Indian Pediatr 2014;51: 399-400
Phenotypic Variability in Congenital Lipoid
Rajesh Joshi, *Dhanjit Das, *Parag Tamhankar and Shakil Shaikh
From Department of Pediatrics, BJ Wadia hospital for
Children, Mumbai and *Genetic Research Centre,
NIRRH, Parel, Mumbai, India.
Correspondence to: Dr Rajesh Joshi, D/3, Om
Parshvanath Apartments, Saibaba Nagar,
Borivali (West), Mumbai 400 092, India.
Received: July 26. 2013;
Initial review: October 04, 2013;
Accepted: February 05, 2014.
Background: Congenital lipoid adrenal hyperplasia presents with
adrenal insufficiency and sex reversal in 46XY genetic males. Case
characteristics: Two patients (46 XY karyotype), one having
ambiguous genitalia and other having female external genitalia,
presented with adrenal crisis at 6 months and 4 weeks of age,
respectively. Observation: Steroidogenic Acute Regulatory
Protein gene sequencing revealed homozygous mutations in both
patients. Outcome: Treatment with hydrocortisone and
fludrocortisone resulted in marked improvement . Message:
Congenital lipoid adrenal hyperplasia should be considered in infants
having female or ambiguous genitalia, and presenting with adrenal
Keywords: Adrenal crisis, Ambiguous genitalia,
Congenital lipoid adrenal hyperplasia (CLAH) due
to steroidogenic acute regulatory protein (STAR) gene mutations
is the most severe form of congenital adrenal hyperplasia, in which all
steroidogenesis is impaired in adrenals and gonads. This results in all
individuals – regardless of karyotype – having female external
genitalia, hyponatremia, hyperkalemia, acidosis and shock . Though
children with 46 XY karyotype have complete sex reversal, few cases with
mild genital virilization have been reported. We report two patients
having CLAH with such phenotypic variability.
Case 1: A two-month old girl born out of
consanguineous union was referred for frequent vomiting, failure to
thrive and increasing dark pigmentation of skin. She had previous
admissions at 4 and 7 weeks of life for severe dehydration, and in one
such admission she was found to have hyponatremia (serum sodium- 113 mEq/L),
hyperkalemia (serum potassium- 6.5 mEq/L) and metabolic acidosis
(pH-7.2, bicarbonate18 mEq/L). She weighed 4 kg (birth weight 3 kg) with
length of 61 cm, and had normal external female genitalia without
palpable gonads. A provisional diagnosis of primary adrenal
insufficiency was made. Blood investigations were: serum sodium 113 mEq/L
, potassium 6.4 mEq/L, glucose 80 mg/dL, cortisol <1 µg/dL, ACTH 3320
pg/mL and 17-hydroxy-progesterone (17OHP)- 0.58 ng/mL (N:0.07-1.7 ng/ml).
Abdominal imaging revealed nodular hyperplasia of adrenals and inguinal
testis (retracting intra-abdominally) with absence of mullerian
structures. Further investigtions showed: Serum testosterone <0.01 ng/mL
(no rise after HCG stimulation), dehydroepiandrosterone (DHEA) 0.28 ng/mL,
androstenidione <0.3 ng/mL and 46XY karyotype. Complete sequencing of
the STAR gene revealed homozygous mutation c.441G>A (p.W147X).
Case 2: A six-month-old child born out of
consanguineous union and reared as girl was brought with adrenal crisis.
She also had failure to thrive and dark pigmentation of skin. She had a
weight of 4 kg (birth weight 2.75 kg) and length of 64 cm. Genital
examination revealed phallus of 2 cm, partial fusion of labioscrotal
folds with palpable gonads, and single opening at junction of phallus
and labioscrotal folds. Investigations revealed: serum Na 119 mEq/L,
serum K 7.8 mEq/L, blood pH 7.23, serum bicarbonate 8 mEq/L, glucose 39
mg/dL, cortisol 7.83 µg/dL (30 and 60 min after ACTH stimulation 9 and
8.4 µg/dL, respectively), ACTH 12490 pg/mL, testosterone <0.08 ng/mL (no
rise after HCG stimulation), DHEA 17.3 ng/mL, androstenidione 0.34 ng/mL,
17-OHP 0.43ng/mL, and 46XY karyotype. Abdominal imaging revealed
inguinal canal testes, normal adrenals and absence of mullerian
structures. Sequencing of the STAR gene revealed homozygous
mutation c.544C>T (p.R182C).
Both patients were treated with hydrocortisone,
fludrocortisone and oral salt. The parents of second patient decided to
rear their child as boy.
STAR mutations are found commonly in Japanese,
Korean and Palestinian populations but are rarely reported elsewhere
. The human STAR gene is localized on chromosome 8p11.2 .
STAR mediates the rapid action of ACTH on the adrenal and of
luteinizing hormone (LH) on the gonad by facilitating rapid movement of
cholesterol from the outer to the inner mitochondrial membrane where it
is converted to pregnenolone. According to the the two-hit model
explaining the pathophysiology of CLAH, this transfer into the
mitochondria does not happen (first hit) resulting in increased ACTH
secretion and subsequently increased cholesterol production that
accumulates as lipid droplets in adrenal cells. This damages the
architecture by mechanical displacement and auto-oxidation (second hit)
Patients with CLAH typically present with a salt
losing crisis in the first 2 months of life (most of them in the first
month) and those with 46XY karyotype have female genitalia because
testosterone synthesis is impaired during fetal development . One of
our patient had classic presentation of CLAH while the other had
atypical presentation marked by mild virilization of genitals and
adrenal crisis at 6 months.The differential diagnoses considered in the
first patient (with sex reversal) were, congenital adrenal hypoplasia
due to SF-1 mutation, mutation of side chain cleavage enzyme (CYP11A1)
gene and Smith Lemli Opitz syndrome. However, adrenal hyperplasia on
imaging made us suspect STAR mutation. The differential diagnoses
considered in second patient were congenital adrenal hypoplasia due to
DAX-1 mutation, 3ß- hydroxysteroid dehydrogenase (3ßHSD)
deficiency and p-450 oxidoreductase (POR) deficiency. Molecular genetic
analysis of DAX-1 and 3ßHSD genes, in our patients,
revealed no abnormality. Normal 17-OHP level, and absence of
craniofacial anomalies or maternal virilization during pregnancy,
suggested a diagnosis of POR deficiency to be unlikely. CLAH may rarely
present with ambiguous genitalia or even normal male genitalia with
delayed clinical manifestations [5-7]. This prompted us to do molecular
genetic analysis for STAR gene mutation in the second patient. At
presentation this patient had detectable cortisol, DHEA and
androstenidione levels indicating some production of adrenal steroids
indicating partial adrenal steroid defect. This could happen before
enough accumulation of lipid to destroy residual steroidogenesis of
adrenal gland (second hit) . A significantly elevated ACTH and poor
response to ACTH stimulation clearly indicated poor adrenal hormone
response. Bhangoo, et al.  have reported a case with
homozygous missense mutation of c.544CÿT (p.R182C) in exon 5 in
genotypic male patients with delayed presentation – quite similar to our
second patient with the same mutation.
This report demonstrates that CLAH is a disease with
variable clinical manifestation and phenotypic spectrum. CLAH should be
considered in infants with female or ambiguous genitalia and adrenal
insufficiency. A molecular genetic analysis helps firmly secure the
diagnosis, and helps to give genetic counseling for future pregnancies.
Acknowledgement: We are grateful to Dr YK Amdekar,
Medical Director, BJ Wadia Hospital for Children, for allowing us to
publish this case report.
Contributors: JR: diagnosed and managed the
patients and drafted the article. DD and TP: performed the molecular
genetic analysis. SS was involved in management of the patients.
Funding: None. Competing interests: None
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