SUN-181 - X-Linked Adrenal Hypoplasia Congenita Misdiagnosed as 11β-Hydroxylase Deficiency

Background:
X-linked adrenal hypoplasia congenita (AHC) is caused by inactivating mutations in the NR0B1 (DAX-1) gene, which is essential for normal adrenal cortical development. AHC typically presents in infancy with primary adrenal insufficiency and salt wasting. Early clinical features often overlap with congenital adrenal hyperplasia (CAH), which can lead to misdiagnosis.

Case:
A 4-year-old male was referred to our clinic with a diagnosis of CAH presumed secondary to 11β-hydroxylase deficiency. He had been diagnosed out of state at 2 weeks of age after presenting with persistent vomiting and adrenal crisis. At his initial visit with us, he was on physiologic hydrocortisone, but unusually high doses of fludrocortisone (0.3 mg daily) and sodium chloride (2 g daily).

Re-evaluation demonstrated suppressed adrenal androgens, including 17-hydroxyprogesterone and androstenedione, with acceptable ACTH and suppressed plasma renin activity. Hydrocortisone and fludrocortisone doses were gradually reduced to the low end of maintenance; however, adrenal androgens remained undetectable. The patient subsequently developed fatigue, skin hyperpigmentation, and markedly elevated ACTH [265 pg/mL (normal 9–57)].

Hydrocortisone was adjusted to physiologic replacement, and fludrocortisone was titrated to maintain a normal renin level. Genetic testing was performed due to suspicion for adrenal hypoplasia and revealed a variant of uncertain significance in NR0B1 (c.797T>C). He is currently stable on hydrocortisone 10–12 mg/m²/day and fludrocortisone 0.1 mg daily. He was subsequently diagnosed with growth hormone deficiency and hypogonadotropic hypogonadism, the latter a well-recognized feature of X-linked AHC.

Conclusion:
This case highlights a missed diagnosis of AHC initially classified as CAH. Early elevations in 11-deoxycortisol may only be detectable in infancy. Transient neonatal elevations in 17-hydroxyprogesterone and relative mineralocorticoid resistance likely contributed to the initial misclassification as 11β-hydroxylase deficiency.

Clinical Implications:
NR0B1 testing should be considered in patients with suspected 11β-hydroxylase deficiency who exhibit atypical features, including absence of hypertension, persistent need for mineralocorticoid and salt supplementation, and suppressed adrenal steroid precursors with elevated ACTH. Early recognition enables anticipatory management of hypogonadotropic hypogonadism and improved long-term outcomes.

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