MON-196 - Unraveling Triple A Syndrome: A Rare Cause of Severe Adrenal Insufficiency with Phenotypic Heterogeneity and Long Term Follow Up.

Introduction: Triple A syndrome (TAS), also known as AAA or Allgrove syndrome, is a rare autosomal recessive multisystem disorder classically defined by the triad of ACTH resistant adrenal insufficiency, alacrima, and achalasia. It is caused by mutations in the AAAS gene, leading to truncation or dysfunction of the ALADIN protein, a key component of the nuclear pore complex involved in nucleocytoplasmic transport, DNA repair, and oxidative stress regulation. These molecular defects explain the broad phenotypic spectrum, progressive nature, and frequent neurologic and autonomic involvement observed in affected patients.

Case: We report the case of a 9-year-old girl Pakistani descendent, born to third-degree consanguineous parents, who presented with progressive fatigue and hyperpigmentation since 5 years of age and alacrima since 8 years of age. Biochemical evaluation confirmed severe primary adrenal insufficiency (cortisol of 0.28 µg/dL and a post-ACTH cortisol of 0.3 µg/dL, alongside an elevated ACTH level of 358 pg/mL) with normal plasma renin activity and electrolytes. Imaging studies, including brain MRI and abdominal ultrasonography, excluded pituitary and adrenal masses. Genetic testing identified a homozygous pathogenic variant in the AAAS gene (R478X), confirming the diagnosis. The patient was started on physiologic hydrocortisone replacement with stress-dose education and demonstrated excellent outcomes.

Results: During more than ten years of follow-up, she achieved normal growth (height 29th percentile, weight 63rd percentile), pubertal development and regular menses (Menarche: 15 years of age). She remained free of gastrointestinal or neurological complications. Her ACTH levels remained persistently elevated (241–1100 pg/mL), while plasma renin activity stayed within normal limits; she continues to be metabolically stable on hydrocortisone (~9.3 mg/m²/day).

Conclusion: This case highlights the importance of early diagnosis of adrenal insufficiency (AI) due to TAS, in particular, with chronic fatigue and hyperpigmentation necessitating timely treatment. High phenotypic heterogeneity and progressive nature disease warrants continuous ongoing vigilance. Long-term follow-up studies are needed for this multisystemic rare genetic disorder.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*