Pediatric non-congenital adrenal hyperplasia related primary adrenal insufficiency: a single-center 20-year case series

ORIGINAL ARTICLE

Pediatric non-congenital adrenal hyperplasia related primary adrenal insufficiency: a single-center 20-year case series

Maria Inês Neto¹, Inês Pereira², Ana Raquel Henriques³, Brígida Robalo³, Maria de Lurdes Sampaio³, Carla Pereira³.

¹Pediatrics Department, Unidade Local de Saúde do Arco Ribeirinho, Barreiro, Portugal,
²Pediatrics Department, Unidade Local de Saúde de Santa Maria, Lisboa, Portugal,
³Pediatric Endocrinology Unit, Pediatrics Department, Unidade Local de Saúde de Santa Maria, Lisboa, Portugal.

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Abstract
Introduction: Primary adrenal insufficiency (PAI) in children is rare and life-threatening, with nonspecific clinical presentations that often delay diagnosis. Non-congenital adrenal hyperplasia (non-CAH) etiologies are less frequent and include autoimmune and monogenic disorders.
Objective: Review pediatric non-CAH PAI cases over a 20-year period in a tertiary care hospital.
Methods: Retrospective analysis of children diagnosed with non-CAH PAI between January 2004 and December 2024. Data were collected from medical records and analyzed descriptively.
Results: Six patients were identified (5 males, 1 female; median age 10.9 years). Etiologies included autoimmune adrenalitis (n=3), Triple A (Allgrove) syndrome (n=2), and X-linked adrenoleukodystrophy (ALD, n=1). Clinical presentation was variable: hyperpigmentation (83%), vomiting (83%), fatigue (33%), seizures (33%); two patients required ICU (Intensive Care Unit) admission. Biochemical findings included hyponatremia in 57% and hyperkalemia in 29%; all patients presented markedly elevated ACTH and low cortisol. All received hydrocortisone; five also required fludrocortisone. Genetic confirmation was achieved in ALD and one Triple A patient. Four patients (67%) had neurodevelopmental comorbidities.
Discussion: Non-CAH PAI in childhood often presents with nonspecific symptoms, while classic features such as hyperpigmentation may be absent. Autoimmune adrenalitis was the most common etiology, whereas genetic disorders, namely ALD and Triple A syndrome, accounted for a substantial proportion of cases. Laboratory hallmarks include hyponatremia, elevated ACTH, and low cortisol. Clinical and biochemical findings, together with molecular analysis, allow precise etiologic diagnosis, guiding prognosis, treatment optimization, and family screening. Clinicians should maintain a high index of suspicion to prevent adrenal crisis.

Why this article important?

Pediatric primary adrenal insufficiency unrelated to congenital adrenal hyperplasia represents a diagnostically challenging and potentially life-threatening condition, yet data on its etiology and presentation remain limited. This manuscript is important because it provides real-world evidence from a long-term cohort, highlighting patterns that may be underrecognized in clinical practice. The observed male predominance in autoimmune adrenal insufficiency contrasts with the female predominance reported in adults, suggesting age-related differences in disease expression. Additionally, the relatively high frequency of adrenoleukodystrophy and Triple A syndrome underscores the relevance of rare monogenic causes in pediatric populations. The study also illustrates that nonspecific manifestations, such as gastrointestinal complaints and neurological events, may precede diagnosis and that biochemical findings alone do not allow reliable etiologic classification. By integrating clinical, biochemical, and genetic data, this work contributes clinically relevant insights that may help reduce diagnostic delay and prevent adrenal crises.

Summary of article

This manuscript presents a 20-year single-center case series of pediatric primary adrenal insufficiency not caused by congenital adrenal hyperplasia from a large tertiary referral hospital. By focusing on non–congenital adrenal hyperplasia etiologies, which are less frequently described in children, the study offers a detailed overview of the spectrum of disease in this population. The analysis comprehensively describes clinical presentation, biochemical abnormalities, and underlying genetic diagnoses, including both common and rare conditions. By integrating long-term clinical experience, this case series provides clinically relevant information that may assist clinicians in recognizing disease patterns, refining diagnostic strategies, and optimizing the care of children with primary adrenal insufficiency.

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