Autoimmune polyglandular syndrome 1
Autoimmune polyglandular syndrome type 1 (APS-1, also called APECED) is caused by mutation of the AIRE gene, which normally drives thymic negative selection against self-reactive T cells; loss of AIRE produces the classic triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. Management is component-specific and lifelong: fluconazole for candidiasis, calcium and calcitriol for hypoparathyroidism, and glucocorticoid plus mineralocorticoid replacement for adrenal insufficiency, with structured lifelong screening for additional autoimmune endocrinopathies as they emerge.
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What this article covers
- Overview
Autoimmune polyglandular syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is caused by mutation of the autoimmune regulator (AIRE) gene.
- Epidemiology
APS-1 is a rare monogenic autoimmune disease driven by AIRE mutation, in contrast to the more common autoimmune polyglandular syndrome type 2, which does not follow a single-gene pattern.
- Risk factors
A confirmed or suspected AIRE mutation in a first-degree relative is the dominant risk factor, given the monogenic basis of the disease.
- Pathophysiology
Loss of AIRE function impairs negative selection of autoreactive T cells in the thymic medulla, allowing T cells with high affinity for self-antigens to escape deletion (or conversion to regulatory T cells) and enter the circulation.
- Clinical features
The clinical diagnosis is established once at least two of the three triad components are present: chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency.
- Differential diagnosis
Autoimmune polyglandular syndrome type 2 (Schmidt syndrome): shares autoimmune adrenal insufficiency but pairs it with autoimmune thyroid disease and/or type 1 diabetes rather than hypoparathyroidism…
- Diagnosis
The diagnosis is clinical, established by the presence of at least two of the three triad components (chronic mucocutaneous candidiasis, hypoparathyroidism, primary adrenal insufficiency) in the same…
- Management
First, treat chronic mucocutaneous candidiasis with fluconazole 100-200 mg PO once daily, with the duration guided by the clinical response and recurrence pattern; azole resistance can emerge with…
- Complications
Hypocalcemic crisis (laryngeal stridor, seizure, tetany) from undertreated or inadequately monitored hypoparathyroidism.
- Prognosis
With component-specific hormone replacement and antifungal therapy, individual manifestations of APS-1 are generally well controlled, though patients require lifelong medication adherence and monitoring rather than a curative intervention.
- Prevention
There is no primary prevention for the underlying AIRE mutation; prevention efforts focus on early recognition, structured surveillance, and prevention of acute decompensation from the recognized components.
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- Primary adrenal insufficiency
Primary adrenal insufficiency (Addison disease) is destruction or dysfunction of the adrenal cortex, most often autoimmune, causing combined cortisol and aldosterone deficiency with hyperpigmentation, hyponatremia, and hyperkalemia. Lifelong glucocorticoid replacement with hydrocortisone plus mineralocorticoid replacement with fludrocortisone is required, with sick-day dose increases to prevent adrenal crisis.
- Hypoparathyroidism
Hypoparathyroidism is PTH deficiency causing hypocalcemia and hyperphosphatemia, most often from inadvertent parathyroid injury during anterior neck surgery. First-line treatment is oral calcium plus calcitriol titrated to a low-normal serum calcium, with recombinant PTH reserved for inadequate control.
- Autoimmune polyglandular syndrome 2
Autoimmune polyglandular syndrome type 2 (APS-2, or Schmidt syndrome) is the co-occurrence of autoimmune primary adrenal insufficiency with autoimmune thyroid disease and/or type 1 diabetes, plus often primary ovarian insufficiency, pernicious anemia, celiac disease, or vitiligo, over a patient's lifetime. Management is component-specific hormone replacement, with adrenal insufficiency treated first because untreated hypothyroidism can mask it and starting levothyroxine before glucocorticoid replacement can precipitate adrenal crisis.