The pivotal role of etiology in managing Non-CAH primary adrenal insufficiency in pediatric and adolescent populations: A Single-Center study.

backgroundPrimary adrenal insufficiency (PAI) in children, outside of congenital adrenal hyperplasia (CAH), represents a rare and genetically diverse group of disorders often leading to diagnostic delays. Advances in molecular genetics have uncovered a wide spectrum of non-CAH etiologies, yet real-world data from pediatric cohorts remain limited.

methodsWe retrospectively reviewed 11 children diagnosed with non-CAH PAI at a single tertiary care center between March 2015 and December 2024. Clinical, biochemical, and genetic findings were evaluated using targeted Sanger sequencing or next-generation sequencing panels. Variants were classified according to ACMG/AMP criteria.

resultsPathogenic or likely pathogenic variants were identified in MC2R (n = 3), NR0B1 (n = 2), ABCD1 (n = 2), MRAP (n = 1), AIRE (n = 1), and AAAS (n = 1) genes, while one patient remained genetically undiagnosed. In total, five novel variants were identified: one in MC2R (shared by two siblings), and one each in NR0B1, ABCD1, and AAAS. Clinical presentations ranged from neonatal adrenal crisis to later-onset symptoms such as fatigue, hyperpigmentation, or hypoglycemia. Consanguinity was present in 45% of cases. One MC2R case required only stress-dose glucocorticoid therapy, while most others required lifelong hormone replacement. Notably, we describe the first homozygous MC2R p.Arg128His variant causing partial adrenal insufficiency without long-term glucocorticoid treatment, and a unique case of PAI co-occurring with genetically confirmed Marfan syndrome.

conclusionThis single-center cohort underscores the clinical and genetic heterogeneity of pediatric non-CAH PAI. The identification of five novel variants expands the mutational spectrum and provides new insights into genotype–phenotype correlations, reinforcing the importance of early genetic testing for optimal management.