X-linked adrenal hypoplasia congenita (AHC)

X-linked recessive; NR0B1 (encodes DAX1, a nuclear receptor) at Xp21. Contiguous gene deletions can include neighboring genes (GK causing glycerol kinase deficiency, DMD causing Duchenne); recognize this combo.

• Primary adrenal insufficiency: typically presents in infancy with salt-wasting crisis, but milder cases present later in childhood/adulthood
• Hypogonadotropic hypogonadism: failure of pubertal onset; testes small; sperm production absent even with gonadotropin replacement
• Carrier females: usually asymptomatic; rarely have mild adrenal symptoms with skewed X-inactivation

• CAH: CYP21A2, AR; virilizes females, ambiguous genitalia at birth; 17-OHP elevated
• AHC: NR0B1, X-linked; males predominantly; genitalia typically normal at birth; 17-OHP normal, ACTH elevated

Newborn screen for 17-OHP does not catch AHC because the enzyme block is upstream of 17-OHP synthesis.

• Adrenal insufficiency labs: low cortisol, low aldosterone, high ACTH, high renin, 17-OHP NOT elevated (key contrast with CAH)
• Imaging: small/absent adrenal glands
• Confirmatory: NR0B1 sequencing or deletion analysis (CMA if contiguous gene deletion suspected)

• CAH (21-hydroxylase deficiency): see above
• Adrenoleukodystrophy (X-linked): adrenal insufficiency + later neurologic decline; ABCD1
• Familial glucocorticoid deficiency: isolated cortisol deficiency, AR
• Triple A syndrome (Allgrove): adrenal insufficiency + achalasia + alacrima

• Glucocorticoid + mineralocorticoid replacement (hydrocortisone, fludrocortisone): lifelong, with stress dosing
• Pubertal induction with testosterone in adolescence
• Fertility counseling: sperm production is generally not rescuable even with gonadotropins; consider donor sperm or adoption
• Carrier testing of female relatives; CMA in families with a contiguous gene deletion suspected