-Bey-Abina S, Garrigue A, Wang GP, et al: Insertional
Engl J Med 360:1971–1980, 2009. oncogenesis in 4 patients after retrovirus-mediated gene therapy
112. Byun M, Abhyankar A, Lelarge V, et al: Whole-exome sequencing- of SCID-X1. J Clin Invest 118:3132–3142, 2008.
based discovery of STIM1 deficiency in a child with fatal classic 134. Howe SJ, Mansour MR, Schwarzwaelder K, et al: Insertional
Kaposi sarcoma. J Exp Med 207:2307–2312, 2010. mutagenesis combined with acquired somatic mutations causes

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

leukemogenesis following gene therapy of SCID-X1 patients. J 158. Lanzi G, Moratto D, Vairo D, et al: A novel primary human
Clin Invest 118:3143–3150, 2008. immunodeficiency due to deficiency in the WASP-interacting
135. Ming JE, Stiehm ER, Graham JM, Jr: Syndromic immunodeficien- protein WIP. J Exp Med 209:29–34, 2012.
cies: genetic syndromes associated with immune abnormalities. 159. Oskarsdottir S, Persson C, Eriksson BO, et al: Presenting pheno-
Crit Rev Clin Lab Sci 40:587–642, 2003. type in 100 children with the 22q11 deletion syndrome. Eur J
136. Ochs HD, Filipovich AH, Veys P, et al: Wiskott-Aldrich syn- Pediatr 164:146–153, 2005.
drome: diagnosis, clinical and laboratory manifestations, and 160. McDonald-McGinn DM, Sullivan KE: Chromosome 22q11.2
treatment. Biol Blood Marrow Transplant 15:84–90, 2009. deletion syndrome (DiGeorge syndrome/velocardiofacial syn-
137. Pellier I, Dupuis Girod S, Loisel D, et al: Occurrence of aortic drome). Medicine 90:1–18, 2011.
aneurysms in 5 cases of Wiskott-Aldrich syndrome. Pediatrics 161. Green T, Gothelf D, Glaser B, et al: Psychiatric disorders and
127:e498–e504, 2011. intellectual functioning throughout development in velocardiofa-
138. Albert MH, Bittner TC, Nonoyama S, et al: X-linked thrombocy- cial (22q11.2 deletion) syndrome. J Am Acad Child Adolesc Psych
topenia (XLT) due to WAS mutations: clinical characteristics, 48:1060–1068, 2009.
long-term outcome, and treatment options. Blood 115:3231– 162. Markert ML, Devlin BH, Alexieff MJ, et al: Review of 54 patients
3238, 2010. with complete DiGeorge anomaly enrolled in protocols for thymus
139. Notarangelo LD, Mazza C, Giliani S, et al: Missense mutations transplantation: outcome of 44 consecutive transplants. Blood
of the WASP gene cause intermittent X-linked thrombocytopenia. 109:4539–4547, 2007.
Blood 99:2268–2269, 2002. 163. Kar PS, Ogoe B, Poole R, et al: DiGeorge syndrome presenting
140. Mahlaoui N, Pellier I, Mignot C, et al: Characteristics and with hypocalcaemia in adulthood: two case reports and a review.
outcome of early-onset, severe forms of Wiskott-Aldrich syn- J Clin Pathol 58:655–657, 2005.
drome. Blood 121:1510–1516, 2012. 164. Staple L, Andrews T, McDonald-McGinn D, et al: Allergies in
141. Moratto D, Giliani S, Bonfim C, et al: Long-term outcome and patients with chromosome 22q11.2 deletion syndrome (DiGeorge
lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome/velocardiofacial syndrome) and patients with chronic
syndrome treated by hematopoietic cell transplantation in the granulomatous disease. Pediatr Allergy Immunol 16:226–230,
period 1980-2009: an international collaborative study. Blood 2005.
118:1675–1684, 2011. 165. Jawad AF, McDonald-Mcginn DM, Zackai E, et al: Immunologic
142. Thrasher AJ, Burns SO: WASP: a key immunological multitasker. features of chromosome 22q11.2 deletion syndrome (DiGeorge
Nat Rev Immunol 10:182–192, 2010. syndrome/velocardiofacial syndrome). J Pediatr 139:715–723,
143. Wada T, Schurman SH, Garabedian EK, et al: Analysis of T-cell 2001.
repertoire diversity in Wiskott-Aldrich syndrome. Blood 106: 166. McDonald-McGinn DM, Kirschner R, Goldmuntz E, et al: The
3895–3897, 2005. Philadelphia story: the 22q11.2 deletion: report on 250 patients.
144. Dupuis-Girod S, Medioni J, Haddad E, et al: Autoimmunity in Genet Couns 10:11–24, 1999.
Wiskott-Aldrich syndrome: risk factors, clinical features, and 167. Rope AF, Cragun DL, Saal HM, et al: DiGeorge anomaly in the
outcome in a single-center cohort of 55 patients. Pediatrics 111: absence of chromosome 22q11.2 deletion. J Pediatr 155:560–565,
e622–e627, 2003. 2009.
145. Park JY, Shcherbina A, Rosen FS, et al: Phenotypic perturbation 168. Driscoll DA: Molecular and genetic aspects of DiGeorge/
of B cells in the Wiskott-Aldrich syndrome. Clin Exp Immunol velocardiofacial syndrome. Methods Mol Med 126:43–55,
139:297–305, 2005. 2006.
146. Villa A, Notarangelo L, Macchi P, et al: X-linked thrombocyto- 169. Lindsay EA, Botta A, Jurecic V, et al: Congenital heart disease in
penia and Wiskott-Aldrich syndrome are allelic diseases with mice deficient for the DiGeorge syndrome region. Nature
mutations in the WASP gene. Nat Genet 9:414–417, 1995. 401:379–383, 1999.
147. Devriendt K, Kim AS, Mathijs G, et al: Constitutively activating 170. Yagi H, Furutani Y, Hamada H, et al: Role of TBX1 in human
mutation in WASP causes X-linked severe congenital neutropenia. del22q11.2 syndrome. Lancet 362:1366–1373, 2003.
Nat Genet 27:313–317, 2001. 171. Paylor R, Glaser B, Mupo A, et al: Tbx1 haploinsufficiency is
148. Ancliff PJ, Blundell MP, Cory GO, et al: Two novel activating linked to behavioral disorders in mice and humans: implications
mutations in the Wiskott-Aldrich syndrome protein result in con- for 22q11 deletion syndrome. Proc Natl Acad Sci U S A 103:7729–
genital neutropenia. Blood 108:2182–2189, 2006. 7734, 2006.
149. Jin Y, Mazza C, Christie JR, et al: Mutations of the Wiskott- 172. Zweier C, Sticht H, Aydin-Yaylagul I, et al: Human TBX1 mis-
Aldrich Syndrome Protein (WASP): hotspots, effect on transcrip- sense mutations cause gain of function resulting in the same phe-
tion, and translation and phenotype/genotype correlation. Blood notype as 22q11.2 deletions. Am J Hum Genet 80:510–517,
104:4010–4019, 2004. 2007.
150. Massaad MJ, Ramesh N, Le Bras S, et al: A peptide derived from 173. Daw SC, Taylor C, Kraman M, et al: A common region of 10p
the Wiskott-Aldrich syndrome (WAS) protein-interacting protein deleted in DiGeorge and velocardiofacial syndromes. Nat Genet
(WIP) restores WAS protein level and actin cytoskeleton reorga- 13:458–460, 1996.
nization in lymphocytes from patients with WAS mutations that 174. Markert ML, Devlin BH, McCarthy EA: Thymus transplantation.
disrupt WIP binding. J Allergy Clin Immunol 127:998–1005, Clin Immunol 135:236–246, 2010.
e1–2, 2011. 175. Janda A, Sedlacek P, Honig M, et al: Multicenter survey on the
151. Davis BR, Candotti F: Revertant somatic mosaicism in the outcome of transplantation of hematopoietic cells in patients with
Wiskott-Aldrich syndrome. Immunol Res 44:127–131, 2009. the complete form of DiGeorge anomaly. Blood 116:2229–2236,
152. Wengler GS, Parolini O, Fiorini M, et al: A PCR-based non- 2010.
radioactive X-chromosome inactivation assay for genetic counsel- 176. Frank J, Pignata C, Panteleyev AA, et al: Exposing the human
ing in X-linked primary immunodeficiencies. Life Sci 61:1405– nude phenotype. Nature 398:473–474, 1999.
1411, 1997. 177. Vigliano I, Gorrese M, Fusco A, et al: FOXN1 mutation abrogates
153. Parolini O, Ressmann G, Haas OA, et al: X-linked Wiskott- prenatal T-cell development in humans. J Med Genet 48:413–416,
Aldrich syndrome in a girl. N Engl J Med 338:291–295, 1998. 2011.
154. Andreu N, Pujol-Moix N, Martinez-Lostao L, et al: Wiskott- 178. Markert ML, Marques JG, Neven B, et al: First use of thymus
Aldrich syndrome in a female with skewed X-chromosome inac- transplantation therapy for FOXN1 deficiency (nude/SCID): a
tivation. Blood Cells Mol Dis 31:332–337, 2003. report of 2 cases. Blood 117:688–696, 2011.
155. Lutskiy MI, Sasahara Y, Kenney DM, et al: Wiskott-Aldrich syn- 179. Pignata C, Gaetaniello L, Masci AM, et al: Human equivalent of
drome in a female. Blood 100:2763–2768, 2002. the mouse Nude/SCID phenotype: long-term evaluation of immu-
156. Inoue H, Kurosawa H, Nonoyama S, et al: X-linked thrombocy- nologic reconstitution after bone marrow transplantation. Blood
topenia in a girl. Br J Haematol 118:1163–1165, 2002. 97:880–885, 2001.
157. Proust A, Guillet B, Pellier I, et al: Recurrent V75M mutation 180. Swift M, Morrell D, Cromartie E, et al: The incidence and gene
within the Wiskott-Aldrich syndrome protein: description of a frequency of ataxia-telangiectasia in the United States. Am J Hum
homozygous female patient. Eur J Haematol 75:54–59, 2005. Genet 39:573–583, 1986.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases  921.e5

181. Chun HH, Gatti RA: Ataxia-telangiectasia, an evolving pheno- facial anomalies syndrome type 2. Am J Hum Genet 88:796–804,
type. DNA Repair (Amst) 3:1187–1196, 2004. 2011.
182. Chiam LY, Verhagen MM, Haraldsson A, et al: Cutaneous granu- 207. Gineau L, Cognet C, Kara N, et al: Partial MCM4 deficiency in
lomas in ataxia telangiectasia and other primary immunodeficien- patients with growth retardation, adrenal insufficiency, and
cies: reflection of inappropriate immune regulation? Dermatology natural killer cell deficiency. J Clin Invest 122:821–832, 2012.
223:13–19, 2011. 208. Hughes CR, Guasti L, Meimaridou E, et al: MCM4 mutation
183. Schubert R, Reichenbach J, Zielen S: Growth factor deficiency in causes adrenal failure, short stature, and natural killer cell defi-
patients with ataxia telangiectasia. Clin Exp Immunol 140:517– ciency in humans. J Clin Invest 122:814–820, 2012.
519, 2005. 209. Forsburg SL: Eukaryotic MCM proteins: beyond replication ini-
184. Crawford TO, Skolasky RL, Fernandez R, et al: Survival proba- tiation. Microbiol Mol Biol Rev MMBR 68:109–131, 2004.
bility in ataxia telangiectasia. Arch Dis Child 91:610–611, 2006. 210. Kaplan J, De Domenico I, Ward DM: Chediak-Higashi syndrome.
185. Gumy-Pause F, Wacker P, Sappino AP: ATM gene and lymphoid Curr Opin Hematol 15:22–29, 2008.
malignancies. Leukemia 18:238–242, 2004. 211. Nagle DL, Karim MA, Woolf EA, et al: Identification and muta-
186. Schroeder SA, Swift M, Sandoval C, et al: Interstitial lung disease tion analysis of the complete gene for Chediak-Higashi syndrome.
in patients with ataxia-telangiectasia. Pediatr Pulmonol 39:537– Nat Genet 14:307–311, 1996.
543, 2005. 212. Menasche G, Pastural E, Feldmann J, et al: Mutations in RAB27A
187. Morrell D, Cromartie E, Swift M: Mortality and cancer incidence cause Griscelli syndrome associated with haemophagocytic syn-
in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst 77: drome. Nat Genet 25:173–176, 2000.
89–92, 1986. 213. Badolato R, Parolini S: Novel insights from adaptor protein
188. Perlman S, Becker-Catania S, Gatti RA: Ataxia-telangiectasia: 3 complex deficiency. J Allergy Clin Immunol 120:735–741,
diagnosis and treatment. Semin Pediatr Neurol 10:173–182, 2003. 2007.
189. Mallott J, Kwan A, Church J, et al: Newborn screening for SCID 214. Dell’Angelica EC, Shotelersuk V, Aguilar RC, et al: Altered traf-
identifies patients with ataxia telangiectasia. J Clin Immunol ficking of lysosomal proteins in Hermansky-Pudlak syndrome due
33:540–549, 2012. to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell
190. Carbonari M, Cherchi M, Paganelli R, et al: Relative increase of 3:11–21, 1999.
T cells expressing the gamma/delta rather than the alpha/beta 215. Cullinane AR, Curry JA, Carmona-Rivera C, et al: A BLOC-1
receptor in ataxia-telangiectasia. N Engl J Med 322:73–76, 1990. mutation screen reveals that PLDN is mutated in Hermansky-
191. Sadighi Akha AA, Humphrey RL, Winkelstein JA, et al: Oligo-/ Pudlak Syndrome type 9. Am J Hum Genet 88:778–787, 2011.
monoclonal gammopathy and hypergammaglobulinemia in 216. Badolato R, Prandini A, Caracciolo S, et al: Exome sequencing
ataxia-telangiectasia. A study of 90 patients. Medicine 78:370– reveals a pallidin mutation in a Hermansky-Pudlak-like primary
381, 1999. immunodeficiency syndrome. Blood 119:3185–3187, 2012.
192. Noordzij JG, Wulffraat NM, Haraldsson A, et al: Ataxia- 217. Courtois G, Gilmore TD: Mutations in the NF-kappaB signaling
telangiectasia patients presenting with hyper-IgM syndrome. Arch pathway: implications for human disease. Oncogene 25:6831–
Dis Child 94:448–449, 2009. 6843, 2006.
193. Sanal O, Ersoy F, Yel L, et al: Impaired IgG antibody production 218. Hanson EP, Monaco-Shawver L, Solt LA, et al: Hypomorphic
to pneumococcal polysaccharides in patients with ataxia- nuclear factor-kappaB essential modulator mutation database and
telangiectasia. J Clin Immunol 19:326–334, 1999. reconstitution system identifies phenotypic and immunologic
194. Lavin MF: Ataxia-telangiectasia: from a rare disorder to a para- diversity. J Allergy Clin Immunol 122:1169–1177, e16, 2008.
digm for cell signalling and cancer. Nat Rev Mol Cell Biol 9:759– 219. Jain A, Ma CA, Liu S, et al: Specific missense mutations in NEMO
769, 2008. result in hyper-IgM syndrome with hypohydrotic ectodermal dys-
195. Nakamura H, Yasui Y, Saito N, et al: DNA repair defect in AT plasia. Nat Immunol 2:223–228, 2001.
cells and their hypersensitivity to low-dose-rate radiation. Radiat 220. Doffinger R, Smahi A, Bessia C, et al: X-linked anhidrotic ecto-
Res 165:277–282, 2006. dermal dysplasia with immunodeficiency is caused by impaired
196. Taylor AM, Byrd PJ: Molecular pathology of ataxia telangiectasia. NF-kappaB signaling. Nat Genet 27:277–285, 2001.
J Clin Pathol 58:1009–1015, 2005. 221. Kawai T, Nishikomori R, Izawa K, et al: Frequent somatic mosa-
197. Reina-San-Martin B, Chen HT, Nussenzweig A, et al: ATM is icism of NEMO in T cells of patients with X-linked anhidrotic
required for efficient recombination between immunoglobulin ectodermal dysplasia with immunodeficiency. Blood 119:5458–
switch regions. J Exp Med 200:1103–1110, 2004. 5466, 2012.
198. Giardino G, Fusco A, Romano R, et al: Betamethasone therapy 222. Nenci A, Becker C, Wullaert A, et al: Epithelial NEMO links
in ataxia telangiectasia: unraveling the rationale of this serendipi- innate immunity to chronic intestinal inflammation. Nature
tous observation on the basis of the pathogenesis. Eur J Neurol 446:557–561, 2007.
20:740–747, 2013. 223. Permaul P, Narla A, Hornick JL, et al: Allogeneic hematopoietic
199. Renwick A, Thompson D, Seal S, et al: ATM mutations that cause stem cell transplantation for X-linked ectodermal dysplasia and
ataxia-telangiectasia are breast cancer susceptibility alleles. Nat immunodeficiency: case report and review of outcomes. Immunol
Genet 38:873–875, 2006. Res 44:89–98, 2009.
200. Frappart PO, Tong WM, Demuth I, et al: An essential function 224. Courtois G, Smahi A, Reichenbach J, et al: A hypermorphic Ikap-
for NBS1 in the prevention of ataxia and cerebellar defects. Nat paBalpha mutation is associated with autosomal dominant anhi-
Med 11:538–544, 2005. drotic ectodermal dysplasia and T cell immunodeficiency. J Clin
201. Taylor AM, Groom A, Byrd PJ: Ataxia-telangiectasia-like disorder Invest 112:1108–1115, 2003.
(ATLD)—its clinical presentation and molecular basis. DNA 225. Lopez-Granados E, Keenan JE, Kinney MC, et al: A novel muta-
Repair (Amst) 3:1219–1225, 2004. tion in NFKBIA/IKBA results in a degradation-resistant N-
202. Peron S, Metin A, Gardes P, et al: Human PMS2 deficiency is truncated protein and is associated with ectodermal dysplasia with
associated with impaired immunoglobulin class switch recombi- immunodeficiency. Hum Mutat 29:861–868, 2008.
nation. J Exp Med 205:2465–2472, 2008. 226. Puel A, Yang K, Ku CL, et al: Heritable defects of the human TLR
203. Gardes P, Forveille M, Alyanakian MA, et al: Human MSH6 signalling pathways. J Endotoxin Res 11:220–224, 2005.
deficiency is associated with impaired antibody maturation. J 227. Ku CL, von Bernuth H, Picard C, et al: Selective predisposition
Immunol 188:2023–2029, 2012. to bacterial infections in IRAK-4-deficient children: IRAK-4-de-
204. Ellis NA, Groden J, Ye TZ, et al: The Bloom’s syndrome gene pendent TLRs are otherwise redundant in protective immunity. J
product is homologous to RecQ helicases. Cell 83:655–666, Exp Med 204:2407–2422, 2007.
1995. 228. Picard C, Casanova JL, Puel A: Infectious diseases in patients with
205. Hansen RS, Wijmenga C, Luo P, et al: The DNMT3B DNA meth- IRAK-4, MyD88, NEMO, or IkappaBalpha deficiency. Clin
yltransferase gene is mutated in the ICF immunodeficiency syn- Microbiol Rev 24:490–497, 2011.
drome. Proc Natl Acad Sci U S A 96:14412–14417, 1999. 229. Picard C, von Bernuth H, Ghandil P, et al: Clinical features and
206. de Greef JC, Wang J, Balog J, et al: Mutations in ZBTB24 are outcome of patients with IRAK-4 and MyD88 deficiency. Medi-
associated with immunodeficiency, centromeric instability, and cine 89:403–425, 2010.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

230. Hernandez PA, Gorlin RJ, Lukens JN, et al: Mutations in the 253. Ridanpaa M, van Eenennaam H, Pelin K, et al: Mutations in the
chemokine receptor gene CXCR4 are associated with WHIM RNA component of RNase MRP cause a pleiotropic human
syndrome, a combined immunodeficiency disease. Nat Genet disease, cartilage-hair hypoplasia. Cell 104:195–203, 2001.
34:70–74, 2003. 254. Moshous D, Meyts I, Fraitag S, et al: Granulomatous inflamma-
231. Gulino AV, Moratto D, Sozzani S, et al: Altered leukocyte response tion in cartilage-hair hypoplasia: risks and benefits of anti-TNF-
to CXCL12 in patients with warts hypogammaglobulinemia, alpha mAbs. J Allergy Clin Immunol 128:847–853, 2011.
infections, myelokathexis (WHIM) syndrome. Blood 104:444– 255. Kavadas FD, Giliani S, Gu Y, et al: Variability of clinical and
452, 2004. laboratory features among patients with ribonuclease mitochon-
232. Tassone L, Moratto D, Vermi W, et al: Defect of plasmacytoid drial RNA processing endoribonuclease gene mutations. J Allergy
dendritic cells in warts, hypogammaglobulinemia, infections, Clin Immunol 122:1178–1184, 2008.
myelokathexis (WHIM) syndrome patients. Blood 116:4870– 256. Roifman CM, Gu Y, Cohen A: Mutations in the RNA component
4873, 2010. of RNase mitochondrial RNA processing might cause Omenn
233. Mc Guire PJ, Cunningham-Rundles C, Ochs H, et al: Oligoclonal- syndrome. J Allergy Clin Immunol 117:897–903, 2006.
ity, impaired class switch and B-cell memory responses in WHIM 257. de la Fuente MA, Recher M, Rider NL, et al: Reduced thymic
syndrome. Clin Immunol 135:412–421, 2010. output, cell cycle abnormalities, and increased apoptosis of T
234. McDermott DH, Liu Q, Ulrick J, et al: The CXCR4 antagonist lymphocytes in patients with cartilage-hair hypoplasia. J Allergy
plerixafor corrects panleukopenia in patients with WHIM syn- Clin Immunol 128:139–146, 2011.
drome. Blood 118:4957–4962, 2011. 258. Bordon V, Gennery AR, Slatter MA, et al: Clinical and immuno-
235. Buckley RH, Wray BB, Belmaker EZ: Extreme hyperimmuno- logic outcome of patients with cartilage hair hypoplasia after
globulinemia E and undue susceptibility to infection. Pediatrics hematopoietic stem cell transplantation. Blood 116:27–35,
49:59–70, 1972. 2010.
236. Sowerwine KJ, Holland SM, Freeman AF: Hyper-IgE syndrome 259. Saraiva JM, Dinis A, Resende C, et al: Schimke immuno-osseous
update. Ann N Y Acad Sci 1250:25–32, 2012. dysplasia: case report and review of 25 patients. J Med Genet
237. Ling JC, Freeman AF, Gharib AM, et al: Coronary artery aneu- 36:786–789, 1999.
rysms in patients with hyper IgE recurrent infection syndrome. 260. Boerkoel CF, Takashima H, John J, et al: Mutant chromatin
Clin Immunol 122:255–258, 2007. remodeling protein SMARCAL1 causes Schimke immuno-osseous
238. Minegishi Y, Saito M, Tsuchiya S, et al: Dominant-negative muta- dysplasia. Nat Genet 30:215–220, 2002.
tions in the DNA-binding domain of STAT3 cause hyper-IgE syn- 261. Watkins D, Rosenblatt DS: Inborn errors of cobalamin absorption
drome. Nature 448:1058–1062, 2007. and metabolism. Am J Med Genet 157:33–44, 2011.
239. Holland SM, DeLeo FR, Elloumi HZ, et al: STAT3 mutations in 262. Kaikov Y, Wadsworth LD, Hall CA, et al: Transcobalamin II
the hyper-IgE syndrome. N Engl J Med 357:1608–1619, 2007. deficiency: case report and review of the literature. Eur J Pediatr
240. Minegishi Y, Saito M, Nagasawa M, et al: Molecular explanation 150:841–843, 1991.
for the contradiction between systemic Th17 defect and localized 263. Zittoun J, Fischer A, Marquet J, et al: Megaloblastic anemia and
bacterial infection in hyper-IgE syndrome. J Exp Med 206:1291– immune abnormalities in a patient with methionine synthase defi-
1301, 2009. ciency. Acta Paediatr Scand 76:991–998, 1987.
241. Grimbacher B, Schaffer AA, Holland SM, et al: Genetic linkage 264. Borzutzky A, Crompton B, Bergmann AK, et al: Reversible severe
of hyper-IgE syndrome to chromosome 4. Am J Hum Genet 65: combined immunodeficiency phenotype secondary to a mutation
735–744, 1999. of the proton-coupled folate transporter. Clin Immunol 133:287–
242. Woellner C, Gertz EM, Schaffer AA, et al: Mutations in STAT3 294, 2009.
and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin 265. Keller MD, Ganesh J, Heltzer M, et al: Severe combined immu-
Immunol 125:424–432, e8, 2010. nodeficiency resulting from mutations in MTHFD1. Pediatrics
243. Gennery AR, Flood TJ, Abinun M, et al: Bone marrow transplan- 131:e629–e634, 2013.
tation does not correct the hyper IgE syndrome. Bone Marrow 266. Vinh DC, Patel SY, Uzel G, et al: Autosomal dominant and spo-
Transplant 25:1303–1305, 2000. radic monocytopenia with susceptibility to mycobacteria, fungi,
244. Goussetis E, Peristeri I, Kitra V, et al: Successful long-term papillomaviruses, and myelodysplasia. Blood 115:1519–1529,
immunologic reconstitution by allogeneic hematopoietic stem 2010.
cell transplantation cures patients with autosomal dominant 267. Bigley V, Haniffa M, Doulatov S, et al: The human syndrome of
hyper-IgE syndrome. J Allergy Clin Immunol 126:392–394, dendritic cell, monocyte, B and NK lymphoid deficiency. J Exp
2010. Med 208:227–234, 2011.
245. Minegishi Y, Saito M, Morio T, et al: Human tyrosine kinase 2 268. Calvo KR, Vinh DC, Maric I, et al: Myelodysplasia in autosomal
deficiency reveals its requisite roles in multiple cytokine signals dominant and sporadic monocytopenia immunodeficiency syn-
involved in innate and acquired immunity. Immunity 25:745–755, drome: diagnostic features and clinical implications. Haemato-
2006. logica 96:1221–1225, 2011.
246. Kilic SS, Hacimustafaoglu M, Boisson-Dupuis S, et al: A patient 269. Ishida H, Imai K, Honma K, et al: GATA-2 anomaly and clinical
with tyrosine kinase 2 deficiency without hyper-IgE syndrome. J phenotype of a sporadic case of lymphedema, dendritic cell,
Pediatr 160:1055–1057, 2012. monocyte, B- and NK-cell (DCML) deficiency, and myelodyspla-
247. Puel A, Cypowyj S, Marodi L, et al: Inborn errors of human IL-17 sia. Eur J Pediatr 171:1273–1276, 2012.
immunity underlie chronic mucocutaneous candidiasis. Curr Opin 270. Mace EM, Hsu AP, Monaco-Shawver L, et al: Mutations in
Allergy Clin Immunol 12:616–622, 2012. GATA2 cause human NK cell deficiency with specific loss of the
248. Puel A, Cypowyj S, Bustamante J, et al: Chronic mucocutaneous CD56(bright) subset. Blood 121:2669–2677, 2013.
candidiasis in humans with inborn errors of interleukin-17 immu- 271. Dickinson RE, Griffin H, Bigley V, et al: Exome sequencing identi-
nity. Science 332:65–68, 2011. fies GATA-2 mutation as the cause of dendritic cell, monocyte, B
249. Liu L, Okada S, Kong XF, et al: Gain-of-function human STAT1 and NK lymphoid deficiency. Blood 118:2656–2658, 2011.
mutations impair IL-17 immunity and underlie chronic mucocu- 272. Hsu AP, Sampaio EP, Khan J, et al: Mutations in GATA2 are
taneous candidiasis. J Exp Med 208:1635–1648, 2011. associated with the autosomal dominant and sporadic monocyto-
250. van de Veerdonk FL, Plantinga TS, Hoischen A, et al: STAT1 penia and mycobacterial infection (MonoMAC) syndrome. Blood
mutations in autosomal dominant chronic mucocutaneous candi- 118:2653–2655, 2011.
diasis. N Engl J Med 365:54–61, 2011. 273. Kazenwadel J, Secker GA, Liu YJ, et al: Loss-of-function germline
251. Glocker EO, Hennigs A, Nabavi M, et al: A homozygous CARD9 GATA2 mutations in patients with MDS/AML or MonoMAC
mutation in a family with susceptibility to fungal infections. N syndrome and primary lymphedema reveal a key role for GATA2
Engl J Med 361:1727–1735, 2009. in the lymphatic vasculature. Blood 119:1283–1291, 2012.
252. Thiel CT, Rauch A: The molecular basis of the cartilage-hair 274. Rodrigues NP, Janzen V, Forkert R, et al: Haploinsufficiency of
hypoplasia-anauxetic dysplasia spectrum. Best Pract Res Clin GATA-2 perturbs adult hematopoietic stem-cell homeostasis.
Endocrinol Metab 25:131–142, 2011. Blood 106:477–484, 2005.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases  921.e7

275. Hsu AP, Johnson KD, Falcone EL, et al: GATA2 haploinsuffi- 299. Chun HJ, Zheng L, Ahmad M, et al: Pleiotropic defects in lym-
ciency caused by mutations in a conserved intronic element leads phocyte activation caused by caspase-8 mutations lead to human
to MonoMAC syndrome. Blood 121:3830–3837, 2013. immunodeficiency. Nature 419:395–399, 2002.
276. Cuellar-Rodriguez J, Gea-Banacloche J, Freeman AF, et al: Suc- 300. Wang J, Zheng L, Lobito A, et al: Inherited human Caspase 10
cessful allogeneic hematopoietic stem cell transplantation for mutations underlie defective lymphocyte and dendritic cell apop-
GATA2 deficiency. Blood 118:3715–3720, 2011. tosis in autoimmune lymphoproliferative syndrome type II. Cell
277. An autoimmune disease, APECED, caused by mutations in a novel 98:47–58, 1999.
gene featuring two PHD-type zinc-finger domains. Nat Genet 301. Caminha I, Fleisher TA, Hornung RL, et al: Using biomarkers to
17:399–403, 1997. predict the presence of FAS mutations in patients with features of
278. Nagamine K, Peterson P, Scott HS, et al: Positional cloning of the the autoimmune lymphoproliferative syndrome. J Allergy Clin
APECED gene. Nat Genet 17:393–398, 1997. Immunol 125:946–949, e6, 2010.
279. Anderson MS, Venanzi ES, Klein L, et al: Projection of an immu- 302. Oliveira JB, Bidere N, Niemela JE, et al: NRAS mutation causes
nological self shadow within the thymus by the aire protein. a human autoimmune lymphoproliferative syndrome. Proc Natl
Science 298:1395–1401, 2002. Acad Sci U S A 104:8953–8958, 2007.
280. Mathis D, Benoist C: Aire. Annu Rev Immunol 27:287–312, 2009. 303. Niemela JE, Lu L, Fleisher TA, et al: Somatic KRAS mutations
281. Kisand K, Link M, Wolff AS, et al: Interferon autoantibodies associated with a human nonmalignant syndrome of autoimmu-
associated with AIRE deficiency decrease the expression of IFN- nity and abnormal leukocyte homeostasis. Blood 117:2883–2886,
stimulated genes. Blood 112:2657–2666, 2008. 2011.
282. Kisand K, Boe Wolff AS, Podkrajsek KT, et al: Chronic mucocu- 304. Takagi M, Shinoda K, Piao J, et al: Autoimmune lymphoprolifera-
taneous candidiasis in APECED or thymoma patients correlates tive syndrome-like disease with somatic KRAS mutation. Blood
with autoimmunity to Th17-associated cytokines. J Exp Med 117:2887–2890, 2011.
207:299–308, 2010. 305. Rao VK, Oliveira JB: How I treat autoimmune lymphoprolifera-
283. Puel A, Doffinger R, Natividad A, et al: Autoantibodies against tive syndrome. Blood 118:5741–5751, 2011.
IL-17A, IL-17F, and IL-22 in patients with chronic mucocutane- 306. Lohr NJ, Molleston JP, Strauss KA, et al: Human ITCH E3 ubiq-
ous candidiasis and autoimmune polyendocrine syndrome type I. uitin ligase deficiency causes syndromic multisystem autoimmune
J Exp Med 207:291–297, 2010. disease. Am J Hum Genet 86:447–453, 2010.
284. Josefowicz SZ, Lu LF, Rudensky AY: Regulatory T cells: mecha- 307. Parravicini V, Field AC, Tomlinson PD, et al: Itch-/- alphabeta and
nisms of differentiation and function. Annu Rev Immunol gammadelta T cells independently contribute to autoimmunity in
30:531–564, 2012. Itchy mice. Blood 111:4273–7282, 2008.
285. Rudensky AY: Regulatory T cells and Foxp3. Immunol Rev 241: 308. de Saint Basile G, Menasche G, Fischer A: Molecular mechanisms
260–268, 2011. of biogenesis and exocytosis of cytotoxic granules. Nat Rev
286. Chatila TA, Blaeser F, Ho N, et al: JM2, encoding a fork head- Immunol 10:568–579, 2010.
related protein, is mutated in X-linked autoimmunity-allergic dis- 309. de Saint Basile G, Menasche G, Latour S: Inherited defects causing
regulation syndrome. J Clin Invest 106:R75–R81, 2000. hemophagocytic lymphohistiocytic syndrome. Ann N Y Acad Sci
287. Wildin RS, Ramsdell F, Peake J, et al: X-linked neonatal diabetes 1246:64–76, 2011.
mellitus, enteropathy and endocrinopathy syndrome is the human 310. Henter JI, Horne A, Arico M, et al: HLH-2004: Diagnostic and
equivalent of mouse scurfy. Nat Genet 27:18–20, 2001. therapeutic guidelines for hemophagocytic lymphohistiocytosis.
288. Barzaghi F, Passerini L, Bacchetta R: Immune dysregulation, poly- Pediatr Blood Cancer 48:124–131, 2007.
endocrinopathy, enteropathy, x-linked syndrome: a paradigm of 311. Jordan MB, Allen CE, Weitzman S, et al: How I treat hemophago-
immunodeficiency with autoimmunity. Front Immunol 3:211, cytic lymphohistiocytosis. Blood 118:4041–4052, 2011.
2012. 312. Marsh RA, Jordan MB, Filipovich AH: Reduced-intensity condi-
289. Burroughs LM, Torgerson TR, Storb R, et al: Stable hematopoi- tioning haematopoietic cell transplantation for haemophagocytic
etic cell engraftment after low-intensity nonmyeloablative condi- lymphohistiocytosis: an important step forward. Br J Haematol
tioning in patients with immune dysregulation, polyendocrinopathy, 154:556–563, 2011.
enteropathy, X-linked syndrome. J Allergy Clin Immunol 126: 313. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al: Perforin gene
1000–1005, 2010. defects in familial hemophagocytic lymphohistiocytosis. Science
290. Caudy AA, Reddy ST, Chatila T, et al: CD25 deficiency causes 286:1957–1959, 1999.
an immune dysregulation, polyendocrinopathy, enteropathy, X- 314. Feldmann J, Callebaut I, Raposo G, et al: Munc13-4 is essential
linked-like syndrome, and defective IL-10 expression from CD4 for cytolytic granules fusion and is mutated in a form of familial
lymphocytes. J Allergy Clin Immunol 119:482–487, 2007. hemophagocytic lymphohistiocytosis (FHL3). Cell 115:461–473,
291. Sharfe N, Dadi HK, Shahar M, et al: Human immune disorder 2003.
arising from mutation of the alpha chain of the interleukin-2 315. zur Stadt U, Rohr J, Seifert W, et al: Familial hemophagocytic
receptor. Proc Natl Acad Sci U S A 94:3168–3171, 1997. lymphohistiocytosis type 5 (FHL-5) is caused by mutations in
292. Kofoed EM, Hwa V, Little B, et al: Growth hormone insensitivity Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet
associated with a STAT5b mutation. N Engl J Med 349:1139– 85:482–492, 2009.
1147, 2003. 316. Cote M, Menager MM, Burgess A, et al: Munc18-2 deficiency
293. Nadeau K, Hwa V, Rosenfeld RG: STAT5b deficiency: an unsus- causes familial hemophagocytic lymphohistiocytosis type 5 and
pected cause of growth failure, immunodeficiency, and severe pul- impairs cytotoxic granule exocytosis in patient NK cells. J Clin
monary disease. J Pediatr 158:701–708, 2011. Invest 119:3765–3773, 2009.
294. Teachey DT: New advances in the diagnosis and treatment of 317. Coffey AJ, Brooksbank RA, Brandau O, et al: Host response to
autoimmune lymphoproliferative syndrome. Curr Opin Pediatr EBV infection in X-linked lymphoproliferative disease results
24:1–8, 2012. from mutations in an SH2-domain encoding gene. Nat Genet
295. Dowdell KC, Niemela JE, Price S, et al: Somatic FAS mutations 20:129–135, 1998.
are common in patients with genetically undefined autoimmune 318. Sayos J, Wu C, Morra M, et al: The X-linked lymphoproliferative-
lymphoproliferative syndrome. Blood 115:5164–5169, 2010. disease gene product SAP regulates signals induced through the
296. Holzelova E, Vonarbourg C, Stolzenberg MC, et al: Autoimmune co-receptor SLAM. Nature 395:462–469, 1998.
lymphoproliferative syndrome with somatic Fas mutations. N 319. Parolini S, Bottino C, Falco M, et al: X-linked lymphoproliferative
Engl J Med 351:1409–1418, 2004. disease. 2B4 molecules displaying inhibitory rather than activating
297. Del-Rey M, Ruiz-Contreras J, Bosque A, et al: A homozygous Fas function are responsible for the inability of natural killer cells to
ligand gene mutation in a patient causes a new type of autoim- kill Epstein-Barr virus-infected cells. J Exp Med 192:337–346,
mune lymphoproliferative syndrome. Blood 108:1306–1312, 2006. 2000.
298. Bolze A, Byun M, McDonald D, et al: Whole-exome-sequencing- 320. Qi H, Cannons JL, Klauschen F, et al: SAP-controlled T-B cell
based discovery of human FADD deficiency. Am J Hum Genet interactions underlie germinal centre formation. Nature 455:764–
87:873–881, 2010. 769, 2008.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

321. Rigaud S, Fondaneche MC, Lambert N, et al: XIAP deficiency in 344. Kieft R, Capewell P, Turner CM, et al: Mechanism of Trypano-
humans causes an X-linked lymphoproliferative syndrome. Nature soma brucei gambiense (group 1) resistance to human trypano-
444:110–114, 2006. some lytic factor. Proc Natl Acad Sci U S A 107:16137–16141,
322. Booth C, Gilmour KC, Veys P, et al: X-linked lymphoproliferative 2010.
disease due to SAP/SH2D1A deficiency: a multicenter study on the 345. Molina-Portela MP, Samanovic M, Raper J: Distinct roles of apo-
manifestations, management and outcome of the disease. Blood lipoprotein components within the trypanosome lytic factor
117:53–62, 2011. complex revealed in a novel transgenic mouse model. J Exp Med
323. Filipovich AH, Zhang K, Snow AL, et al: X-linked lymphoprolif- 205:1721–1728, 2008.
erative syndromes: brothers or distant cousins? Blood 116:3398– 346. Pays E, Vanhollebeke B: Human innate immunity against
3408, 2010. African trypanosomes. Curr Opin Immunol 21:493–498,
324. Yang X, Kanegane H, Nishida N, et al: Clinical and genetic char- 2009.
acteristics of XIAP deficiency in Japan. J Clin Immunol 32:411– 347. Vanhollebeke B, Truc P, Poelvoorde P, et al: Human Trypanosoma
420, 2012. evansi infection linked to a lack of apolipoprotein L-I. N Engl J
325. Marsh RA, Rao K, Satwani P, et al: Allogeneic hematopoietic cell Med 355:2752–2756, 2006.
transplantation for XIAP deficiency: an international survey 348. Wheeler RJ: The trypanolytic factor-mechanism, impacts and
reveals poor outcomes. Blood 121:877–883, 2013. applications. Trends Parasitol 26:457–464, 2010.
326. Huck K, Feyen O, Niehues T, et al: Girls homozygous for an IL- 349. Genovese G, Friedman DJ, Ross MD, et al: Association of trypa-
2-inducible T cell kinase mutation that leads to protein deficiency nolytic ApoL1 variants with kidney disease in African Americans.
develop fatal EBV-associated lymphoproliferation. J Clin Invest Science 329:841–845, 2010.
119:1350–1358, 2009. 350. Khan WN: Colonel Bruton’s kinase defined the molecular basis of
327. Salzer E, Daschkey S, Choo S, et al: Combined immunodeficiency X-linked agammaglobulinemia, the first primary immunodefi-
with life-threatening EBV-associated lymphoproliferative disorder ciency. J Immunol 188:2933–2935, 2012.
in patients lacking functional CD27. Haematologica 98:473–478, 351. Lee PP, Chen TX, Jiang LP, et al: Clinical characteristics and
2013. genotype-phenotype correlation in 62 patients with X-linked
328. van Montfrans JM, Hoepelman AI, Otto S, et al: CD27 deficiency agammaglobulinemia. J Clin Immunol 30:121–131, 2010.
is associated with combined immunodeficiency and persistent 352. Lopez-Granados E, Perez de Diego R, Ferreira Cerdan A, et al: A
symptomatic EBV viremia. J Allergy Clin Immunol 129:787–793, genotype-phenotype correlation study in a group of 54 patients
e6, 2012. with X-linked agammaglobulinemia. J Allergy Clin Immunol
329. Grier JT, Forbes LR, Monaco-Shawver L, et al: Human 116:690–697, 2005.
immunodeficiency-causing mutation defines CD16 in spontaneous 353. Winkelstein JA, Marino MC, Lederman HM, et al: X-linked
NK cell cytotoxicity. J Clin Invest 122:3769–3780, 2012. agammaglobulinemia: report on a United States registry of 201
330. Casanova JL, Abel L: Human genetics of infectious diseases: a patients. Medicine (Baltimore) 85:193–202, 2006.
unified theory. EMBO J 26:915–922, 2007. 354. Conley ME, Broides A, Hernandez-Trujillo V, et al: Genetic analy-
331. Al-Muhsen S, Casanova JL: The genetic heterogeneity of mende- sis of patients with defects in early B-cell development. Immunol
lian susceptibility to mycobacterial diseases. J Allergy Clin Rev 203:216–234, 2005.
Immunol 122:1043–1051, 2008. 355. Sigmon JR, Kasasbeh E, Krishnaswamy G: X-linked agamma-
332. Hoshina T, Takada H, Sasaki-Mihara Y, et al: Clinical and host globulinemia diagnosed late in life: case report and review of the
genetic characteristics of Mendelian susceptibility to mycobacte- literature. Clin Mol Allergy 6:5, 2008.
rial diseases in Japan. J Clin Immunol 31:309–314, 2011. 356. Ferrari S, Lougaris V, Caraffi S, et al: Mutations of the Igbeta gene
333. Lee WI, Huang JL, Wu TS, et al: Patients with inhibitory and cause agammaglobulinemia in man. J Exp Med 204:2047–2051,
neutralizing auto-antibodies to interferon-gamma resemble the 2007.
sporadic adult-onset phenotype of Mendelian Susceptibility to 357. Conley ME, Dobbs AK, Quintana AM, et al: Agammaglobulin-
Mycobacterial Disease (MSMD) lacking Bacille Calmette-Guerin emia and absent B lineage cells in a patient lacking the p85alpha
(BCG)-induced diseases. Immunobiology 218:762–771, 2013. subunit of PI3K. J Exp Med 209:463–470, 2012.
334. Wang LH, Yen CL, Chang TC, et al: Impact of molecular diag- 358. Sawada A, Takihara Y, Kim JY, et al: A congenital mutation of
nosis on treating Mendelian susceptibility to mycobacterial dis- the novel gene LRRC8 causes agammaglobulinemia in humans. J
eases. J Microbiol Immunol Infect 45:411–417, 2012. Clin Invest 112:1707–1713, 2003.
335. Gober MD, Rady PL, He Q, et al: Novel homozygous frameshift 359. Bonilla FA, Geha RS: Common variable immunodeficiency.
mutation of EVER1 gene in an epidermodysplasia verruciformis Pediatr Res 65:13R–19R, 2009.
patient. J Invest Dermatol 127:817–820, 2007. 360. Chapel H, Lucas M, Lee M, et al: Common variable immunode-
336. Orth G: Host defenses against human papillomaviruses: lessons ficiency disorders: division into distinct clinical phenotypes. Blood
from epidermodysplasia verruciformis. Curr Top Microbiol 112:277–286, 2008.
Immunol 321:59–83, 2008. 361. Chapel H, Lucas M, Patel S, et al: Confirmation and improvement
337. Castro-Perez GA, Sorin I, Bravo AI: Mazzuoccolo LD. Acquired of criteria for clinical phenotyping in common variable immuno-
epidermodysplasia verruciformis in a patient with congenital HIV deficiency disorders in replicate cohorts. J Allergy Clin Immunol
infection. Actas Dermosifiliogr 104:731–733, 2013. 130:1197–1198, e9, 2012.
338. Kaushal A, Silver S, Kasper K, et al: Epidermodysplasia verruci- 362. Cunningham-Rundles C, Maglione PJ: Common variable
formis in an HIV-infected man: a case report and review of the immunodeficiency. J Allergy Clin Immunol 129:1425–1426, e3,
literature. Top Antivir Med 20:173–179, 2012. 2012.
339. Herman M, Ciancanelli M, Ou YH, et al: Heterozygous TBK1 363. Wehr C, Kivioja T, Schmitt C, et al: The EUROclass trial: defining
mutations impair TLR3 immunity and underlie herpes simplex subgroups in common variable immunodeficiency. Blood 111:77–
encephalitis of childhood. J Exp Med 209:1567–1582, 2012. 85, 2008.
340. Perez de Diego R, Sancho-Shimizu V, Lorenzo L, et al: Human 364. Dhalla F, da Silva SP, Lucas M, et al: Review of gastric cancer risk
TRAF3 adaptor molecule deficiency leads to impaired Toll-like factors in patients with common variable immunodeficiency dis-
receptor 3 response and susceptibility to herpes simplex encepha- orders, resulting in a proposal for a surveillance programme. Clin
litis. Immunity 33:400–411, 2010. Exp Immunol 165:1–7, 2011.
341. Sancho-Shimizu V, Perez de Diego R, Lorenzo L, et al: Herpes 365. Morimoto Y, Routes JM: Granulomatous disease in common
simplex encephalitis in children with autosomal recessive and variable immunodeficiency. Curr Allergy Asthma Rep 5:370–375,
dominant TRIF deficiency. J Clin Invest 121:4889–4902, 2011. 2005.
342. Sancho-Shimizu V, Zhang SY, Abel L, et al: Genetic susceptibility 366. Park JH, Levinson AI: Granulomatous-lymphocytic interstitial
to herpes simplex virus 1 encephalitis in mice and humans. Curr lung disease (GLILD) in common variable immunodeficiency
Opin Allergy Clin Immunol 7:495–505, 2007. (CVID). Clin Immunol 134:97–103, 2010.
343. Zhang SY, Jouanguy E, Ugolini S, et al: TLR3 deficiency in 367. Agondi RC, Barros MT, Rizzo LV, et al: Allergic asthma in
patients with herpes simplex encephalitis. Science 317:1522–1527, patients with common variable immunodeficiency. Allergy 65:510–
2007. 515, 2010.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases  921.e9

368. Khodadad A, Aghamohammadi A, Parvaneh N, et al: Gastroin- 391. Fried AJ, Rauter I, Dillon SR, et al: Functional analysis of trans-
testinal manifestations in patients with common variable immu- membrane activator and calcium-modulating cyclophilin ligand
nodeficiency. Dig Dis Sci 52:2977–2983, 2007. interactor (TACI) mutations associated with common variable
369. Podjasek JC, Abraham RS: Autoimmune cytopenias in common immunodeficiency. J Allergy Clin Immunol 128:226–228, e1, 2011.
variable immunodeficiency. Front Immunol 3:189, 2012. 392. Salzer U, Warnatz K, Peter HH: Common variable
370. Warnatz K, Voll RE: Pathogenesis of autoimmunity in common immunodeficiency—an update. Arthritis Res Ther 14:223, 2012.
variable immunodeficiency. Front Immunol 3:210, 2012. 393. Salzer U, Bacchelli C, Buckridge S, et al: Relevance of biallelic
371. Cunningham-Rundles C: The many faces of common variable versus monoallelic TNFRSF13B mutations in distinguishing
immunodeficiency. Hematology Am Soc Hematol Educ Program disease-causing from risk-increasing TNFRSF13B variants in anti-
2012:301–305, 2012. body deficiency syndromes. Blood 113:1967–1976, 2009.
372. Resnick ES, Moshier EL, Godbold JH, et al: Morbidity and mor- 394. Orange JS, Glessner JT, Resnick E, et al: Genome-wide association
tality in common variable immune deficiency over 4 decades. identifies diverse causes of common variable immunodeficiency. J
Blood 119:1650–1657, 2012. Allergy Clin Immunol 127:1360–1367, e6, 2011.
373. Salavoura K, Kolialexi A, Tsangaris G, et al: Development of 395. Yong PF, Salzer U, Grimbacher B: The role of costimulation in
cancer in patients with primary immunodeficiencies. Anticancer antibody deficiencies: ICOS and common variable immunodefi-
Res 28:1263–1269, 2008. ciency. Immunol Rev 229:101–113, 2009.
374. Al Kindi M, Mundy J, Sullivan T, et al: Utility of peripheral blood 396. Kanegane H, Agematsu K, Futatani T, et al: Novel mutations in
B cell subsets analysis in common variable immunodeficiency. Clin a Japanese patient with CD19 deficiency. Genes Immun 8:663–
Exp Immunol 167:275–281, 2012. 670, 2007.
375. Bright P, Grigoriadou S, Kamperidis P, et al: Changes in B cell 397. van Zelm MC, Reisli I, van der Burg M, et al: An antibody-
immunophenotype in common variable immunodeficiency: cause deficiency syndrome due to mutations in the CD19 gene. N Engl
or effect—is bronchiectasis indicative of undiagnosed immunode- J Med 354:1901–1912, 2006.
ficiency? Clin Exp Immunol 171:195–200, 2013. 398. Frank MM: CD21 deficiency, complement, and the development
376. Koopmans W, Woon ST, Zeng IS, et al: Variability of memory B of common variable immunodeficiency. J Allergy Clin Immunol
cell markers in a cohort of common variable immune deficiency 129:811–813, 2012.
patients over six months. Scand J Immunol 77:470–475, 2013. 399. Thiel J, Kimmig L, Salzer U, et al: Genetic CD21 deficiency is
377. Piqueras B, Lavenu-Bombled C, Galicier L, et al: Common vari- associated with hypogammaglobulinemia. J Allergy Clin Immunol
able immunodeficiency patient classification based on impaired B 129:801–810, e6, 2012.
cell memory differentiation correlates with clinical aspects. J Clin 400. van Zelm MC, Smet J, Adams B, et al: CD81 gene defect in
Immunol 23:385–400, 2003. humans disrupts CD19 complex formation and leads to antibody
378. Warnatz K, Denz A, Drager R, et al: Severe deficiency of switched deficiency. J Clin Invest 120:1265–1274, 2010.
memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups of patients 401. Warnatz K, Salzer U, Rizzi M, et al: B-cell activating factor recep-
with common variable immunodeficiency: a new approach to tor deficiency is associated with an adult-onset antibody deficiency
classify a heterogeneous disease. Blood 99:1544–1551, 2002. syndrome in humans. Proc Natl Acad Sci U S A 106:13945–
379. Warnatz K, Schlesier M: Flowcytometric phenotyping of common 13950, 2009.
variable immunodeficiency. Cytometry B Clin Cytom 74:261– 402. Di Renzo M, Pasqui AL, Voltolini L, et al: Myelodysplasia and
271, 2008. Good syndrome. A case report. Clin Exp Med 8:171–173, 2008.
380. Schatorje EJ, Gemen EF, Driessen GJ, et al: Age-matched reference 403. Federico P, Imbimbo M, Buonerba C, et al: Is hypogammaglobu-
values for B-lymphocyte subpopulations and CVID classifications linemia a constant feature in Good’s syndrome? Int J Immuno-
in children. Scand J Immunol 74:502–510, 2011. pathol Pharmacol 23:1275–1279, 2010.
381. van de Ven AA, van de Corput L, van Tilburg CM, et al: Lym- 404. Kelesidis T, Yang O: Good’s syndrome remains a mystery after 55
phocyte characteristics in children with common variable immu- years: A systematic review of the scientific evidence. Clin Immunol
nodeficiency. Clin Immunol 135:63–71, 2010. 135:347–363, 2010.
382. Vlkova M, Fronkova E, Kanderova V, et al: Characterization of 405. Kitamura A, Takiguchi Y, Tochigi N, et al: Durable hypogam-
lymphocyte subsets in patients with common variable immunode- maglobulinemia associated with thymoma (Good syndrome).
ficiency reveals subsets of naive human B cells marked by CD24 Intern Med 48:1749–1752, 2009.
expression. J Immunol 185:6431–6438, 2010. 406. Ogoshi T, Ishimoto H, Yatera K, et al: A case of Good syndrome
383. Bateman EA, Ayers L, Sadler R, et al: T cell phenotypes in patients with pulmonary lesions similar to diffuse panbronchiolitis. Intern
with common variable immunodeficiency disorders: associations Med 51:1087–1091, 2012.
with clinical phenotypes in comparison with other groups with 407. Rachid R, Bonilla FA: The role of anti-IgA antibodies in causing
recurrent infections. Clin Exp Immunol 170:202–211, 2012. adverse reactions to gamma globulin infusion in immunodeficient
384. Genre J, Errante PR, Kokron CM, et al: Reduced frequency of patients: a comprehensive review of the literature. J Allergy Clin
CD4(+)CD25(HIGH)FOXP3(+) cells and diminished FOXP3 Immunol 129:628–634, 2012.
expression in patients with Common Variable Immunodeficiency: 408. Amanzadeh A, Amirzargar AA, Mohseni N, et al: Association of
a link to autoimmunity? Clin Immunol 132:215–221, 2009. HLA-DRB1, DQA1 and DQB1 alleles and haplotypes with
385. Melo KM, Carvalho KI, Bruno FR, et al: A decreased frequency common variable immunodeficiency in Iranian patients. Avicenna
of regulatory T cells in patients with common variable immuno- J Med Biotechnol 4:103–112, 2012.
deficiency. PLoS ONE 4:e6269, 2009. 409. Ferreira RC, Pan-Hammarstrom Q, Graham RR, et al: High-
386. Eastwood D, Gilmour KC, Nistala K, et al: Prevalence of SAP density SNP mapping of the HLA region identifies multiple inde-
gene defects in male patients diagnosed with common variable pendent susceptibility loci associated with selective IgA deficiency.
immunodeficiency. Clin Exp Immunol 137:584–588, 2004. PLoS Genet 8:e1002476, 2012.
387. Salzer U, Hagena T, Webster DB, et al: Sequence analysis of 410. Aghamohammadi A, Cheraghi T, Gharagozlou M, et al: IgA defi-
BIRC4/XIAP in male patients with common variable immunode- ciency: correlation between clinical and immunological pheno-
ficiency. Int Arch Allergy Immunol 147:147–151, 2008. types. J Clin Immunol 29:130–136, 2009.
388. de Saint Basile G, Tabone MD, Durandy A, et al: CD40 ligand 411. Edwards E, Razvi S, Cunningham-Rundles C: IgA deficiency:
expression deficiency in a female carrier of the X-linked hyper- clinical correlates and responses to pneumococcal vaccine. Clin
IgM syndrome as a result of X chromosome lyonization. Eur J Immunol 111:93–97, 2004.
Immunol 29:367–373, 1999. 412. Jorgensen GH, Gardulf A, Sigurdsson MI, et al: Clinical symp-
389. Castigli E, Wilson S, Garibyan L, et al: Reexamining the role of toms in adults with selective IgA deficiency: a case-control study.
TACI coding variants in common variable immunodeficiency and J Clin Immunol 33:742–747, 2013.
selective IgA deficiency. Nat Genet 39:430–431, 2007. 413. Wang N, Hammarstrom L: IgA deficiency: what is new? Curr
390. Dong X, Hoeltzle MV, Hagan JB, et al: Phenotypic and clinical Opin Allergy Clin Immunol 12:602–608, 2012.
heterogeneity associated with monoallelic TNFRSF13B-A181E 414. Aghamohammadi A, Mohammadi J, Parvaneh N, et al: Progres-
mutations in common variable immunodeficiency. Hum Immunol sion of selective IgA deficiency to common variable immunodefi-
71:505–511, 2010. ciency. Int Arch Allergy Immunol 147:87–92, 2008.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

415. Kutukculer N, Karaca NE, Demircioglu O, et al: Increases in 436. Jeurissen A, Moens L, Raes M, et al: Laboratory diagnosis of
serum immunoglobulins to age-related normal levels in children specific antibody deficiency to pneumococcal capsular polysac-
with IgA and/or IgG subclass deficiency. Pediatr Allergy Immunol charide antigens. Clin Chem 53:505–510, 2007.
18:167–173, 2007. 437. Lim MT, Jeyarajah K, Jones P, et al: Specific antibody deficiency
416. Santaella ML, Peredo R, Disdier OM: IgA deficiency: clinical cor- in children with chronic wet cough. Arch Dis Child 97:478–480,
relates with IgG subclass and mannan-binding lectin deficiencies. 2012.
P R Health Sci J 24:107–110, 2005. 438. Orange JS, Ballow M, Stiehm ER, et al: Use and interpretation of
417. Aghamohammadi A, Abolhassani H, Biglari M, et al: Analysis of diagnostic vaccination in primary immunodeficiency: a working
switched memory B cells in patients with IgA deficiency. Int Arch group report of the Basic and Clinical Immunology Interest
Allergy Immunol 156:462–468, 2011. Section of the American Academy of Allergy, Asthma & Immunol-
418. Hammarstrom L, Vorechovsky I, Webster D: Selective IgA defi- ogy. J Allergy Clin Immunol 130:S1–S24, 2012.
ciency (SIgAD) and common variable immunodeficiency (CVID). 439. Paris K, Sorensen RU: Assessment and clinical interpretation of
Clin Exp Immunol 120:225–231, 2000. polysaccharide antibody responses. Ann Allergy Asthma Immunol
419. Alper CA, Marcus-Bagley D, Awdeh Z, et al: Prospective analysis 99:462–464, 2007.
suggests susceptibility genes for deficiencies of IgA and several 440. Shrimpton A, Duddridge M, Ziegler-Heitbrock L: Vaccination
other immunoglobulins on the [HLA-B8, SC01, DR3] conserved with polysaccharide-conjugate-vaccines in adult patients with spe-
extended haplotype. Tissue Antigens 56:207–216, 2000. cific antibody deficiency. Vaccine 24:3574–3580, 2006.
420. Kralovicova J, Hammarstrom L, Plebani A, et al: Fine-scale 441. Siber GR, Chang I, Baker S, et al: Estimating the protective con-
mapping at IGAD1 and genome-wide genetic linkage analysis centration of anti-pneumococcal capsular polysaccharide antibod-
implicate HLA-DQ/DR as a major susceptibility locus in selective ies. Vaccine 25:3816–3826, 2007.
IgA deficiency and common variable immunodeficiency. J Immunol 442. Javier FC, 3rd, Moore CM, Sorensen RU: Distribution of primary
170:2765–2775, 2003. immunodeficiency diseases diagnosed in a pediatric tertiary hos-
421. Fiore M, Pera C, Delfino L, et al: DNA typing of DQ and DR pital. Ann Allergy Asthma Immunol 84:25–30, 2000.
alleles in IgA-deficient subjects. Eur J Immunogenet 22:403–411, 443. Keles S, Artac H, Kara R, et al: Transient hypogammaglobu-
1995. linemia and unclassified hypogammaglobulinemia: “similarities
422. Ferrante A, Beard LJ, Feldman RG: IgG subclass distribution of and differences”. Pediatr Allergy Immunol 21:843–851, 2010.
antibodies to bacterial and viral antigens. Pediatr Infect Dis J 9: 444. Moschese V, Graziani S, Avanzini MA, et al: A prospective study
S16–S24, 1990. on children with initial diagnosis of transient hypogammaglobu-
423. Buckley RH: Immunoglobulin G subclass deficiency: fact or linemia of infancy: results from the Italian Primary Immunodefi-
fancy? Curr Allergy Asthma Rep 2:356–360, 2002. ciency Network. Int J Immunopathol Pharmacol 21:343–352,
424. Abrahamian F, Agrawal S, Gupta S: Immunological and clinical 2008.
profile of adult patients with selective immunoglobulin subclass 445. Ozen A, Baris S, Karakoc-Aydiner E, et al: Outcome of hypogam-
deficiency: response to intravenous immunoglobulin therapy. Clin maglobulinemia in children: immunoglobulin levels as predictors.
Exp Immunol 159:344–350, 2010. Clin Immunol 137:374–383, 2010.
425. Meyts I, Bossuyt X, Proesmans M, et al: Isolated IgG3 defi- 446. Ricci G, Piccinno V, Giannetti A, et al: Evolution of hypogam-
ciency in children: to treat or not to treat? Case presentation maglobulinemia in premature and full-term infants. Int J Immu-
and review of the literature. Pediatr Allergy Immunol 17:544– nopathol Pharmacol 24:721–726, 2011.
550, 2006. 447. Whelan MA, Hwan WH, Beausoleil J, et al: Infants presenting
426. Olinder-Nielsen AM, Granert C, Forsberg P, et al: Immunoglobu- with recurrent infections and low immunoglobulins: characteris-
lin prophylaxis in 350 adults with IgG subclass deficiency and tics and analysis of normalization. J Clin Immunol 26:7–11, 2006.
recurrent respiratory tract infections: a long-term follow-up. 448. Dorsey MJ, Orange JS: Impaired specific antibody response and
Scand J Infect Dis 39:44–50, 2007. increased B-cell population in transient hypogammaglobulinemia
427. Ozkan H, Atlihan F, Genel F, et al: IgA and/or IgG subclass defi- of infancy. Ann Allergy Asthma Immunol 97:590–595, 2006.
ciency in children with recurrent respiratory infections and its 449. Kemp A: Use of the term “hyper IgM syndrome”. J Paediatr Child
relationship with chronic pulmonary damage. J Investig Allergol Health 44:155–156, 2008.
Clin Immunol 15:69–74, 2005. 450. Cabral-Marques O, Schimke LF, Pereira PV, et al: Expanding the
428. Shackelford PG: IgG subclasses: importance in pediatric practice. clinical and genetic spectrum of human CD40L deficiency: the
Pediatr Rev 14:291–296, 1993. occurrence of paracoccidioidomycosis and other unusual infec-
429. Alachkar H, Taubenheim N, Haeney MR, et al: Memory switched tions in Brazilian patients. J Clin Immunol 32:212–220, 2012.
B cell percentage and not serum immunoglobulin concentration is 451. Davies EG, Thrasher AJ: Update on the hyper immunoglobulin
associated with clinical complications in children and adults with M syndromes. Br J Haematol 149:167–180, 2010.
specific antibody deficiency and common variable immunodefi- 452. Kracker S, Gardes P, Mazerolles F, et al: Immunoglobulin class
ciency. Clin Immunol 120:310–318, 2006. switch recombination deficiencies. Clin Immunol 135:193–203,
430. Tashita H, Fukao T, Kaneko H, et al: Molecular basis of selective 2010.
IgG2 deficiency. The mutated membrane-bound form of gamma2 453. Longo NS, Lugar PL, Yavuz S, et al: Analysis of somatic hyper-
heavy chain caused complete IGG2 deficiency in two Japanese mutation in X-linked hyper-IgM syndrome shows specific deficien-
siblings. J Clin Invest 101:677–681, 1998. cies in mutational targeting. Blood 113:3706–3715, 2009.
431. Lefranc MP, Lefranc G, Rabbitts TH: Inherited deletion of immu- 454. Notarangelo LD, Lanzi G, Peron S, et al: Defects of class-switch
noglobulin heavy chain constant region genes in normal human recombination. J Allergy Clin Immunol 117:855–864, 2006.
individuals. Nature 300:760–762, 1982. 455. Schleithoff LS, Seelig HP: Gene symbol: TNFSF5. Disease: hyper-
432. Plebani A, Ugazio AG, Meini A, et al: Extensive deletion of immu- IgM syndrome. Accession #Hm0539. Hum Genet 118:778,
noglobulin heavy chain constant region genes in the absence of 2006.
recurrent infections: when is IgG subclass deficiency clinically 456. Jesus AA, Duarte AJ, Oliveira JB: Autoimmunity in hyper-IgM
relevant? Clin Immunol Immunopathol 68:46–50, 1993. syndrome. J Clin Immunol 28(Suppl 1):S62–S66, 2008.
433. Plebani A, Carbonara AO, Bottaro A, et al: Two siblings with 457. Al-Dhekri H, Al-Sum Z, Al-Saud B, et al: Successful outcome in
deficiency of IgA1, IgG2, IgG4 and IgE due to deletion of immu- two patients with CD40 deficiency treated with allogeneic HCST.
noglobulin heavy chain constant region genes. Year Immunol Clin Immunol 143:96–98, 2012.
7:231–235, 1993. 458. Karaca NE, Forveille M, Aksu G, et al: Hyper-immunoglobulin
434. Depiero A, Kaminski DA, Halsey JF, et al: Immunologic compen- M syndrome type 3 with normal CD40 cell surface expression.
sation in a patient with a large IgH constant region deletion. J Scand J Immunol 76:21–25, 2012.
Allergy Clin Immunol 107:1051–1055, 2001. 459. Catalan N, Selz F, Imai K, et al: The block in immunoglobulin
435. Olsson PG, Rabbani H, Hammarstrom L, et al: Novel human class switch recombination caused by activation-induced cytidine
immunoglobulin heavy chain constant region gene deletion hap- deaminase deficiency occurs prior to the generation of DNA
lotypes characterized by pulsed-field electrophoresis. Clin Exp double strand breaks in switch mu region. J Immunol 171:2504–
Immunol 94:84–90, 1993. 2509, 2003.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases  921.e11

460. Quartier P, Bustamante J, Sanal O, et al: Clinical, immunologic immunodeficiency: correlations with clinical phenotype and poly-
and genetic analysis of 29 patients with autosomal recessive hyper- morphism of the neonatal Fc receptor. Clin Exp Immunol
IgM syndrome due to activation-induced cytidine deaminase defi- 171:186–194, 2013.
ciency. Clin Immunol 110:22–29, 2004. 482. Kasztalska K, Ciebiada M, Cebula-Obrzut B, et al: Intravenous
461. Ta VT, Nagaoka H, Catalan N, et al: AID mutant analyses indi- immunoglobulin replacement therapy in the treatment of patients
cate requirement for class-switch-specific cofactors. Nat Immunol with common variable immunodeficiency disease: an open-label
4:843–848, 2003. prospective study. Clin Drug Investig 31:299–307, 2011.
462. Imai K, Slupphaug G, Lee WI, et al: Human uracil-DNA glyco- 483. Quinti I, Di Pietro C, Martini H, et al: Health related quality of
sylase deficiency associated with profoundly impaired immuno- life in common variable immunodeficiency. Yonsei Med J 53:603–
globulin class-switch recombination. Nat Immunol 4:1023–1028, 610, 2012.
2003. 484. Ballow M: Immunoglobulin therapy: methods of delivery. J
463. Durandy A, Taubenheim N, Peron S, et al: Pathophysiology of Allergy Clin Immunol 122:1038–1039, 2008.
B-cell intrinsic immunoglobulin class switch recombination defi- 485. Abdou NI, Greenwell CA, Mehta R, et al: Efficacy of intravenous
ciencies. Adv Immunol 94:275–306, 2007. gammaglobulin for immunoglobulin G subclass and/or antibody
464. Imai K, Catalan N, Plebani A, et al: Hyper-IgM syndrome type 4 deficiency in adults. Int Arch Allergy Immunol 149:267–274,
with a B lymphocyte-intrinsic selective deficiency in Ig class-switch 2009.
recombination. J Clin Invest 112:136–142, 2003. 486. Duse M, Iacobini M, Leonardi L, et al: Transient hypogamma-
465. Karaca NE, Durandy A, Gulez N, et al: Study of patients with globulinemia of infancy: intravenous immunoglobulin as first line
Hyper-IgM type IV phenotype who recovered spontaneously therapy. Int J Immunopathol Pharmacol 23:349–353, 2010.
during late childhood and review of the literature. Eur J Pediatr 487. Walport MJ: Complement. Second of two parts. N Engl J Med
170:1039–1047, 2011. 344:1140–1144, 2001.
466. Lee WI, Torgerson TR, Schumacher MJ, et al: Molecular analysis 488. Walport MJ: Complement. First of two parts. N Engl J Med
of a large cohort of patients with the hyper immunoglobulin M 344:1058–1066, 2001.
(IgM) syndrome. Blood 105:1881–1890, 2005. 489. Frank MM: Complement disorders and hereditary angioedema. J
467. Balloch A, Licciardi PV, Tang ML: Serotype-specific anti- Allergy Clin Immunol 125:S262–S271, 2010.
pneumococcal IgG and immune competence: critical differences 490. Al-Mayouf SM, Abanomi H: Eldali A. Impact of C1q deficiency
in interpretation criteria when different methods are used. J Clin on the severity and outcome of childhood systemic lupus erythe-
Immunol 33:335–341, 2013. matosus. Int J Rheum Dis 14:81–85, 2011.
468. Go ES, Ballas ZK: Anti-pneumococcal antibody response in 491. Kallel-Sellami M, Baili-Klila L, Zerzeri Y, et al: Pediatric systemic
normal subjects: a meta-analysis. J Allergy Clin Immunol 98:205– lupus erythematosus with C1q deficiency. Ann N Y Acad Sci 1108:
215, 1996. 193–196, 2007.
469. Whaley MJ, Rose C, Martinez J, et al: Interlaboratory comparison 492. Martens HA, Zuurman MW, de Lange AH, et al: Analysis of C1q
of three multiplexed bead-based immunoassays for measuring polymorphisms suggests association with systemic lupus erythe-
serum antibodies to pneumococcal polysaccharides. Clin Vaccine matosus, serum C1q and CH50 levels and disease severity. Ann
Immunol 17:862–869, 2010. Rheum Dis 68:715–720, 2009.
470. Licciardi PV, Balloch A, Russell FM, et al: Pneumococcal polysac- 493. Sontheimer RD, Racila E, Racila DM: C1q: its functions within
charide vaccine at 12 months of age produces functional immune the innate and adaptive immune responses and its role in lupus
responses. J Allergy Clin Immunol 129:794–800, e2, 2012. autoimmunity. J Invest Dermatol 125:14–23, 2005.
471. Wood P, Stanworth S, Burton J, et al: Recognition, clinical diag- 494. Chen Z, Wang GS, Wang GH, et al: Anti-C1q antibody is a valu-
nosis and management of patients with primary antibody deficien- able biological marker for prediction of renal pathological char-
cies: a systematic review. Clin Exp Immunol 149:410–423, 2007. acteristics in lupus nephritis. Clin Rheumatol 31:1323–1329,
472. Orange JS, Hossny EM, Weiler CR, et al: Use of intravenous 2012.
immunoglobulin in human disease: a review of evidence by 495. Katsumata Y, Miyake K, Kawaguchi Y, et al: Anti-C1q antibodies
members of the Primary Immunodeficiency Committee of the are associated with systemic lupus erythematosus global activity
American Academy of Allergy, Asthma and Immunology. J Allergy but not specifically with nephritis: a controlled study of 126 con-
Clin Immunol 117:S525–S553, 2006. secutive patients. Arthritis Rheum 63:2436–2444, 2011.
473. Quartier P, Debre M, De Blic J, et al: Early and prolonged intra- 496. Vanhecke D, Roumenina LT, Wan H, et al: Identification of a
venous immunoglobulin replacement therapy in childhood agam- major linear C1q epitope allows detection of systemic lupus ery-
maglobulinemia: a retrospective survey of 31 patients. J Pediatr thematosus anti-C1q antibodies by a specific peptide-based
134:589–596, 1999. enzyme-linked immunosorbent assay. Arthritis Rheum 64:3706–
474. Bonagura VR: Using intravenous immunoglobulin (IVIG) to treat 3714, 2012.
patients with primary immune deficiency disease. J Clin Immunol 497. Yin Y, Wu X, Shan G, et al: Diagnostic value of serum anti-C1q
33(Suppl 2):S90–S94, 2013. antibodies in patients with lupus nephritis: a meta-analysis. Lupus
475. Fried AJ, Bonilla FA: Pathogenesis, diagnosis, and management of 21:1088–1097, 2012.
primary antibody deficiencies and infections. Clin Microbiol Rev 498. Jonsson G, Lood C, Gullstrand B, et al: Vaccination against
22:396–414, 2009. encapsulated bacteria in hereditary C2 deficiency results in anti-
476. Howard V, Greene JM, Pahwa S, et al: The health status and body response and opsonization due to antibody-dependent com-
quality of life of adults with X-linked agammaglobulinemia. Clin plement activation. Clin Immunol 144:214–227, 2012.
Immunol 118:201–208, 2006. 499. Hauck F, Lee-Kirsch MA, Aust D, et al: Complement C2 defi-
477. Maarschalk-Ellerbroek LJ, Hoepelman IM, Ellerbroek PM: ciency disarranging innate and adaptive humoral immune
Immunoglobulin treatment in primary antibody deficiency. Int J responses in a pediatric patient: treatment with rituximab. Arthri-
Antimicrob Agents 37:396–404, 2011. tis Care Res 63:454–459, 2011.
478. Soresina A, Nacinovich R, Bomba M, et al: The quality of life of 500. Yuste J, Sen A, Truedsson L, et al: Impaired opsonization with
children and adolescents with X-linked agammaglobulinemia. J complement and phagocytosis of Streptococcus pyogenes in sera
Clin Immunol 29:501–507, 2009. from subjects with inherited C2 deficiency. Microbes Infect
479. Winkelstein JA, Conley ME, James C, et al: Adults with X-linked 12:626–634, 2010.
agammaglobulinemia: impact of disease on daily lives, quality 501. Jonsson G, Sjoholm AG, Truedsson L, et al: Rheumatological
of life, educational and socioeconomic status, knowledge of manifestations, organ damage and autoimmunity in hereditary C2
inheritance, and reproductive attitudes. Medicine 87:253–258, deficiency. Rheumatology 46:1133–1139, 2007.
2008. 502. Helal I, Goucha R, Hamida FB, et al: Renal AA amyloidosis in a
480. Detkova D, Espanol T: An update on treatment strategies for patient with hereditary complete complement C4 deficiency. Saudi
common variable immunodeficiency. Expert Rev Clin Immunol J Kidney Dis Transpl 22:1008–1011, 2011.
5:381–390, 2009. 503. Lhotta K, Wurzner R, Rumpelt HJ, et al: Membranous nephropa-
481. Gouilleux-Gruart V, Chapel H, Chevret S, et al: Efficiency of thy in a patient with hereditary complete complement C4 defi-
immunoglobulin G replacement therapy in common variable ciency. Nephrol Dial Transplant 19:990–993, 2004.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

504. Lhotta K, Wurzner R, Rosenkranz AR, et al: Cerebral vasculitis 528. Henic E, Thiel S, Mardh PA: Mannan-binding lectin in women
in a patient with hereditary complete C4 deficiency and systemic with a history of recurrent vulvovaginal candidiasis. Eur J Obstet
lupus erythematosus. Lupus 13:139–141, 2004. Gynecol Reprod Biol 148:163–165, 2010.
505. Queiro R, Weruaga A, Riestra JL: C4 deficiency state in antiphos- 529. Smithson A, Munoz A, Suarez B, et al: Association between
pholipid antibody-related recurrent preeclampsia evolving into mannose-binding lectin deficiency and septic shock following
systemic lupus erythematosus. Rheumatol Int 22:126–128, acute pyelonephritis due to Escherichia coli. Clin Vaccine Immunol
2002. 14:256–261, 2007.
506. Azofra J, Lopez-Trascasa M: C4 deficiency in chronic angio- 530. Garcia-Laorden MI, Sole-Violan J, Rodriguez de Castro F, et al:
edema. Allergy 56:1106–1107, 2001. Mannose-binding lectin and mannose-binding lectin-associated
507. Stefansson Thors V, Kolka R, Sigurdardottir SL, et al: Increased serine protease 2 in susceptibility, severity, and outcome of pneu-
frequency of C4B*Q0 alleles in patients with Henoch-Schönlein monia in adults. J Allergy Clin Immunol 122:368–374, 74 e1–2,
purpura. Scand J Immunol 61:274–278, 2005. 2008.
508. Fielder AH, Walport MJ, Batchelor JR, et al: Family study of the 531. Lambourne J, Agranoff D, Herbrecht R, et al: Association of
major histocompatibility complex in patients with systemic lupus mannose-binding lectin deficiency with acute invasive aspergillosis
erythematosus: importance of null alleles of C4A and C4B in in immunocompromised patients. Clin Infect Dis 49:1486–1491,
determining disease susceptibility. Br Med J (Clin Res Ed) 286: 2009.
425–428, 1983. 532. Altorjay I, Vitalis Z, Tornai I, et al: Mannose-binding lectin defi-
509. Boteva L, Morris DL, Cortes-Hernandez J, et al: Genetically ciency confers risk for bacterial infections in a large Hungarian
determined partial complement C4 deficiency states are not inde- cohort of patients with liver cirrhosis. J Hepatol 53:484–491,
pendent risk factors for SLE in UK and Spanish populations. Am 2010.
J Hum Genet 90:445–456, 2012. 533. Worthley DL, Johnson DF, Eisen DP, et al: Donor mannose-
510. Pickering MC, Botto M, Taylor PR, et al: Systemic lupus erythe- binding lectin deficiency increases the likelihood of clinically sig-
matosus, complement deficiency, and apoptosis. Adv Immunol nificant infection after liver transplantation. Clin Infect Dis
76:227–324, 2000. 48:410–417, 2009.
511. Fearon DT, Carroll MC: Regulation of B lymphocyte responses 534. Mullighan CG, Bardy PG: Mannose-binding lectin and infection
to foreign and self-antigens by the CD19/CD21 complex. Annu following allogeneic hemopoietic stem cell transplantation. Leuk
Rev Immunol 18:393–422, 2000. Lymphoma 45:247–256, 2004.
512. Okura Y, Nawate M, Takahashi Y, et al: Rheumatoid factor- 535. Kwakkel-van Erp JM, Paantjens AW, van Kessel DA, et al:
positive synovitis in a patient with C3 deficiency. Scand J Rheu- Mannose-binding lectin deficiency linked to cytomegalovirus
matol 41:405–406, 2012. (CMV) reactivation and survival in lung transplantation. Clin Exp
513. Okura Y, Yamada M, Takezaki S, et al: Novel compound hetero- Immunol 165:410–416, 2011.
zygous mutations in the C3 gene: hereditary C3 deficiency. Pediatr 536. Bathum L, Hansen H, Teisner B, et al: Association between com-
Int 53:e16–e19, 2011. bined properdin and mannose-binding lectin deficiency and infec-
514. Singh DK, Rai R: Recurrent meningitis secondary to isolated C3 tion with Neisseria meningitidis. Mol Immunol 43:473–479,
deficiency. Indian J Pediatr 76:95–96, 2009. 2006.
515. Gulati S, Agarwal S, Vasudhev S, et al: Properdin is critical for 537. Fevang B, Mollnes TE, Holm AM, et al: Common variable immu-
antibody-dependent bactericidal activity against Neisseria gonor- nodeficiency and the complement system; low mannose-binding
rhoeae that recruit C4b-binding protein. J Immunol 188:3416– lectin levels are associated with bronchiectasis. Clin Exp Immunol
3425, 2012. 142:576–584, 2005.
516. Mayilyan KR: Complement genetics, deficiencies, and disease 538. Mullighan CG, Marshall SE, Welsh KI: Mannose binding lectin
associations. Protein Cell 3:487–496, 2012. polymorphisms are associated with early age of disease onset and
517. Schejbel L, Rosenfeldt V, Marquart H, et al: Properdin deficiency autoimmunity in common variable immunodeficiency. Scand J
associated with recurrent otitis media and pneumonia, and iden- Immunol 51:111–122, 2000.
tification of male carrier with Klinefelter syndrome. Clin Immunol 539. Fildes JE, Shaw SM, Walker AH, et al: Mannose-binding lectin
131:456–462, 2009. deficiency offers protection from acute graft rejection after heart
518. Tedesco F: Inherited complement deficiencies and bacterial infec- transplantation. J Heart Lung Transplant 27:1353–1356, 2008.
tions. Vaccine 26(Suppl 8):I3–I8, 2008. 540. Osthoff M, Katan M, Fluri F, et al: Mannose-binding lectin defi-
519. Abrera-Abeleda MA, Xu Y, Pickering MC, et al: Mesangial ciency is associated with smaller infarction size and favorable
immune complex glomerulonephritis due to complement factor D outcome in ischemic stroke patients. PLoS ONE 6:e21338, 2011.
deficiency. Kidney Int 71:1142–1147, 2007. 541. Vengen IT, Madsen HO, Garred P, et al: Mannose-binding lectin
520. Biesma DH, Hannema AJ, van Velzen-Blad H, et al: A family deficiency is associated with myocardial infarction: the HUNT2
with complement factor D deficiency. J Clin Invest 108:233–240, study in Norway. PLoS ONE 7:e42113, 2012.
2001. 542. Thiel S, Frederiksen PD, Jensenius JC: Clinical manifestations of
521. Sprong T, Roos D, Weemaes C, et al: Deficient alternative comple- mannan-binding lectin deficiency. Mol Immunol 43:86–96, 2006.
ment pathway activation due to factor D deficiency by 2 novel 543. Egli A, Schafer J, Osthoff M, et al: Low levels of mannan-binding
mutations in the complement factor D gene in a family with lectin or ficolins are not associated with an increased risk of cyto-
meningococcal infections. Blood 107:4865–4870, 2006. megalovirus disease in HIV-infected patients. PLoS ONE 8:
522. Weiss SJ, Ahmed AE, Bonagura VR: Complement factor D defi- e51983, 2013.
ciency in an infant first seen with pneumococcal neonatal sepsis. 544. Carlsson M, Sjoholm AG, Eriksson L, et al: Deficiency of the
J Allergy Clin Immunol 102:1043–1044, 1998. mannan-binding lectin pathway of complement and poor outcome
523. Eisen DP: Mannose-binding lectin deficiency and respiratory tract in cystic fibrosis: bacterial colonization may be decisive for a
infection. J Innate Immun 2:114–122, 2010. relationship. Clin Exp Immunol 139:306–313, 2005.
524. Valles X, Roca A, Lozano F, et al: Serotype-specific pneumococcal 545. Buranawuti K, Boyle MP, Cheng S, et al: Variants in mannose-
disease may be influenced by mannose-binding lectin deficiency. binding lectin and tumour necrosis factor alpha affect survival in
Eur Respir J 36:856–863, 2010. cystic fibrosis. J Med Genet 44:209–214, 2007.
525. Grondahl-Yli-Hannuksela K, Viander M, Mertsola J, et al: 546. Davies JC, Turner MW, Klein N, et al: Impaired pulmonary status
Increased risk of pertussis in adult patients with mannose-binding in cystic fibrosis adults with two mutated MBL-2 alleles. Eur
lectin deficiency. APMIS 121:311–315, 2013. Respir J 24:798–804, 2004.
526. Ou XT, Wu JQ, Zhu LP, et al: Genotypes coding for mannose- 547. Olesen HV, Jensenius JC, Steffensen R, et al: The mannan-binding
binding lectin deficiency correlated with cryptococcal meningitis lectin pathway and lung disease in cystic fibrosis–disfunction of
in HIV-uninfected Chinese patients. J Infect Dis 203:1686–1691, mannan-binding lectin-associated serine protease 2 (MASP-2)
2011. may be a major modifier. Clin Immunol 121:324–331, 2006.
527. Kirkpatrick BD, Huston CD, Wagner D, et al: Serum mannose- 548. Trevisiol C, Boniotto M, Giglio L, et al: MBL2 polymorphisms
binding lectin deficiency is associated with cryptosporidiosis in screening in a regional Italian CF Center. J Cyst Fibros 4:189–191,
young Haitian children. Clin Infect Dis 43:289–294, 2006. 2005.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
24  Primary Immunodeficiency Diseases  921.e13

549. Ytting H, Christensen IJ, Steffensen R, et al: Mannan-binding Neisseria meningitidis in complement-deficient individuals. Clin
lectin (MBL) and MBL-associated serine protease 2 (MASP-2) Exp Immunol 120:338–345, 2000.
genotypes in colorectal cancer. Scand J Immunol 73:122–127, 572. Banerji A: Hereditary angioedema: classification, pathogenesis,
2011. and diagnosis. Allergy Asthma Proc 32:403–407, 2011.
550. Petersen KA, Matthiesen F, Agger T, et al: Phase I safety, tolerabil- 573. Bjorkqvist J, Sala-Cunill A, Renne T: Hereditary angioedema: a
ity, and pharmacokinetic study of recombinant human mannan- bradykinin-mediated swelling disorder. Thromb Haemost 109:
binding lectin. J Clin Immunol 26:465–475, 2006. 368–374, 2013.
551. Cedzynski M, Nuytinck L, Atkinson AP, et al: Extremes of 574. Bork K, Hardt J, Witzke G: Fatal laryngeal attacks and mortality
L-ficolin concentration in children with recurrent infections are in hereditary angioedema due to C1-INH deficiency. J Allergy Clin
associated with single nucleotide polymorphisms in the FCN2 Immunol 130:692–697, 2012.
gene. Clin Exp Immunol 150:99–104, 2007. 575. Marcos C, Lopez Lera A, Varela S, et al: Clinical, biochemical,
552. Cedzynski M, Atkinson AP, St Swierzko A, et al: L-ficolin (ficolin- and genetic characterization of type III hereditary angioedema in
2) insufficiency is associated with combined allergic and infectious 13 Northwest Spanish families. Ann Allergy Asthma Immunol
respiratory disease in children. Mol Immunol 47:415–419, 2009. 109:195–200, e2, 2012.
553. Cedzynski M, Szemraj J, Swierzko AS, et al: Mannan-binding 576. Breitbart SI, Bielory L: Acquired angioedema: autoantibody asso-
lectin insufficiency in children with recurrent infections of the ciations and C1q utility as a diagnostic tool. Allergy Asthma Proc
respiratory system. Clin Exp Immunol 136:304–311, 2004. 31:428–434, 2010.
554. Granell M, Urbano-Ispizua A, Suarez B, et al: Mannan-binding 577. Cicardi M, Zanichelli A: Acquired angioedema. Allergy Asthma
lectin pathway deficiencies and invasive fungal infections follow- Clin Immunol 6:14, 2010.
ing allogeneic stem cell transplantation. Exp Hematol 34:1435– 578. Cicardi M, Zanichelli A: The acquired deficiency of C1-inhibitor:
1441, 2006. lymphoproliferation and angioedema. Curr Mol Med 10:354–
555. Schlapbach LJ, Aebi C, Otth M, et al: Deficiency of mannose- 360, 2010.
binding lectin-associated serine protease-2 associated with 579. Cugno M, Castelli R, Cicardi M: Angioedema due to acquired
increased risk of fever and neutropenia in pediatric cancer patients. C1-inhibitor deficiency: a bridging condition between autoim-
Pediatr Infect Dis J 26:989–994, 2007. munity and lymphoproliferation. Autoimmun Rev 8:156–159,
556. Arnaout R, Al Shorbaghi S, Al Dhekri H, et al: C5 complement 2008.
deficiency in a Saudi family, molecular characterization of muta- 580. Healy C, Abuzakouk M, Feighery C, et al: Acquired angioedema
tion and literature review. J Clin Immunol 33:871–875, 2013. in non-Hodgkin’s lymphoma. Oral Surg Oral Med Oral Pathol
557. Lopez-Lera A, Garrido S, de la Cruz RM, et al: Molecular char- Oral Radiol Endod 103:e29–e32, 2007.
acterization of three new mutations causing C5 deficiency in two 581. Lam DH, Levy NB, Nickerson JM, et al: Acquired angioedema
non-related families. Mol Immunol 46:2340–2347, 2009. and marginal zone lymphoma. J Clin Oncol 30:e151–e153, 2012.
558. Moya-Quiles MR, Bernardo-Pisa MV, Martinez P, et al: Comple- 582. Di Leo E, Nettis E, Montinaro V, et al: Acquired angioedema with
ment component C6 deficiency in a Spanish family: implications C1 inhibitor deficiency associated with anticardiolipin antibodies.
for clinical and molecular diagnosis. Gene 2013. Int J Immunopathol Pharmacol 24:1115–1118, 2011.
559. Parham KL, Roberts A, Thomas A, et al: Prevalence of mutations 583. Furlanetto V, Jr, Giassi Kde S, Neves Fde S, et al: Intractable
leading to complete C6 deficiency (C6Q0) in the Western Cape, acquired autoimmune angioedema in a patient with systemic
South Africa and detection of novel mutations leading to C6Q0 lupus erythematosus. Rev Bras Reumatol 50:102–106, 2010.
in an Irish family. Mol Immunol 44:2756–2760, 2007. 584. Szeplaki G, Varga L, Szepvolgyi A, et al: Acquired angioedema
560. Rameix-Welti MA, Regnier CH, Bienaime F, et al: Hereditary associated with primary antiphospholipid syndrome in a patient
complement C7 deficiency in nine families: subtotal C7 deficiency with antithrombin III deficiency. Int Arch Allergy Immunol
revisited. Eur J Immunol 37:1377–1385, 2007. 146:164–168, 2008.
561. Zhu Z, Atkinson TP, Hovanky KT, et al: High prevalence of 585. Bork K: Current management options for hereditary angioedema.
complement component C6 deficiency among African-Americans Curr Allergy Asthma Rep 12:273–280, 2012.
in the south-eastern USA. Clin Exp Immunol 119:305–310, 586. Craig T, Pursun EA, Bork K, et al: WAO guideline for the manage-
2000. ment of hereditary angioedema. WAO J 5:182–199, 2012.
562. Kojima T, Horiuchi T, Nishizaka H, et al: Genetic basis of human 587. Tilles SA, Borish L, Cohen JP: Management of hereditary angio-
complement C8 alpha-gamma deficiency. J Immunol 161:3762– edema in 2012: scientific and pharmacoeconomic perspectives.
3766, 1998. Ann Allergy Asthma Immunol 110:70–74, 2013.
563. Kotnik V, Luznik-Bufon T, Schneider PM, et al: Molecular, 588. Xu YY, Buyantseva LV, Agarwal NS, et  al: Update on treat-
genetic, and functional analysis of homozygous C8 beta-chain ment of hereditary angioedema. Clin Exp Allergy 43:395–405,
deficiency in two siblings. Immunopharmacology 38:215–221, 2013.
1997. 589. Craig TJ, Bewtra AK, Bahna SL, et al: C1 esterase inhibitor con-
564. Saucedo L, Ackermann L, Platonov AE, et al: Delineation of addi- centrate in 1085 Hereditary Angioedema attacks—final results of
tional genetic bases for C8 beta deficiency. Prevalence of null the I.M.P.A.C.T.2 study. Allergy 66:1604–1611, 2011.
alleles and predominance of C–>T transition in their genesis. J 590. Schneider L, Hurewitz D, Wasserman R, et al: C1-INH concen-
Immunol 155:5022–5028, 1995. trate for treatment of acute hereditary angioedema: a pediatric
565. Barba GM, Kaufmann TJ, Schneider PM, et al: Polymorphism of cohort from the I.M.P.A.C.T. studies. Pediatr Allergy Immunol
the complement C8A and -B genes in two families with C8 beta 24:54–60, 2013.
deficiency and neisserial infections. Clin Immunol Immunopathol 591. Caballero T: Efficacy assessments in randomized controlled studies
72:83–89, 1994. of acute therapy for hereditary angioedema. J Clin Immunol
566. Kang HJ, Kim HS, Lee YK, et al: High incidence of complement 32:1204–1212, 2012.
C9 deficiency in Koreans. Ann Clin Lab Sci 35:144–148, 2005. 592. Cronin JA, Maples KM: Treatment of an acute attack of type III
567. Orren A, O’Hara AM, Morgan BP, et al: An abnormal but func- hereditary angioedema with ecallantide. Ann Allergy Asthma
tionally active complement component C9 protein found in an Immunol 108:61–62, 2012.
Irish family with subtotal C9 deficiency. Immunology 108:384– 593. Lumry WR, Bernstein JA, Li HH, et al: Efficacy and safety of
390, 2003. ecallantide in treatment of recurrent attacks of hereditary angio-
568. Khajoee V, Ihara K, Kira R, et al: Founder effect of the C9 R95X edema: open-label continuation study. Allergy Asthma Proc
mutation in Orientals. Hum Genet 112:244–248, 2003. 34:155–161, 2013.
569. Kanda E, Shimamura H, Tamura H, et al: IgA nephropathy with 594. MacGinnitie AJ, Campion M, Stolz LE, et al: Ecallantide for
complement deficiency. Intern Med 40:52–55, 2001. treatment of acute hereditary angioedema attacks: analysis of
570. Ichikawa E, Furuta J, Kawachi Y, et al: Hereditary complement efficacy by patient characteristics. Allergy Asthma Proc 33:178–
(C9) deficiency associated with dermatomyositis. Br J Dermatol 185, 2012.
144:1080–1083, 2001. 595. Boccon-Gibod I, Bouillet L: Safety and efficacy of icatibant self-
571. Fijen CA, Bredius RG, Kuijper EJ, et al: The role of Fcgamma administration for acute hereditary angioedema. Clin Exp
receptor polymorphisms and C3 in the immune defence against Immunol 168:303–307, 2012.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

596. Cole SW, Lundquist LM: Icatibant for the treatment of hereditary 609. Cho HY, Lee BS, Moon KC, et al: Complete factor H deficiency-
angioedema. Ann Pharmacother 47:49–55, 2013. associated atypical hemolytic uremic syndrome in a neonate.
597. Maurer M, Aberer W, Bouillet L, et al: Hereditary angioedema Pediatr Nephrol 22:874–880, 2007.
attacks resolve faster and are shorter after early icatibant treat- 610. Falcao DA, Reis ES, Paixao-Cavalcante D, et al: Deficiency of the
ment. PLoS ONE 8:e53773, 2013. human complement regulatory protein factor H associated with
598. Tang R, Chen S, Zhang HY: Fresh frozen plasma for the treatment low levels of component C9. Scand J Immunol 68:445–455, 2008.
of hereditary angioedema acute attacks. Chin Med Sci J 27:92–95, 611. Koziolek MJ, Zipfel PF, Skerka C, et al: Chronic course of a
2012. hemolytic uremic syndrome caused by a deficiency of factor
599. Gompels MM, Lock RJ: Cinryze (C1-inhibitor) for the treatment H-related proteins (CFHR1 and CFHR3). Kidney Int 74:384–
of hereditary angioedema. Expert Rev Clin Immunol 7:569–573, 388, 2008.
2011. 612. Schejbel L, Schmidt IM, Kirchhoff M, et al: Complement factor
600. Lumry W, Manning ME, Hurewitz DS, et al: Nanofiltered H deficiency and endocapillary glomerulonephritis due to paternal
C1-esterase inhibitor for the acute management and prevention of isodisomy and a novel factor H mutation. Genes Immun 12:90–
hereditary angioedema attacks due to C1-inhibitor deficiency in 99, 2011.
children. J Pediatr 162:1017–1022, 2013. 613. Servais A, Noel LH, Dragon-Durey MA, et al: Heterogeneous
601. Lyseng-Williamson KA: Nanofiltered human C1 inhibitor concen- pattern of renal disease associated with homozygous factor H
trate (Cinryze(R)): in hereditary angioedema. Biodrugs 25:317– deficiency. Hum Pathol 42:1305–1311, 2011.
327, 2011. 614. Sethi SK, Marie-Agnes DD, Thaker N, et al: Hemolytic uremic
602. Branellec A, Bouillet L, Javaud N, et al: Acquired C1-inhibitor syndrome due to homozygous factor H deficiency. Clin Exp
deficiency: 7 patients treated with rituximab. J Clin Immunol Nephrol 13:526–530, 2009.
32:936–941, 2012. 615. Jozsi M, Licht C, Strobel S, et al: Factor H autoantibodies in
603. Alba-Dominguez M, Lopez-Lera A, Garrido S, et al: Complement atypical hemolytic uremic syndrome correlate with CFHR1/
factor I deficiency: a not so rare immune defect: characterization CFHR3 deficiency. Blood 111:1512–1514, 2008.
of new mutations and the first large gene deletion. Orphanet J 616. Lee BH, Kwak SH, Shin JI, et al: Atypical hemolytic uremic syn-
Rare Dis 7:42, 2012. drome associated with complement factor H autoantibodies and
604. Genel F, Sjoholm AG, Skattum L, et al: Complement factor I CFHR1/CFHR3 deficiency. Pediatr Res 66:336–340, 2009.
deficiency associated with recurrent infections, vasculitis and 617. Matsukuma E, Gotoh Y, Kuroyanagi Y, et al: A case of atypical
immune complex glomerulonephritis. Scand J Infect Dis 37:615– hemolytic uremic syndrome due to anti-factor H antibody in a
618, 2005. patient presenting with a factor XII deficiency identified two novel
605. Grumach AS, Leitao MF, Arruk VG, et al: Recurrent infections in mutations. Clin Exp Nephrol 15:269–274, 2011.
partial complement factor I deficiency: evaluation of three genera- 618. Frank MM: Complement deficiencies. Pediatr Clin North Am
tions of a Brazilian family. Clin Exp Immunol 143:297–304, 47:1339–1354, 2000.
2006. 619. Herpers BL, de Jong BA, Dekker B, et al: Hemolytic assay for the
606. Nilsson SC, Trouw LA, Renault N, et al: Genetic, molecular and measurement of functional human mannose-binding lectin: a
functional analyses of complement factor I deficiency. Eur J modification to avoid interference from classical pathway activa-
Immunol 39:310–323, 2009. tion. J Immunol Methods 343:61–63, 2009.
607. Nita IM, Genel F, Nilsson SC, et al: Molecular characterization 620. Wen L, Atkinson JP, Giclas PC: Clinical and laboratory evaluation
of two novel cases of complete complement inhibitor Factor I of complement deficiency. J Allergy Clin Immunol 113:585–593,
deficiency. Mol Immunol 48:1068–1072, 2011. quiz 94, 2004.
608. Bao L, Haas M, Quigg RJ: Complement factor H deficiency accel- 621. Nester CM, Brophy PD: Eculizumab in the treatment of atypical
erates development of lupus nephritis. J Am Soc Nephrol 22:285– haemolytic uraemic syndrome and other complement-mediated
295, 2011. renal diseases. Curr Opin Pediatr 25:225–231, 2013.

Downloaded for Reynaldo Jr. Alvarez (reymalvarez@gmail.com) at University of the East from ClinicalKey.com by Elsevier on January 07, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.