Insights in non-CAH pediatric primary adrenal insufficiency: a single-center experience from India.

Objectives: Pediatric primary adrenal insufficiency (PAI) etiologies beyond congenital adrenal hyperplasia (CAH) show regional variations. Given limited data from India, this study aims to describe the etiological profile, phenotype, and genotype of pediatric PAI in an Indian cohort.

Methods: We conducted a retrospective review of patients with PAI onset before 20 years of age from 1998 to 2023 at a single center. After excluding patients with inadequate data (n=20), CAH (n=218), and bilateral adrenalectomy (n=19), we analyzed demographic, clinical, biochemical, and genetic data of the remaining patients.

Results: Among 54 patients (45 probands), the median age at presentation was 6 years (range 0.1-19). Common clinical features included hyperpigmentation (90.7 %), adrenal crisis (33.3 %), and seizures (29.6 %). Mineralocorticoid deficiency was present in two-third patients including one patient each with AAAS, MRAP, and NNT mutation. Adrenoleukodystrophy (ALD) was the most common cause (40 %), followed by ACTH resistance states (20 %), early steroidogenic defects (13.3 %), congenital adrenal hypoplasia (11.1 %), autoimmune causes (8.9 %), and tuberculosis (4.5 %). Genetics diagnosed 14/15 patients without phenotypic clues and confirmed diagnoses in 21 tested of 30 with phenotypic pointers (alacrimia in AAAS, hypoparathyroidism/candidiasis in autoimmune polyendocrine syndrome-1 and neurodeficit in ALD). Genetics differentiated CYP11A1 mutation from suspected ALD in two siblings with neurological deficits. We identified seven novel gene variants. We report the first case of NNT associated with 46,XY gonadal dysgenesis. Adrenal tuberculosis was a unique cause of pediatric PAI.

Conclusions: This study reveals diverse non-CAH pediatric PAI etiologies in India, emphasizing genetic testing's importance for precise diagnoses and suggests region-specific diagnostic algorithm.