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Indian Pediatr 2016;53:
529-531 |
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X-linked Congenital Adrenal Hypoplasia with a
Novel NR0B1/DAX Gene Mutation
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*Mary B Abraham, *#Vinutha
B Shetty, #$Fiona
McKenzie and *#Jacqueline
Curran
From *Department of Endocrinology, Princess Margaret Hospital,;
#School of Paediatrics and Child Health, The University of Western
Australia; and $Genetic Services of Western Australia, Princess Margaret
Hospital & King Edward Memorial Hospital; Perth, Australia.
Correspondence to: Dr Mary B Abraham, Department of Endocrinology and
Diabetes, Princess Margaret Hospital, Perth, Australia.
Email:
[email protected]
Received: September 07, 2015;
Initial review: December 26, 2015;
Accepted: March 05, 2016.
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Background: The etiology of
primary adrenal insufficiency has implications for further management of
the condition. Case characteristics: A 5-year-old boy presented
in adrenal crisis with glucocorticoid and mineralocorticoid deficiency.
Observation: Investigations confirmed primary adrenal
insufficiency and ruled out the common etiologies. Genetic testing
identified a novel NR0B1/DAX gene mutation. Message: A
genetic diagnosis in children with primary adrenal insufficiency is
useful to provide genetic counselling.
Keywords: Adrenal crisis, Hyponatemia,
Diagnosis.
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P rimary adrenal insufficiency is a
life-threatening condition if not diagnosed promptly and requires
lifelong glucocorticoid and mineralocorticoid replacement [1]. We wish
to highlight the importance of investigating patients with primary
adrenal insufficiency to reach an etiological diagnosis as it enables us
to understand the evolution of the disease, permits follow-up of
extra-adrenal manifestations and offers the option of genetic
counselling to the extended family members. We report a boy with primary
adrenal failure due to X-linked congenital adrenal hypoplasia
secondary to a novel mutation.
Case Report
A 5-year-old Caucasian boy presented to an emergency
department with increasing lethargy, nausea, vomiting, poor oral intake
and weight loss of 3.5 kg over a period of one month. He was born at
term to non-consanguineous parents, was not on any medications, and was
vaccinated to date. There was no family history of sudden deaths, and
adrenal or neurological disorders. He had two brothers, aged 10 years
and 8 years, with no medical concerns. On examination, he was conscious
and oriented but lethargic. He was afebrile with low volume pulses, cold
clammy extremities with poor perfusion, reduced skin turgor, sunken eyes
and dry mucous membranes with a pulse rate of 108/minute and BP of 90/60
mmHg. Normal saline bolus of 20 mL/kg was commenced to improve his
circulatory status. Preliminary investigations revealed significant
hyponatremia (Sodium 98 mmol/L) and hyperkalemia (Potassium 7.6 mmol/L).
He had a compensated metabolic acidosis (pH 7.34, bicarbonate 13.1 mmol/L)
with blood glucose of 60mg/dL. Emergent management of hyperkalemia was
instituted with salbutamol nebulisation and intravenous calcium
gluconate infusion. There were intermittent episodes of up-rolling of
eyes, arching of back and slurring of speech. These symptomatic episodes
of hyponatremia were treated with 3% sodium chloride infusion.
Adrenal pathology was strongly suspected and IV
hydrocortisone 50mg was commenced and continued on maintenance doses.
Sodium corrected from 98 to 112 mmol/L in the first 24 hours, and to 124
mmol/L in the next 24 hours. On further questioning, there was history
of salt craving and increased tanning with hyperpigmentation on
examination. He had no pubarche and was pre-pubertal with 2 cc testes
bilaterally. His weight was 16.6 kg (Z score -1) and height was
108 cms (Z score 0). He was discharged home on day 6 on oral
hydrocortisone 10 mg/m 2/day
(4mg, 2mg, 2mg) and fludrocortisone at 50 mcg twice-a- day.
Investigations confirmed primary adrenal
insufficiency with inappropriately low cortisol at the time of crisis
(220; NR: >550mmol/L), elevated ACTH (325; NR: 2-10pmol/L) and low
aldosterone (<50; NR 100-800pmol/L). 17-hydroxyprogesterone was normal
(<0.2; NR: <3.5nmol/L) with a bone age of 6 years at chronological age
of 5.1 years. Adrenal antibodies were negative. Quantiferon test for
tuberculosis was negative and there was no evidence of EBV and CMV
infections on serology tests. MRI brain did not demonstrate abnormal
signal in white matter and results of very long chain fatty acids
(0.895; NR 0.550-1.150) were normal and ruled out X-linked
adrenoleukodystrophy (X-ALD). Ultrasound of the abdomen revealed normal
adrenal glands with no masses or haemorrhage. As there was no apparent
cause for his adrenal insufficiency, NR0B1 genetic testing was
requested. Genomic DNA sequencing showed a hemizygous novel mutation -
p.Gln282, c.844C>T in exon 1 of the NR0B1 gene, which
creates a premature stop codon resulting in a truncated protein or
nonsense mediated RNA decay. The mother is an unaffected carrier and his
two asymptomatic brothers did not carry the mutation.
At 7 years of age, his weight is 25.4 kg (Z score
0.5) and height is 121.9 cms (Z score 0) and remains stable on
follow-up. Close monitoring of his pubertal status is maintained with a
plan to commence on testosterone replacement, if spontaneous puberty
fails to occur.
Discussion
We report a 5-year-old boy who presented in adrenal
crisis with glucocorticoid and mineralocorticoid deficiency in the
absence of a family history and negative for the common causes of
adrenal insufficiency. Though tuberculosis, fulminant infections and HIV
are common etiologies in the developing world, congenital adrenal
hyperplasia (CAH) and autoimmune adrenalitis are more prevalent in the
developed world [1] and were ruled out in our patient. Investigations
for X-ALD were also negative although this was strongly suspected in the
male child presenting with adrenal insufficiency. Hsieh, et al.
[2] evaluated the presentation of childhood adrenal insufficiency and
only 3 of the 42 children did not have a definite diagnosis. As there
was no apparent cause in our patient, NR0B1 genetic testing was
requested, which revealed a pathogenic mutation.
X-linked congenital adrenal hypoplasia accounts
for half of adrenal failure in boys not caused by CAH, autoimmune
disease, or X-ALD [3]. It is caused by inactivating mutations in DAX1/NR0B1
(dosage-sensitive sex reversal-adrenal hypoplasia congenita critical
region on the X chromosome, gene 1/nuclear receptor subfamily 0, group
B, member 1) [4]. DAX1 nuclear receptor is a transcriptional repressor
of genes involved in steroidogenesis and plays an important role in
adrenal development and function. Adrenal failure reflects a
developmental abnormality in the transition of the foetal to adult zone.
Most patients present with adrenal insufficiency in infancy; and the
remainder present insidiously in childhood. Diagnosis may be delayed
into adulthood as awareness of this condition is limited [5]. The gene
is also expressed in hypothalamus, pituitary and testis and can lead to
hypogonadotropic hypogonadism [6]. Testicular dysfunction affecting
Sertoli cells can further contribute to infertility [7] with reduction
in testosterone and inhibin B seen even in the pre-pubertal period [8].
This diagnosis has implications for monitoring our patient’s puberty
closely with the aim of commencing testosterone replacement if
spontaneous puberty does not occur. Pubertal monitoring in the
pre-pubertal period is also required as cases of transient precocious
puberty have also been reported, the exact cause of which is not well
elucidated [9]. Although there are not many cases reported in
literature, the availability of genetic testing and the awareness of the
impact that the diagnosis has on the management of the individual,
should see an increase in the prevalence of this condition. In such
cases, it is vital to extend screening to other family members to be
able to identify asymptomatic adrenal insufficiency and possibly prevent
sudden unexplained deaths.
This case highlights that DAX gene mutations
should be sought in male patients with primary adrenal insufficiency
after ruling out the more common etiologies as it has implications for
the further management of the patient and extended family members.
Contributors: MA: collated clinical
information of the case and wrote the manuscript; VS, JC: provided
clinical details and FM: provided genetic input; JC: oversaw all
aspects of the manuscript and edited the manuscript. All authors
approved of the final version of the manuscript
Funding: None; Competing interest: None
stated.
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