Cholestasis and Hepatic Iron Deposition in An Infant With Complex Glycerol Kinase Deficiency

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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 his aspartate aminotransferase and and mild hypotonia, but notably no
persistent hyperbilirubinemia, alanine aminotransferase showing hepatomegaly. He also had extremely
hypertriglyceridemia, elevated a persistent fivefold elevation dark skin, which the parents reported
creatine kinase (CK) levels, and despite discontinuation of parenteral was not present at birth but had
transaminitis. He was born at 40 nutrition. He was further noted to developed quickly after birth. The
weeks’ gestation by spontaneous have elevated triglyceride levels up remainder of the examination
vaginal delivery to a 30-year-old to maximum of 811 mg/dL despite was normal. Laboratories in the
gravida 1 para 0 mother who was being fed several different types of first week of admission revealed
Group B Streptococcus positive formula. normal electrolytes but continued
but otherwise had unremarkable hypertriglyceridemia, cholestasis,
Given the continued elevation in
prenatal serologies. Apgar scores transaminitis, and CK elevations
his bilirubin and transaminases, he
were 9 and 9 at 1 and 5 minutes, (Table 1). We investigated for inborn
received an extensive gastrointestinal
respectively, and birth weight errors of bile acid metabolism by
workup, including normal
was 2946 g. Mother received sending total and fractionated bile
abdominal imaging (ultrasound
adequate intrapartum antibiotic acid levels, as elevations of unusual
and upper gastrointestinal series),
prophylaxis but was diagnosed with bile acids have been associated with
normal pancreatic enzyme and
chorioamnionitis; thus, the patient severe cholestasis and subsequent
ammonia levels, and negative
received 48 hours of antibiotics at liver damage.5,6 Although our
hepatitis serologies. A hepatobiliary
birth. He was also noted to have mild patient’s total bile acid levels were
iminodiacetic acid scan conducted at
jaundice in the first few days of life elevated (>128 μmol/L), his profile
1 month of life revealed no excretion
attributed to ABO incompatibility, indicated nonspecific cholestasis
of tracer from the liver; thus, a liver
although his hemoglobin levels given the predominance of primary
biopsy was done, which revealed
showed no evidence of hemolysis. bile acids.
focal intracellular cholestasis
On day of life 5, he became febrile, with giant cell transformation of
Over the next 2 weeks, he remained
lethargic, and more jaundiced. some hepatocytes and moderately
hospitalized working on oral feeds.
He developed severe refractory increased iron stores, but no
Routine laboratories at 7 weeks of
hypotension and respiratory steatosis, fibrosis, necrosis,
age revealed hyponatremia (130
failure. Laboratory testing inflammation, or features of biliary
mmol/L) and hyperkalemia (8.1
revealed a significant coagulopathy atresia. The hepatic siderosis
mmol/L) with normal renal function
(international normalized ratio 3.9), raised concerns for neonatal
(creatinine 0.18 mg/dL) and good
hyponatremia, and hyperkalemia hemochromatosis, a phenotype of
urine output on full enteral feeds
in the setting of significant oliguria. severe liver disease with extrahepatic
and no medications. Although he
He was also noted to have signs iron deposition that can result
remained hemodynamically stable,
of end-organ ischemia with an from various causes.4 Our patient
his ongoing lack of a unifying
elevation in his troponins, creatinine, underwent a buccal biopsy to look
diagnosis and these laboratory
transaminases, and CK levels. He for iron staining and a brain MRI to
findings led to an investigation
was managed with broad-spectrum look for iron deposition, but these
of his adrenal function. Both
antibiotics for presumed sepsis, were both normal. He was evaluated
his cortisol (2.0 μg/dL) and
and with multiple vasopressors and for inborn errors of metabolism
aldosterone (<3.0 ng/dL) levels were
hydrocortisone for his refractory that can cause liver disease, such as
abnormally low. Concurrent plasma
hypotensive shock. He received galactosemia, tyrosinemia, or α-1
adrenocorticotropic hormone and
intramuscular vitamin K and fresh- antitrypsin deficiency, and was found
plasma renin activity levels were
frozen plasma transfusions over to have borderline elevated levels of
noted to be extremely elevated at
several days until normalization of acylcarnitines known to be falsely
3192 pg/mL (normal 5–46 pg/mL)
his international normalized ratio. elevated by parenteral nutrition.
and 66 ng/mL per hour (normal
Otherwise this workup was negative.
Extensive infectious workup, for age <37 mg/mL per hour),
including bacterial, viral, and fungal Given the persistent laboratory respectively. Combining this evidence
studies, remained negative. He slowly abnormalities, transfer to our NICU of adrenal hypofunction with his
improved and was weaned from the was requested. On admission, he elevated CK levels, complex GKD was
ventilator and all blood pressure was clinically stable, but his weight suspected. The laboratory was asked
support, including steroids. All was below the third percentile, to correct his triglyceride levels for
laboratory values normalized with down from the 15th percentile serum glycerols, which revealed a
the exception of his direct bilirubin, at birth. Examination revealed true triglyceride level within the
CK levels, and transaminases, with cryptorchidism, scleral icterus, normal range. Furthermore, glycerol

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e2 MONTOYA-WILLIAMS and MOWITZ
TABLE 1 Summary of Abnormal Laboratory Studies After Admission to Our Hospital at 6 Weeks of Age
Laboratory Test Range Over the First Week of Admission to Our Hospital Reference Ranges for Age
Triglyceride 450–781 mg/dL 30–124 mg/dL
Total bilirubin 9.8–11.6 mg/dL <1.2 mg/dL
Direct bilirubin 7.2–8.9 mg/dL 0–0.2 mg/dL
γ glutamyl transpeptidase 223 U/L 4–120 U/L
Aspartate aminotransferase (serum glutamic-oxaloacetic 193–335 U/L 15–60 U/L
transaminase)
Alanine aminotransferase (serum glutamic-pyruvic transaminase) 97–243 U/L 13–45 U/L
CK 4171 U/L to >20 000 U/L 30–170 U/L

TABLE 2 Results of the Comparative Genomic Hybridization Microarray Study for Our Patient
Chromosomal Region Minimum Size of Maximum Size of Maximum Boundaries (Base Pair Potential Disease(s) or Gene(s) That May Be
Affected Lossa Lossa Coordinates) Associated With This Region
Xp21.3p21.1 ∼7683.0 kb ∼77347.7 kb chrX:25800484–33535137 DMD, GK, IL1RAPL1, NR0B1
Chromosome Xp21 deletion syndrome
Online Mendelian Inheritance in Man: 300679
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 indirectly by measuring serum the first week of life was likely his
elevated at 4384 μmol/L (normal glycerol levels.3,7 When patients first manifestation of his AHC. When
13–66 μmol/L). are also missing either of both an infant presents with symptoms
the dystrophin gene and/or the of adrenal insufficiency, clinicians
Ultimately, a comparative genomic
Nuclear Receptor Subfamily 0, must rightly consider congenital
hybridization microarray study was
Group B, Member 1 (NR0B1) gene, adrenal hyperplasia, as it has a
done, which confirmed an Xp21
the condition is known as complex much higher incidence of 1:5000 to
deletion (Table 2). His mother was
GKD or Chromosome Xp21 deletion 1:15 000 compared with 1:140 000 to
also found to be a carrier of this
syndrome due to the contiguous 1:1 200 000 for AHC.8,9 Importantly,
deletion by fluorescence in situ
position of all 3 loci on the short AHC usually presents with normal
hybridization study.
arm of the X chromosome.2 Each 17-hydroxyprogesterone levels,
Our patient was started on gene deletion contributes to the excluding the most common cause of
replacement fludrocortisone phenotype, with the deletion of the congenital adrenal hyperplasia.10–12
and hydrocortisone; within 4 dystrophin gene causing weakness In addition, given AHC’s involvement
days, his plasma renin activity and muscle breakdown consistent of the entire adrenal gland, it has
levels normalized. Over the with DMD, the deletion of the NR0B1 the potential for an Addisonian-like
course of the next few weeks, his gene causing AHC due to a deficiency presentation of hyperpigmentation,
hyperpigmentation, feeding skills, of the DAX-1 protein and finally, which can help differentiate it from
and weight gain also improved and the deletion of the glycerol kinase other forms of adrenal insufficiency.
he was discharged from the hospital. gene causing elevated glycerol Our patient was born with light
levels.8 When all 3 genes are deleted, brown skin (Fig 1), which darkened
the presentation of this recessive significantly in the first week of life
DISCUSSION X-linked condition is more severe and (Fig 2).
occurs in the infantile period. Due to
GKD can exist alone as an isolated We believe our patient’s persistent
the involvement of NR0B1 in gonadal
deficiency and may cause a Reye-like direct hyperbilirubinemia with
development, cryptorchidism may be
syndrome of vomiting, metabolic biopsy-confirmed cholestasis was
present, as in our patient, and there is
acidosis, and ketotic hypoglycemia also likely related to his AHC. The
potential for later hypogonadotropic
due to hyperglycerolemia and relationship between cortisol
hypogonadism during puberty.8
glyceroluria.2 However, it is often deficiency and cholestasis has been
asymptomatic and discovered Most patients with complex GKD well-described.13 Although the
incidentally later in life through involving the AHC loci will present mechanism is not well understood,
hyperlipidemia testing, given many with an acute adrenal crisis in the it may be related to cortisol’s effect
laboratories’ standard methodology first few weeks to months of life. Our on bile formation. In 1 case series
of reporting serum triglycerides patient’s presumed septic crisis in of 4 neonates with severe cortisol

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PEDIATRICS Volume 140, number 1, July 2017 e3
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
FIGURE 2 GKD: glycerol kinase deficiency
Our patient’s pigmentation at the time of NR0B1: Nuclear Receptor
presentation to our institution at 6 weeks of
FIGURE 1 Subfamily 0, Group B,
age.
Our patient’s skin pigmentation immediately Member 1
after birth.
There have, however, been several
deficiency, cholestasis resolved case reports of patients with
with hydrocortisone replacement.13 adrenal insufficiency who were
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PEDIATRICS Volume 140, number 1, July 2017 e5
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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