Autoimmune Polyglandular Syndrome Type 1 (APS1)
Also known as autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), APS1 is a rare, autosomal recessive disorder characterized by a classic triad of mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. It is less common than APS2 and occurs most frequently in individuals of Finnish and Sardinian descent.


Overview of APS1

  • Inheritance: Autosomal recessive
  • Gene: Caused by mutations in the AIRE (autoimmune regulator) gene
  • Onset: Typically during infancy or childhood
  • Main Triad:
    1. Chronic mucocutaneous candidiasis (skin, nails, oral mucosa, perianal region)
    2. Hypoparathyroidism
    3. Primary adrenal insufficiency

Half of the patients eventually develop all three of these features; the presence of at least two can establish the diagnosis. Siblings of an affected individual may be diagnosed with only one of the three features if the family history is clear.


Major Clinical Features

  1. Chronic Mucocutaneous Candidiasis
    • Usually the first manifestation
    • Recurrent or persistent infections of skin, nail beds, and mucosa
    • May be treatment-refractory and can significantly affect quality of life
  2. Hypoparathyroidism
    • Presents with signs and symptoms of chronic hypocalcemia (e.g., perioral numbness, paresthesias, muscle cramps)
    • Can be insidious, leading to subtle cognitive changes, blurred vision, dental hypoplasia if onset is in childhood
    • Untreated hypocalcemia may result in neurologic manifestations (e.g., seizures, mental status changes) or posterior subcapsular cataracts
  3. Primary Adrenal Insufficiency
    • Symptoms include fatigue, weight loss, hyperpigmentation, hypotension, hypoglycemia, salt craving
    • Typically arises after the other manifestations (average age ~15 years)

Additional Features

  • Primary Hypogonadism: In about 60% of cases, leading to delayed puberty or infertility
  • Malabsorption: In ~25%, can contribute to nutritional deficiencies
  • Alopecia (totalis or areata): In ~20%
  • Pernicious Anemia: In ~16%
  • Vitiligo: In ~4%
  • Others: Abnormal dental enamel, brittle nails, potential stunting of growth if early onset

The specific combination and severity of these features can vary widely among individuals, likely because of additional genetic and environmental factors.


Genetic & Molecular Aspects

  • AIRE Gene:
    • Encodes a transcription factor critical in thymic negative selection of self-reactive T cells
    • Inactivating mutations lead to loss of immune tolerance and multiple autoimmune phenomena

Distinction from APS2

  • APS1 features hypoparathyroidism and mucocutaneous candidiasis, which do not occur in APS2.
  • APS2 (often termed Schmidt syndrome) commonly includes autoimmune thyroid disease, type 1 diabetes mellitus, and primary adrenal insufficiency.
  • Age of Onset: APS2 usually presents in early to mid-adulthood, whereas APS1 presents in infancy or childhood.

Diagnosis

  1. Clinical Criteria:
    • At least two of the classic triad: hypoparathyroidism, chronic mucocutaneous candidiasis, and primary adrenal insufficiency
  2. Laboratory Findings:
    • Chronic hypocalcemia for hypoparathyroidism
    • Low cortisol and high plasma ACTH for adrenal insufficiency
    • Positive fungal cultures or clinical diagnosis for candidiasis
  3. Genetic Testing:
    • AIRE gene mutation analysis can confirm diagnosis and allow family screening

Management & Surveillance

  • Hormone Replacement:
    • Calcium and active vitamin D analogs for hypoparathyroidism
    • Glucocorticoids (and mineralocorticoids, if needed) for adrenal insufficiency
  • Antifungal Therapy:
    • Treatment of mucocutaneous candidiasis to prevent complications
  • Screening & Support:
    • Monitor for other autoimmune features (e.g., hypogonadism, pernicious anemia)
    • Evaluate thyroid function periodically
    • Provide patient education and counseling regarding genetic implications

Life-long follow-up is essential to detect and manage evolving autoimmune disorders and to optimize quality of life.

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