autoimmune polyglandular syndrome

**APS-1 (APECED: Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy)** - Genetics: autosomal RECESSIVE loss-of-function mutation in AIRE (autoimmune regulator) gene on chromosome 21. AIRE normally drives expression of peripheral tissue antigens in medullary thymic epithelial cells, enabling negative selection of self-reactive T cells (central tolerance). Its loss leads to escape of autoreactive T cells, plus defective Treg development. - Onset: infancy/childhood. - Diagnostic triad (need 2 of 3): (1) chronic mucocutaneous candidiasis (usually first manifestation, often <5 yr; linked to neutralizing autoantibodies against IL-17 and IL-22), (2) hypoparathyroidism (usually next, ~age 5-10), (3) primary adrenal insufficiency/Addison disease (usually by adolescence). - Other features: primary gonadal failure, enamel hypoplasia/ectodermal dystrophy (nail dystrophy), alopecia, vitiligo, pernicious anemia, autoimmune hepatitis, malabsorption, asplenia. Autoimmune thyroid disease and T1DM are less common than in APS-2. - Antibodies: anti-interferon (type I IFN) antibodies are highly sensitive; also anti-21-hydroxylase, anti-17α-hydroxylase, anti-side chain cleavage enzyme, anti-aromatic L-amino acid decarboxylase, anti-tryptophan hydroxylase.

**APS-2 (Schmidt syndrome)** - Most common APS. Polygenic, associated with HLA-DR3 and HLA-DR4 (and CTLA-4 variants); NOT AIRE-related. Female predominance, onset in adulthood (20-40s). - Defining feature: Addison disease (autoimmune adrenalitis) plus AT LEAST one of: autoimmune thyroid disease (Hashimoto or Graves) and/or type 1 diabetes mellitus. - Also associated: celiac disease, vitiligo, pernicious anemia, primary ovarian insufficiency, alopecia areata, myasthenia gravis. - NO candidiasis or hypoparathyroidism (key distinguishing features from APS-1). - Classic pearl: Carpenter syndrome variant: Addison + Hashimoto = Schmidt syndrome; Addison + Hashimoto + T1DM often called Carpenter syndrome. Be cautious: starting levothyroxine before glucocorticoid replacement in unrecognized Addison disease can precipitate adrenal crisis (thyroid hormone increases cortisol clearance), so always replace glucocorticoids first.

**APS-3**: Autoimmune thyroid disease + another autoimmune disease (e.g., T1DM, pernicious anemia, vitiligo) WITHOUT Addison disease. Sometimes subdivided (3A-3C); APS-4 is a catch-all for other combinations.

**IPEX (not an APS per se, but related high-yield)**: X-linked FOXP3 mutation, absent Tregs; Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked. Presents in infant males with intractable diarrhea, T1DM (neonatal), eczema, and thyroiditis.

**Mnemonic**: APS-1 = "CHAI-A"/"Candida, Hypoparathyroid, Addison" in a child (AIRE, recessive, chromosome 21). APS-2 = "Addison + thyroid/T1DM" in an adult (HLA-DR3/4). APS-3 = "thyroid + other, no Addison."

**Clinical approach/management**: - Screen patients with one autoimmune endocrinopathy for others (TSH, glucose/HbA1c, 21-hydroxylase Ab, ACTH stimulation test, calcium/PTH, B12, celiac serology). Family screening is recommended. - Treat each deficiency with hormone replacement: glucocorticoid (hydrocortisone) ± mineralocorticoid (fludrocortisone), levothyroxine, insulin, calcium/calcitriol for hypoparathyroidism, antifungals for candidiasis. - Always replace glucocorticoids BEFORE thyroid hormone to avoid adrenal crisis. - Prognosis is good with early recognition; main danger is undiagnosed adrenal crisis and hypocalcemia.

**Board pearls**: A child with recurrent thrush/candidiasis plus hypocalcemic tetany (Chvostek/Trousseau signs) → think APS-1/AIRE. A middle-aged woman with T1DM and hyperpigmentation, hypotension, hyponatremia, hyperkalemia → think APS-2. Primary adrenal insufficiency (high ACTH, hyperpigmentation) in the US is most commonly autoimmune (21-hydroxylase antibodies).