Delayed Diagnosis of Autoimmune Polyendocrine Syndrome Type 2 Highlights Urgent Need for Awareness

Autoimmune polyendocrine syndrome type 2, commonly known as APS-2, is a condition in which the immune system targets multiple endocrine glands at once. The three components most associated with the full syndrome are primary adrenal insufficiency, also called Addison's disease, autoimmune thyroid disease, and type 1 diabetes mellitus. For a diagnosis of APS-2, at least two of these conditions must be present, but many patients eventually develop all three, with years or even decades passing between the appearance of each new component. Despite being the most common of the autoimmune polyendocrine syndromes, APS-2 is frequently missed or misclassified for a frustratingly long time.

A case report and literature review published in Frontiers in Immunology in 2025 by Yao and colleagues describes a patient who had all three components of the APS-2 triad and who ultimately experienced an adrenal crisis, a life-threatening emergency in which the adrenal glands fail to produce adequate cortisol, typically triggered by stress, illness, or inadequate hormone replacement. The authors note that this type of case, where the full triad has been confirmed and then complicated by adrenal crisis, had been documented in fewer than five cases worldwide before this report.

Adrenal insufficiency is particularly dangerous when undiagnosed because the symptoms of a cortisol crisis, including severe fatigue, abdominal pain, vomiting, low blood pressure, and confusion, can mimic many other conditions. If not recognized and treated promptly with intravenous hydrocortisone, an adrenal crisis can be fatal. Patients with APS-2 who already have thyroid disease and type 1 diabetes may have their adrenal symptoms attributed to their existing conditions, further delaying recognition of Addison's disease.

Published estimates suggest that more than 60 percent of APS-2 patients experience significant delays in receiving a full and accurate diagnosis. The heterogeneous nature of the syndrome, where different combinations and sequences of autoimmune conditions can present over time, makes it easy to manage each condition in isolation without connecting them into a unified picture. Endocrinologists and internists who see patients with one autoimmune endocrine condition are encouraged by the authors to screen proactively for the others, particularly for adrenal insufficiency, given its potential to cause sudden, life-threatening emergencies.

The case report also examines the potential role of environmental and pharmacological triggers in unmasking adrenal insufficiency in susceptible individuals. The patient's history included use of traditional herbal medicine, and the authors suggest that systematic research into whether certain exogenous substances can have adrenal toxic effects in patients with underlying autoimmunity remains lacking and warrants further study.

For patients living with type 1 diabetes or autoimmune thyroid conditions, and for their physicians, this report is a reminder that APS-2 is a syndrome that unfolds over time. Regular monitoring for adrenal insufficiency, particularly through early morning cortisol measurements and ACTH stimulation testing when clinically appropriate, can help catch Addison's disease before it reaches the point of crisis. Increased clinical awareness, both in specialty and primary care settings, remains the most powerful tool available for preventing the serious consequences that delayed diagnosis can bring.