Introduction: Congenital adrenal insufficiency is caused by mutation of the genes responsible for steroidogenesis. Although the commonest cause is congenital adrenal hyperplasia (CAH), five other gene mutations have been shown to cause congenital adrenal hypoplasia (AHC). The commonest mutation is DAX1 deficiency due to mutation in the NR0B1 gene. Life threatening adrenal crisis can occur in an affected neonate.
Case Description: We describe here six patients with AHC, all born of non-consanguineous parents. Four patients presented with neonatal hypoglycaemia and normal electrolytes. Cortisol deficiency was identified (and CAH excluded) after a hypoglycemia work up; later ACTH, cortisol and 17 OHP were tested. All the neonates were given hydrocortisone and fludrocortisone. After 8–12 months, three patients had oral hydrocortisone discontinued for 24 hours and tested with an iv bolus of 125 mcg tetracosactide for reconfirmation of the diagnosis of AHC. The test could not be performed on one patient due to a worldwide shortage of tetracosactide. Patient 5 presented with increased pigmentation at age 20 months. She was tested for cortisol, ACTH, and 17 OH-P; her cortisol was undetectable. Patient 6 was documented to have cortisol deficiency (with elevated ACTH) after an insulin tolerance test at age 10 years. She had no other endocrine deficiency, and an MRI of the head was normal. At age 22 years, she was found to have achalasia cardia, at which point genetic studies were done. Commercially available Golden Helix VarSeq 2.2.0, the clinical genomics interpretation and reporting platform, was used for genetic studies. Two patients (numbers 5 and 6) had recognized mutations in the AAAS gene. One patient had a non-specific APC mutation, related to colonic polyps. We did not find any recognized (NR0B1/DAX1 mutation or the NR5A1/SF1 mutation or AAAS gene) mutation for AHC in four patients.
Discussion: AHC was first described by Sikl in 1948 and five gene mutations have been identified in Caucasian populations. The condition has been rarely reported from South Asia. Four of our six recent patients did not have any of the mutations held responsible for AHC. Their genetic mutation(s) are not known at present. None of the neonates had a salt losing crisis, although this was the standard presentation reported in the literature. All of them presented with hypoglycemia. The patients with AAA or achalasia alacrimia adrenal insufficiency syndrome had the typical mutation seen in this condition. Patient 5, age 19 years, currently has no achalasia or alacrimia and patient 6 recently developed achalasia at age 22 years. We conclude that patients with AHC in South Asia differ clinically and genetically from Western patients.
.jpg)