Targeted Genetic Testing Helps Identify Rare Causes of Non-CAH Adrenal Insufficiency in Children: Study
A recent eight-year retrospective study published in the Indian Journal of Endocrinology and Metabolism in August 2025 reveals the critical diagnostic power of targeted genetic testing for rare, non-CAH primary adrenal insufficiency (PAI) in children.
Although congenital adrenal hyperplasia (CAH) is the most common genetic cause of pediatric primary adrenal insufficiency (PAI), non-CAH etiologies are rare and lack comprehensive clinical data. To address this knowledge gap, Anand Sheya and colleagues at the Sri Ramachandra Institute in Chennai, India, investigated the clinical, biochemical, and genetic profiles of non-CAH PAI in South Indian children.
Therefore, the eight-year retrospective study evaluated 12 pediatric patients (<18 years) with non-CAH primary adrenal insufficiency, identified from 85 PAI cases at an Indian tertiary center. Excluding classical CAH, the research analyzed clinical and biochemical presentations, alongside genetic profiles and therapeutic responses to hormone replacement.
Key Clinical Findings of he Study Includes:
Universal Clinical Presentation: Researchers reported that generalized hyperpigmentation was a universal clinical sign, present in 100% of the non-CAH PAI cohort at a median diagnosis age of 2.5 years, often alongside recurrent infections and gastrointestinal distress.
Hemodynamic Alterations: Analysis revealed that hypotension occurred in 58% of patients, while classic electrolyte abnormalities like hyponatremia were observed in 50% and hyperkalemia in 45%, suggesting electrolytes are not consistently reliable for initial screening.
High Genetic Diversity: Testing successfully identified seven distinct pathogenic or likely pathogenic variants (including AAAS, MC2R, ABCD1, CYP11A1, NNT, NROB1, and TXNRD2) across 75% of the index cases, reflecting substantial genetic heterogeneity and a strong link to consanguinity.
Targeted Interventions: Investigators noted that all 12 patients necessitated immediate glucocorticoid replacement therapy, predominantly utilizing hydrocortisone, while 50% of the cohort required additional fludrocortisone for concurrent mineralocorticoid deficiency management.
The results suggest that integrating targeted genetic evaluations into routine diagnostic algorithms is highly effective for identifying the specific etiology of non-CAH PAI in pediatric cases, especially given that 66% of these children presented with critical symptoms during early infancy or childhood.
Thus, the study concludes clinicians may consider maintaining a high index of clinical suspicion for rare genetic mutations when evaluating children with adrenal dysfunction, as precise etiological identification can gently guide optimized, long-term therapeutic management and support proactive family counseling.
Although the study provides valuable clinical insights, its retrospective nature, incomplete datasets, and small sample size may limit broader generalizability; therefore, expanding genetic databases through larger multicentric studies could further enrich our understanding of regional and ethnic variations in pediatric PAI.
Reference
Sheya A, Namratha GS, Mahadevan S, Ashirvatham AR, Ranjan A. Inherited, non‑CAH primary adrenal insufficiency in children: A genetic and clinical profile from a tertiary care center. Indian J Endocr Metab 2025;29:440‑5.
