A novel missense mutation in Dax-1 with an unusual presentation of X-linked adrenal hypoplasia congenita

A male presented at age 2.2 years with a 6-week history of intermittent vomiting and hyperpigmentation. Investigations showed salt wasting with hyperkalaemia, a grossly impaired cortisol response to ACTH stimulation, elevated renin and ACTH. Family history revealed that two maternal uncles had died soon after birth. A third uncle failed to thrive during infancy but improved with a course of cortisone, then being untreated until further investigation revealed adrenal insufficiency. A fourth uncle died aged 10 days, with urinary salt loss and hypoplastic adrenal glands at postmortem. Molecular studies on the proband, his mother, maternal grandmother, and surviving uncle showed a novel C to G substitution at nucleotide position 794 (missense mutation T265R) in the DAX1 (NR0B1) gene. The proband has responded well to steroid replacement but has proved sensitive to 9α-fludrocortisone treatment, developing hypertension on a dose of 133 μg/m2/day. At 8.8 years he was noted to have testicular volumes of 4 ml, despite no other evidence of secondary sexual development and prepubertal gonadotrophin levels. Novel features of this family include a novel DAX1 mutation, marked variability in age of presentation, hypertension on ‘standard’ doses of 9α-fludrocortisone and mild testicular enla

X-linked congenital adrenal hypoplasia associated with hypospadias in an Egyptian baby: a case report

<p>Abstract</p> <p>Introduction</p> <p>X-linked congenital adrenal hypoplasia is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the <it>dosage-sensitive sex reversal adrenal hypoplasia congenita critical region of the X chromosome, gene 1</it> (<it>DAX-1</it>) gene. Most affected children present with failure to thrive, salt wasting and hypoglycemic convulsions in the first months of life. Hypospadias affects approximately one in 250 live male births. Mutations in the <it>mastermind-like domain-containing 1</it> (<it>MAMLD1</it>) gene have been implicated as one of the causes of hypospadias in children. To the best of our knowledge, an association between congenital adrenal hypoplasia due to a <it>DAX-1</it> mutation and hypospadias due to mutation of the <it>MAMLD1</it> gene has not previously been reported in the literature.</p> <p>Case presentation</p> <p>A 35-day-old male Egyptian baby was referred to our institution for the evaluation of a two-week history of recurrent vomiting associated with electrolyte imbalance. On examination, our patient was found to have hypotension and dehydration. A genital examination showed distal penile hypospadias with chordee and normal testes. He had hyponatremia, hyperkalemia, hypoglycemia and metabolic acidosis. Endocrinological investigations revealed low levels of cortisol, 17-hydroxyprogesterone and aldosterone, with a high level of adrenocorticotrophic hormone. A provisional diagnosis of congenital adrenal hypoplasia associated with hypospadias was made. A molecular genetics study confirmed the diagnosis of X-linked congenital adrenal hypoplasia due to <it>DAX-1</it> mutations and hypospadias due to <it>MAMLD1</it> mutation. He was started on hydrocortisone and fludrocortisone treatment. After three weeks of treatment, his symptoms improved and his blood sugar, sodium, potassium and cortisol levels normalized.</p> <p>Conclusions</p> <p>We report the case of an Egyptian baby with an association of congenital adrenal hypoplasia due to <it>DAX-1</it> mutation and hypospadias due to <it>MAMLD1</it> mutation. Early diagnosis of this association and determining its optimal treatment are vital in helping to avoid its fatal course.</p