Severe Combined Immunodeficiency

rarediseases.org/rare-diseases/severe-combined-immunodeficiency/

NORD gratefully acknowledges Lisa Vawter, PhD, Medical Writer, and Eric Allenspach, MD, PhD,
University of Washington, for assistance in the preparation of this report.

Synonyms of Severe Combined Immunodeficiency

bubble boy syndrome
SCID

Subdivisions of Severe Combined Immunodeficiency

leaky or atypical SCID
typical or classic SCID
variant SCID

General Discussion
Severe combined immunodeficiency (SCID) is a group of rare congenital syndromes
with little or no immune responses. This results in frequent recurring infections with
bacteria, fungi, and viruses. Infections that are minor in most people can be
life‑threatening in people with SCID. The immune system includes specialized white
blood cells that work together to fight off bacteria, fungi, and viruses. These white blood
cells include T lymphocytes (T cells) that are central mediators of the immune response
and also directly attack viruses. B lymphocytes (B cells) produce antibodies that attach
to invaders and mark them to be destroyed, but they need T cells to work effectively.
Natural killer (NK) cells are specialized to help fight viruses as well. Patients with SCID
have a genetic defect that affects T cells and at least one other type of immune cell
(hence “combined immunodeficiency”). Types of SCID are classified by which immune
cells, T, B, and/or NK cells, are defective. There are several types of SCID, each caused by
a different genetic (hereditary) defect. Despite the type of SCID, the primary symptom is
reduced or absent immune function and all forms of classic SCID are lethal unless
treated appropriately. The type of SCID helps determine the best treatment. Most
states now have newborn screening for SCID to help detect and treat babies prior to
them becoming sick. Early detection by newborn screening has dramatically increased
the success of the bone marrow transplantation as babies with SCID can avoid early
infections.

Signs & Symptoms

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All newborn babies receive antibodies from their mothers during pregnancy that
protect them from infections during the first few months of their lives. In the absence of
family history of SCID and prior to newborn screening, babies with SCID often
presented to medical attention between three and six months with severe infections as
their maternal antibodies naturally decreased. Symptoms included rashes, diarrhea,
recurrent infections, difficulty gaining weight, weakness and/or growth delay.

Organisms that would cause mild to moderate illnesses in healthy people may cause
life‑threatening infections in babies with SCID. Even organisms that do not ordinarily
make people sick may make a child with SCID very ill. Babies with SCID typically suffer
from many, severe cases of yeast (thrush or diaper rash), chicken pox, measles, herpes
virus (cold sores), ear infections, meningitis (brain infections), or pneumonia that do not
respond well to standard medical treatments. Children with SCID may also become
infected with viruses (cytomegalovirus) from breastmilk, other live viruses (for example,
the rotavirus or chickenpox) from vaccination or from common colds (viruses or
bacteria) from siblings or surrounding children with healthy immune systems that can
get rid of those infections.

It is critical that a child with SCID receive a stem cell transplant as soon as possible and
preferably in the first few months of life. Children with SCID should avoid any live
vaccines, young children that can often transmit common infections, and breast feeding
until the milk can be tested to ensure the best success of the bone marrow transplant.

Causes
Typical or Classic SCID

SCID may be inherited as an autosomal recessive genetic trait or an X-linked trait.

Human traits, including the classic genetic diseases, are the product of the interaction of
two genes: one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits two copies of an

abnormal gene for the same trait, one from each parent. If an individual inherits one
normal gene and one gene for the disease, the person will be a carrier for the disease
but usually will not show symptoms. The risk for two carrier parents to both pass the
altered gene and have an affected child is 25% with each pregnancy. The risk to have a
child who is a carrier like the parents is 50% with each pregnancy. The chance for a
child to receive normal genes from both parents is 25%. The risk is the same for males
and females.

SCID can also be inherited as an X-linked disorder. X-linked genetic disorders are
caused by an abnormal gene on the X chromosome and manifest mostly in males.
Females that have an altered gene present on one of their X chromosomes are carriers
for that disorder. Carrier females usually do not display symptoms because females
have two X chromosomes and only one carries the altered gene. Males have one X
chromosome that is inherited from their mother and if a male inherits an X
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chromosome that contains an altered gene he will develop the disease. Female carriers
of an X-linked disorder have a 25% chance with each pregnancy to have a carrier
daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to
have a son affected with the disease and a 25% chance to have an unaffected son. If a
male with an X-linked disorder is able to reproduce, he will pass the altered gene to all
of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons
because males always pass their Y chromosome instead of their X chromosome to male
offspring.

Newborn babies with SCID develop similar symptoms including difficulty gaining weight,
diarrhea and recurrent infections. There are four main categories of typical or classic
SCID based upon which immune cells (T, B, or NK cells) are defective. The categories are
most important for treatment considerations.

B-positive, NK-negative severe combined immunodeficiency (T-B+NK- SCID)

T-negative, B-positive, natural killer (NK)-negative (T-B+NK-) SCID is a type of SCID that
occurs when T cells and NK cells cannot respond to growth factors (cytokines) needed to
develop and survive in the body. The most common cause of T-B+NK- SCID, is X‑linked
recessive SCID (X-SCID) caused by an altered IL2RG gene found on the X chromosome.
The IL2RG gene codes for the protein gamma subunit (γ c) of the cytokine receptors for
interleukin (IL-)2, IL-4, IL-7, IL-9, IL-15, and IL-21. The γc receptor is defective in boys with
X-SCID and cannot send signals from the growth factors needed to make functional T
cells and NK cells. The B cells in these patients are also non-functional without the help
from T cells.

T-B+NK- SCID can also be caused by autosomal recessive mutations in the JAK3 gene. As
in X-SCID, the T cells and NK cells in the body need the JAK3 protein to respond to the
growth factors needed to develop and survive in the body. Defects in the JAK3 gene are
now known to cause most autosomal recessive cases of T-B+NK- SCID.

B-negative, NK-positive severe combined immunodeficiency (T-B-NK+ SCID)

T-B-NK+ SCID is caused by a defect in both T and B cells, but not NK cells. The T cells
and B cells in the body need both growth factors and expression of an antigen receptor
to develop and survive. Each T cell or B cell recognizes a unique antigen (part of an
invading bacteria, fungi or virus) through its particular antigen receptor. The cellular
machinery needed to make a unique antigen receptor includes recombinase activating
genes 1 (RAG1) and 2 (RAG2). Many mutations in RAG1 or RAG2 result in absent or non-
functional protein causing T-B-NK+ SCID. If a mutation causes a reduced function the
RAG1 or RAG2 proteins, then Atypical or Leaky SCID can occur (see below).

Other rarer causes of T-B-NK+ SCID result from defects in other genes also needed to
make the antigen receptor including DCLRE1C gene that encodes for Artemis protein,
notably with a higher frequency in the southwestern Athabascan-speaking Native

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American population. Other radiation sensitive disorders caused by autosomal
recessive genes (PRKDC, LIG4, NHEJ1) have been rarely reported to cause T-B-NK+ SCID
as well. These are all autosomal recessive forms of SCID.

B-negative, NK-negative severe combined immunodeficiency (T-B-NK- SCID)

Adenosine deaminase deficiency is the most common cause of T-B-NK- SCID. ADA‑SCID,
caused by an altered ADA gene, is autosomal recessive. Individuals with ADA‑SCID have
no T, B, or NK cells and so tend to get bacterial, fungal, and viral diseases. There is some
variation in when ADA-SCID patients develop symptoms depending upon the particular
defect in the ADA gene. Some patients develop symptoms shortly after birth (early
onset), and others later (delayed or late onset). Individuals with delayed ADA-SCID can
be missed by the newborn screening test because they may have detectable numbers
of lymphocytes. ADA functional testing is then needed to make the diagnosis.

Another form of T-B-NK- SCID is caused by mutations in adenylate kinase 2 (AK2), a gene
involved in the development of lymphocytes and other white blood cells in the bone
marrow needed to fight infection. Defects in AK2 result in a severe form of SCID termed
reticular dysgenesis and is usually accompanied by defects in hearing and low
neutrophils as well. The profound neutropenia results in earlier risk for severe
infections.

B-positive, NK-positive severe combined immunodeficiency (T-B+NK+ SCID)

Defects selective only to the T cells cause T-B+NK+ SCID and result from either loss of a
cytokine (or growth factor) receptor or T cell antigen receptor, both needed for T cells to
develop and survive. Deficiency of the alpha chain of the IL‑7 receptor (IL7R gene) is the
most common form of this category of SCID. In humans, IL-7 is critical for the survival
of T cells, but not B cells nor NK cells. Rarer defects in the components of the T cell
antigen receptor have been reported to cause T-B+NK+ SCID including mutations in
CD3D, CD3E, and CD247. In addition, PTPRC gene encodes a CD45 protein that is a
critical regulator of the T cell antigen receptor. Several cases of mutations in PTPRC
gene have been reported to cause T-B-NK+ SCID. All of these genes are autosomal
recessive.

Leaky SCID (also known as Omenn syndrome or atypical SCID)

Some infants with SCID may have detectable or even elevated T cell numbers in a
condition termed atypical or leaky SCID. These patients have only partial defects in
known SCID-causing genes allowing for production of small numbers of T cells. These T
cells do not provide protection from infections but are over-activated causing
inflammation and damage similar to an autoimmune disease. Leaky SCID is the clinical
syndrome that occurs with severe itchy rashes, enlarged lymph nodes, spleen and liver
and chronic diarrhea. Typically leaky SCID is from partial function of either RAG1 or
RAG2 genes, but has been reported in other forms of SCID as well. Importantly, leaky
SCID must be distinguished from engraftment of maternal T cells that can cross the
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placental during pregnancy or delivery and in the absence of fetal T cells can persist in
the baby after birth. These cells can be destructive to the infant and cause similar
symptoms further complicating the diagnosis.

Variant SCID (persistently low T-cells but no defect in known SCID genes)

The rise of newborn screening has increased the detection of infants with persistently
low T-cells with no known defect in a known SCID gene. These children require special
considerations for further work up and management and may represent a combined
immunodeficiency or SCID-like disorder.

Affected Populations
All types of SCID are very rare disorders that occur in approximately 1 or fewer births in
100,000 in the United States. SCID may be more common in people with Navajo,
Apache, or Turkish ancestry.

Related Disorders
Symptoms of the following disorders can be similar to those of SCID. Comparisons may
be useful for a differential diagnosis:

Infection (HIV or congenital rubella)

DiGeorge syndrome (12q11.2 deletion syndrome)
CHARGE syndrome (CHD7)
Zap70 deficiency (ZAP70)
Cartilage hair hypoplasia (RMRP)
MHC class II deficiency (MHC2TA, RFX5, RFXAP, RFXANK)
PNP deficiency (PNP)

Diagnosis
SCID is now diagnosed mainly through from newborn screening in most states. The
screen is performed using the dried blood spot from newborn screening (or Guthrie)
cards measuring levels T-cell receptor excision circles (or TREC). Although each state
has a slightly different methods and thresholds, a low TREC test means the infant has
low numbers of lymphocytes in the blood at the time of the test. The result must then
be confirmed with additional testing. A complete blood count (CBC) coupled with
lymphocyte subset testing may show low levels of B, T, and/or NK cells. Additional tests
can show that one or more of these cell types aren’t functioning properly. Genetic and
biochemical (protein expression) tests are available for some forms of SCID. A
combination of these tests may be required to make an accurate diagnosis needed to
plan treatment.

Standard Therapies
Treatment
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Transplant of stem cells taken from the bone marrow of a healthy, matching donor,
usually by the age of about 3 months, is generally considered the best treatment for
SCID. A bone marrow transplantation center is needed to evaluate the patient for
potential matching donors through national searches, determine the options for each
patient and explain the risks of each treatment option. The type of SCID and the bone
marrow match available to the patient are both two important considerations. While
waiting for a bone marrow transplant, avoiding sick contacts and avoiding breast
feeding is critical to prevent transmission of infections that can make a transplant less
successful. If diagnosis is delayed and infections occur, they must be treated
aggressively. Gene therapy for SCID is still considered to be experimental
(investigational), but considered in patients not eligible for a bone marrow transplant.

An enzyme replacement therapy, where a missing enzyme is injected regularly into the
patient, is available for ADA SCID. This is a treatment, not a cure. Transplant of stem
cells from the bone marrow of a healthy, matching, donor is the only cure for SCID
currently.

An enzyme replacement therapy, where a missing enzyme is injected regularly into the
patient, is available for ADA SCID. This is a treatment, not a cure. Transplant of stem
cells from the bone marrow of a healthy, matching, donor is the only cure for SCID
currently.

In 2018, the enzyme replacement therapy Revcovi (elapegademase-lvlr) was approved

for the treatment of ADA-SCID in pediatric and adult patients. Revcovi is manufactured
by Leadiant Biosciences.

Investigational Therapies
Gene therapy for SCID is being investigated, because it can be difficult or impossible to
find a tissue match for a stem cell transplant in some cases, and because stem cell
transplants are not always successful.

The first gene therapy trial for X-SCID used a retroviral vector to deliver a normal copy of
the IL2RG gene and restored T cell function in children with X-SCID. Unfortunately, in
2005, five of those children developed leukemia after being treated in Paris and
London. Since that time the vectors have been redesigned with new safe guards to
remove the likely cancer-causing elements. Several new clinical trials are underway at
several children’s hospital and at the National Institutes of Health. The goal of this type
therapy is to restore immune function while avoiding complications such as repeat
transplants, incomplete cure of the immune system, exposure to chemotherapy, and
graft versus host disease.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov.

All studies receiving U.S. government funding, and some supported by private industry,
are posted on this government website.

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For information about clinical trials being conducted at the National Institutes of Health
(NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-
recruitment/

For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

For information about clinical trials conducted in Europe, contact:

https://www.clinicaltrialsregister.eu/

NORD Member Organizations

Immune Deficiency Foundation
110 West Road
Suite 300
Towson, MD 21204
Phone: (410) 321-6647
Toll-free: (800) 296-4433
Email: [email protected]
Website: http://www.primaryimmune.org

Other Organizations
European Society for Immunodeficiencies
c/o Kenes International ,
Olga Coschina 7, rue François-Versonnex
Geneva 6, CP 6053 1207 Switzerland
Phone: 41229069163
Email: [email protected]
Website: http://www.esid.org
Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Phone: (301) 251-4925
Toll-free: (888) 205-2311
Website: http://rarediseases.info.nih.gov/GARD/

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 International Patient Organization for Primary Immunodeficiencies
Firside Main Road
Downderry
Cornwall, PL11 3LE United Kingdom
Phone: 441503250668
Email: [email protected]
Website: http://www.ipopi.org/
Rare Diseases Clinical Research Network
Cincinnati Children’s Hospital Medical Center
3333 Burnett Avenue, MLC 5041
Cincinnati, OH 45229 USA
Phone: (813) 396-9501
Toll-free: (866) 533-9104
Email: [email protected]
Website: http://rarediseasesnetwork.epi.usf.edu/registry/

References
TEXTBOOKS

Sullivan KE, Stiehm ER, eds. Stiehm’s Immune Deficiencies. 1st ed. Academic Press,
Waltham, Massachusetts, 2014.

JOURNAL ARTICLES

Cicalese MP, Aiuti A. Clinical applications of gene therapy for primary

immunodeficiencies. Hum Gene Ther. 2015 Apr;26(4):210-9.

Cirillo E, Giardino G, Gallo V, D’Assante R, Grasso F, Romano R, Lillo CD, Galasso G,

Pignata C. Severe combined immunodeficiency-an update. Ann N Y Acad Sci. 2015 Jul
31.

de la Morena MT, Nelson RP Jr. Recent advances in transplantation for primary immune
deficiency diseases: a comprehensive review. Clin Rev Allergy Immunol. 2014
Apr;46(2):131-44.

Dvorak CC, Cowan MJ, Logan BR, Notarangelo LD, Griffith LM, Puck JM, et al. The natural
history of children with severe combined immunodeficiency: baseline features of the
first fifty patients of the primary immune deficiency treatment consortium prospective
study 6901. J Clin Immunol. 2013 Oct;33(7):1156-64.

Hernandez-Trujillo V. New genetic discoveries and primary immune deficiencies. Clin

Rev Allergy Immunol. 2014 Apr;46(2):145-53.

Kohn DB. Gene therapy outpaces haplo for SCID-X1. Blood. 2015 Jun 4;125(23):3521-2.

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Lombardo A, Naldini L. Genome editing: a tool for research and therapy: targeted
genome editing hits the clinic. Nat Med. 2014 Oct;20(10):1101-3.

Pai SY, Cowan MJ. Stem cell transplantation for primary immunodeficiency diseases: the
North American experience. Curr Opin Allergy Clin Immunol. 2014 Dec;14(6):521-6.

Qasim W, Gennery AR. Gene therapy for primary immunodeficiencies: current status
and future prospects. Drugs. 2014 Jun;74(9):963-9.

Touzot F, Hacein-Bey-Abina S, Fischer A, Cavazzana M. Gene therapy for inherited

immunodeficiency. Expert Opin Biol Ther. 2014 Jun;14(6):789-98.

van der Spek J, Groenwold RH, van der Burg M, van Montfrans JM. TREC Based Newborn
Screening for Severe Combined Immunodeficiency Disease: A Systematic Review. J Clin
Immunol. 2015 May;35(4):416-30.

INTERNET

Allenspach E, Rawlings DJ, Scharenberg AM. X-Linked Severe Combined

Immunodeficiency. 2003 Aug 26 [Updated 2015 Jul 30]. In: Pagon RA, Adam MP,
Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of
Washington, Seattle; 1993-2015. Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1410/ Accessed February 24, 2016.

McKusick VA., Ed. Online Mendelian Inheritance in Man (OMIM). Severe Combined
Immunodeficiency, X-linked. Available at http://omim.org/entry/300400 Last Update:
02/11/2014. Accessed February 24, 2016.

Patient and Family Handbook for Primary Immunodeficiency Diseases. Available at:
http://primaryimmune.org/wp-
content/uploads/2013/06/IDF_Patient_Family_Handbook_5th_Edition.pdf. Copyright
2013 Immune Deficiency Foundation.

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