Cholestasis and Hepatic Iron

Deposition in an Infant With Complex

Glycerol Kinase Deficiency
Diana Montoya-Williams, MD, Meredith Mowitz, MD, MS

We present a 6-week-old male infant with persistent hyperbilirubinemia, abstract

hypertriglyceridemia, elevated creatine kinase levels, and transaminitis
since the second week of life. When he developed hyperkalemia,
clinical suspicion was raised for adrenal insufficiency despite
hemodynamic stability. A full endocrine workup revealed nearly
absent adrenocorticotropic hormone. Coupled with his persistent
hypertriglyceridemia (peak of 811 mg/dL) and elevated creatine kinase
levels (>20 000 U/L), his corticotropin level lead to a clinical diagnosis of
complex glycerol kinase deficiency (GKD), also known as Xp21 deletion
syndrome. This complex disorder encompasses the phenotype of
Duchenne muscular dystrophy, GKD, and congenital adrenal hypoplasia
due to the deletion of 3 contiguous genetic loci on the X chromosome.
Division of Neonatology, Department of Pediatrics,
Our case exemplifies the presentation of this disorder and highlights the University of Florida, Gainesville, Florida
important lesson of distinguishing between adrenal hypoplasia congenita
Dr Montoya-Williams cared for the patient and
and congenital adrenal hyperplasia, as well as the sometimes subtle drafted the initial manuscript; Dr Mowitz cared
presentation of adrenal insufficiency. To our knowledge, it is also the first for the patient and reviewed and edited the
reported case of complex GKD deficiency with the additional finding of manuscript; and both authors approved the final
manuscript and agree to be accountable for all
hepatic iron deposition, which may indicate a potential area for exploration
aspects of the work.
regarding the pathogenesis of liver injury and cholestasis seen in cortisol-
DOI: https://doi.org/10.1542/peds.2016-1479
related endocrinopathies.
Accepted for publication Dec 12, 2016
Address correspondence to Diana Montoya-
Williams, MD, Department of Pediatrics, Division of
Adrenal hypoplasia congenita (AHC) (DMD), which is then often labeled Neonatology, University of Florida, PO Box 100296,
is a rare cause of congenital adrenal complex GKD or Chromosome Xp21 Gainesville, FL 32610. E-mail: dmontoyafontalvo@
insufficiency that often presents deletion syndrome due to the position peds.ufl.edu
early in life, with salt wasting and of all 3 loci on the short arm of the X PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
hypoglycemia leading to growth chromosome.2 Isolated GKD can cause 1098-4275).
failure and hemodynamic crises.1 metabolic acidosis and hypoglycemia Copyright © 2017 by the American Academy of
It may present similarly to the but is usually asymptomatic and Pediatrics
more common congenital adrenal detected incidentally through FINANCIAL DISCLOSURE: The authors have
hyperplasia, but has important hyperlipidemia testing, as it causes indicated they have no financial relationships
a pseudohypertriglyceridemia.3 relevant to this article to disclose.
clinical distinctions, such as the
potential for hyperpigmentation, Complex GKD, however, carries a FUNDING: No external funding.
cryptorchidism and other signs of much more serious prognosis, as it can POTENTIAL CONFLICT OF INTEREST: The authors
hypogonadotropic hypogonadism, lead to life-threatening adrenal crises have indicated they have no potential conflicts of
if unrecognized. interest to disclose.
and associated disorders. AHC can
be autosomal recessive or present
as part of a contiguous X-linked To cite: Montoya-Williams D and Mowitz M.
recessive genetic syndrome together
PRESENTATION Cholestasis and Hepatic Iron Deposition in an
Infant With Complex Glycerol Kinase Deficiency.
with glycerol kinase deficiency (GKD) The case was a 3100-g 6-week-
Pediatrics. 2017;140(1):e20161479
and Duchenne muscular dystrophy old male infant transferred to our

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PEDIATRICS Volume 140, number 1, July 2017:e20161479 CASE REPORT
NICU for further evaluation of
persistent hyperbilirubinemia,
hypertriglyceridemia, elevated
creatine kinase (CK) levels, and
transaminitis. He was born at 40
weeks’ gestation by spontaneous
vaginal delivery to a 30-year-old
gravida 1 para 0 mother who was
Group B Streptococcus positive
but otherwise had unremarkable
prenatal serologies. Apgar scores
were 9 and 9 at 1 and 5 minutes,
respectively, and birth weight
was 2946 g. Mother received
adequate intrapartum antibiotic
prophylaxis but was diagnosed with
chorioamnionitis; thus, the patient
received 48 hours of antibiotics at
birth. He was also noted to have mild
jaundice in the first few days of life
attributed to ABO incompatibility,
although his hemoglobin levels
showed no evidence of hemolysis.
On day of life 5, he became febrile,
lethargic, and more jaundiced.
He developed severe refractory
hypotension and respiratory
failure. Laboratory testing
revealed a significant coagulopathy
(international normalized ratio 3.9),
hyponatremia, and hyperkalemia
in the setting of significant oliguria.
He was also noted to have signs
of end-organ ischemia with an
elevation in his troponins, creatinine,
transaminases, and CK levels. He
was managed with broad-spectrum
antibiotics for presumed sepsis,
and with multiple vasopressors and
hydrocortisone for his refractory
hypotensive shock. He received
intramuscular vitamin K and fresh-
frozen plasma transfusions over
several days until normalization of
his international normalized ratio.
Extensive infectious workup,
including bacterial, viral, and fungal
studies, remained negative. He slowly
improved and was weaned from the
ventilator and all blood pressure
support, including steroids. All
laboratory values normalized with
the exception of his direct bilirubin,
CK levels, and transaminases, with
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e2
his aspartate aminotransferase and and mild hypotonia, but notably no
alanine aminotransferase showing hepatomegaly. He also had extremely
a persistent fivefold elevation dark skin, which the parents reported
despite discontinuation of parenteral was not present at birth but had
nutrition. He was further noted to developed quickly after birth. The
have elevated triglyceride levels up remainder of the examination
to maximum of 811 mg/dL despite was normal. Laboratories in the
being fed several different types of first week of admission revealed
formula. normal electrolytes but continued
hypertriglyceridemia, cholestasis,
Given the continued elevation in
transaminitis, and CK elevations
his bilirubin and transaminases, he
(Table 1). We investigated for inborn
received an extensive gastrointestinal
errors of bile acid metabolism by
workup, including normal
sending total and fractionated bile
abdominal imaging (ultrasound
acid levels, as elevations of unusual
and upper gastrointestinal series),
bile acids have been associated with
normal pancreatic enzyme and
severe cholestasis and subsequent
ammonia levels, and negative
liver damage.5,6 Although our
hepatitis serologies. A hepatobiliary
patient’s total bile acid levels were
iminodiacetic acid scan conducted at
elevated (>128 μmol/L), his profile
1 month of life revealed no excretion
indicated nonspecific cholestasis
of tracer from the liver; thus, a liver
given the predominance of primary
biopsy was done, which revealed
bile acids.
focal intracellular cholestasis
with giant cell transformation of
Over the next 2 weeks, he remained
some hepatocytes and moderately
hospitalized working on oral feeds.
increased iron stores, but no
Routine laboratories at 7 weeks of
steatosis, fibrosis, necrosis,
age revealed hyponatremia (130
inflammation, or features of biliary
mmol/L) and hyperkalemia (8.1
atresia. The hepatic siderosis
mmol/L) with normal renal function
raised concerns for neonatal
(creatinine 0.18 mg/dL) and good
hemochromatosis, a phenotype of
urine output on full enteral feeds
severe liver disease with extrahepatic
and no medications. Although he
iron deposition that can result
remained hemodynamically stable,
from various causes.4 Our patient
his ongoing lack of a unifying
underwent a buccal biopsy to look
diagnosis and these laboratory
for iron staining and a brain MRI to
findings led to an investigation
look for iron deposition, but these
of his adrenal function. Both
were both normal. He was evaluated
his cortisol (2.0 μg/dL) and
for inborn errors of metabolism
aldosterone (<3.0 ng/dL) levels were
that can cause liver disease, such as
abnormally low. Concurrent plasma
galactosemia, tyrosinemia, or α-1
adrenocorticotropic hormone and
antitrypsin deficiency, and was found
plasma renin activity levels were
to have borderline elevated levels of
noted to be extremely elevated at
acylcarnitines known to be falsely
3192 pg/mL (normal 5–46 pg/mL)
elevated by parenteral nutrition.
and 66 ng/mL per hour (normal
Otherwise this workup was negative.
for age <37 mg/mL per hour),
Given the persistent laboratory respectively. Combining this evidence
abnormalities, transfer to our NICU of adrenal hypofunction with his
was requested. On admission, he elevated CK levels, complex GKD was
was clinically stable, but his weight suspected. The laboratory was asked
was below the third percentile, to correct his triglyceride levels for
down from the 15th percentile serum glycerols, which revealed a
at birth. Examination revealed true triglyceride level within the
cryptorchidism, scleral icterus, normal range. Furthermore, glycerol
MONTOYA-WILLIAMS and MOWITZ
TABLE 1 Summary of Abnormal Laboratory Studies After Admission to Our Hospital at 6 Weeks of Age
Laboratory Test
Triglyceride
Total bilirubin
Direct bilirubin
γ glutamyl transpeptidase
Aspartate aminotransferase (serum glutamic-oxaloacetic
transaminase)
Alanine aminotransferase (serum glutamic-pyruvic transaminase)
CK
TABLE 2 Results of the Comparative Genomic Hybridization Microarray Study for Our Patient
Chromosomal Region Minimum Size of
Affected Lossa
Xp21.3p21.1 ∼7683.0 kb
a A minimum size value represents the actual base pair coordinates of the probes detected as a copy number change, whereas a maximum size value includes the gap distances to
bordering unaffected probes that may potentially include additional materials involved in the change detected.
kinase levels were confirmed to be
elevated at 4384 μmol/L (normal
13–66 μmol/L).
Ultimately, a comparative genomic
hybridization microarray study was
done, which confirmed an Xp21
deletion (Table 2). His mother was
also found to be a carrier of this
deletion by fluorescence in situ
hybridization study.
Our patient was started on
replacement fludrocortisone
and hydrocortisone; within 4
days, his plasma renin activity
levels normalized. Over the
course of the next few weeks, his
hyperpigmentation, feeding skills,
and weight gain also improved and
he was discharged from the hospital.
DISCUSSION
GKD can exist alone as an isolated
deficiency and may cause a Reye-like
syndrome of vomiting, metabolic
acidosis, and ketotic hypoglycemia
due to hyperglycerolemia and
glyceroluria.2 However, it is often
asymptomatic and discovered
incidentally later in life through
hyperlipidemia testing, given many
laboratories’ standard methodology
of reporting serum triglycerides
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PEDIATRICS Volume 140, number 1, July 2017
Range Over the First Week of Admission to Our Hospital
450–781 mg/dL
9.8–11.6 mg/dL
7.2–8.9 mg/dL
223 U/L
193–335 U/L
97–243 U/L
4171 U/L to >20 000 U/L
Maximum Size of Maximum Boundaries (Base Pair
Lossa Coordinates)
∼77347.7 kb chrX:25800484–33535137
indirectly by measuring serum
glycerol levels.3,7 When patients
are also missing either of both
the dystrophin gene and/or the
Nuclear Receptor Subfamily 0,
Group B, Member 1 (NR0B1) gene,
the condition is known as complex
GKD or Chromosome Xp21 deletion
syndrome due to the contiguous
position of all 3 loci on the short
arm of the X chromosome.2 Each
gene deletion contributes to the
phenotype, with the deletion of the
dystrophin gene causing weakness
and muscle breakdown consistent
with DMD, the deletion of the NR0B1
gene causing AHC due to a deficiency
of the DAX-1 protein and finally,
the deletion of the glycerol kinase
gene causing elevated glycerol
levels.8 When all 3 genes are deleted,
the presentation of this recessive
X-linked condition is more severe and
occurs in the infantile period. Due to
the involvement of NR0B1 in gonadal
development, cryptorchidism may be
present, as in our patient, and there is
potential for later hypogonadotropic
hypogonadism during puberty.8
Most patients with complex GKD
involving the AHC loci will present
with an acute adrenal crisis in the
first few weeks to months of life. Our
patient’s presumed septic crisis in
Reference Ranges for Age
30–124 mg/dL
<1.2 mg/dL
0–0.2 mg/dL
4–120 U/L
15–60 U/L
13–45 U/L
30–170 U/L
Potential Disease(s) or Gene(s) That May Be
Associated With This Region
DMD, GK, IL1RAPL1, NR0B1
Chromosome Xp21 deletion syndrome
Online Mendelian Inheritance in Man: 300679
the first week of life was likely his
first manifestation of his AHC. When
an infant presents with symptoms
of adrenal insufficiency, clinicians
must rightly consider congenital
adrenal hyperplasia, as it has a
much higher incidence of 1:5000 to
1:15 000 compared with 1:140 000 to
1:1 200 000 for AHC.8,9 Importantly,
AHC usually presents with normal
17-hydroxyprogesterone levels,
excluding the most common cause of
congenital adrenal hyperplasia.10–12
In addition, given AHC’s involvement
of the entire adrenal gland, it has
the potential for an Addisonian-like
presentation of hyperpigmentation,
which can help differentiate it from
other forms of adrenal insufficiency.
Our patient was born with light
brown skin (Fig 1), which darkened
significantly in the first week of life
(Fig 2).
We believe our patient’s persistent
direct hyperbilirubinemia with
biopsy-confirmed cholestasis was
also likely related to his AHC. The
relationship between cortisol
deficiency and cholestasis has been
well-described.13 Although the
mechanism is not well understood,
it may be related to cortisol’s effect
on bile formation. In 1 case series
of 4 neonates with severe cortisol
e3

FIGURE 1
Our patient’s skin pigmentation immediately
after birth.
deficiency, cholestasis resolved
with hydrocortisone replacement.13
We witnessed this same pattern in
our patient, whose direct bilirubin
peaked at 8.9 mg/dL but improved
down to 3.6 mg/dL after replacement
steroid therapy.
Our patient, however, uniquely
exhibited iron deposition on his liver
biopsy. To our knowledge, hepatic
siderosis has not been previously
documented in any of the reported
cases of isolated AHC, GKD, DMD,
or complex GKD. It is possible that
his siderosis was related to other
etiologies. For instance, hepatic
siderosis has been documented
in cases of neonatal acute liver
failure.14 Our patient’s history of
coagulopathy, transaminitis, and
direct hyperbilirubinemia during
his early hypotensive shock episode
indicate that he likely suffered at
least acute hepatic injury; however,
his coagulopathy quickly improved
and he never developed episodes of
bleeding, ascites, or hepatomegaly.
Additionally, the liver biopsy did
not have any of the hepatocyte loss,
inflammation, or necrosis typically
associated with acute liver failure, or
any cirrhosis or fibrosis indicative of
chronic liver injury.
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e4
FIGURE 2
Our patient’s pigmentation at the time of
presentation to our institution at 6 weeks of
age.
There have, however, been several
case reports of patients with
adrenal insufficiency who were
found to have increased hepatic
iron deposition.15,16 In addition,
there is at least 1 reported case
of improvement in liver failure
after corticosteroid replacement
for adrenal insufficiency, possibly
indicating a relationship between
these 2 disease processes.17 Given
this literature, it is possible that our
patient’s siderosis was related to his
adrenal hypofunction and not simply
a manifestation of our patient’s initial
acute hepatic injury. Future efforts to
understand this contiguous deletion
syndrome may therefore benefit from
the exploration of the potential link
among adrenal insufficiency, hepatic
iron deposition, and cholestatic liver
injury.
CONCLUSIONS
It is important for clinicians to
consider AHC and its associated
genetic syndromes when evaluating
infants with suspected adrenal
insufficiency. Further studies
focused on the relationship between
cholestasis and cortisol deficiency
are warranted, as they may provide
insight into the pathophysiology of
disorders such as complex GKD.
ACKNOWLEDGMENTS
The authors acknowledge the parents
of this infant who gave informed
consent to describe this patient
for a case report and provided
photographs.
ABBREVIATIONS
AHC: adrenal hypoplasia
congenita
CK: creatine kinase
DMD: Duchenne muscular
dystrophy
GKD: glycerol kinase deficiency
NR0B1: Nuclear Receptor
Subfamily 0, Group B,
Member 1
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 Cholestasis and Hepatic Iron Deposition in an Infant With Complex Glycerol
Kinase Deficiency
Diana Montoya-Williams and Meredith Mowitz
Pediatrics originally published online June 29, 2017;

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Cholestasis and Hepatic Iron Deposition in an Infant With Complex Glycerol
Kinase Deficiency
Diana Montoya-Williams and Meredith Mowitz
Pediatrics originally published online June 29, 2017;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/early/2017/06/27/peds.2016-1479

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