Primary adrenal insufficiency in children excluding congenital adrenal hyperplasia: insights from 33-year single-center experience in Tunisia.

Background: Primary adrenal insufficiency (PAI) is a rare but potentially life-threatening condition. Congenital adrenal hyperplasia (CAH) is the most common cause of PAI in children. To date, numerous non-CAH causes have been identified through genetic analysis but they remain poorly characterized.

Objective: We aimed to describe the clinical presentation, etiology, genetic analysis, and long-term outcome of non-CAH PAI in children.

Methods: We retrospectively collected clinical and laboratory data from patients with non-CAH PAI who were followed up during a period of 33 years (1988-2020) at the pediatric department of a university hospital center in southern Tunisia.

Results: We identified 52 patients with non-CAH PAI (35 boys and 17 girls). The mean age at diagnosis was 4.8 years (0.05-18.7 years). Hyperpigmentation was the most frequent symptom at diagnosis (92.3%), followed by asthenia (84.6%), weight loss (57.7%), recurrent vomiting (53.8%), and dehydration (42.3%). The most prominent biochemical findings were hyponatremia (60.4%), hypoglycemia (35.4%), and hyperkalemia (16.6%). A total of 21patients (40.4%) presented with adrenal crisis at disease onset. The most common causes of non-CAH PAI were inherited genetic conditions and included Allgrove syndrome (n=15), X-linked adrenoleukodystrophy (n=10), autoimmune polyglandular syndrome (APS) type 2 (n=2), familial glucocorticoid deficiency type 1 (n=1), MCM4 mutation responsible for DNA repair defect (n=1), SF1 deficiency (n=1), APS type 1 (n=1), and autoimmune PAI (n=3). The cause of PAI remained unknown in 34.6% of cases. During follow-up, 24 patients (46.2%) presented with statural growth delay, and eight patients (15.4%) developed obesity.

Conclusion: Allgrove syndrome was the most common etiology of non-CAH PAI in our study, followed by X-linked adrenoleukodystrophy. Today, advanced molecular analysis can be useful for diagnostic investigations, especially in patients with no specific diagnostic features.