What is Autoimmune Polyendocrine Syndrome Type I (APS I)?

Autoimmune Polyendocrine Syndrome Type I (APS-I)

Autoimmune Polyendocrine Syndrome Type I (APS-I) is a rare monogenic autoimmune disorder caused by mutations in the AIRE gene, defined by the presence of at least two of three major components: chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. 1, 2

Definition and Genetics

APS-I, also known as APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy), is an autosomal recessive disorder with:

• Genetic basis: Mutations in the Autoimmune Regulator (AIRE) gene on chromosome 21
• Prevalence: Rare disease, with highest rates (1:6,500-1:9,000) in genetically isolated populations 3
• Inheritance: Autosomal recessive pattern
• Pathophysiology: Disrupted mechanism of normal antigen expression leading to formation of abnormal immune cell clones and autoimmune damage to multiple organs 3

Diagnostic Criteria

APS-I is diagnosed when at least two of the three major components are present:

1. Chronic mucocutaneous candidiasis
2. Hypoparathyroidism
3. Primary adrenal insufficiency (Addison's disease) 1, 2

Clinical Manifestations

Major Components

• Chronic mucocutaneous candidiasis: Often the earliest manifestation, typically appearing in childhood
• Hypoparathyroidism: Usually presents in childhood with hypocalcemia, tetany, and seizures
• Primary adrenal insufficiency: Presents with fatigue, hypotension, hyperpigmentation, hyponatremia, and hyperkalemia 1, 4

Other Common Manifestations

• Endocrine disorders:

  • Premature ovarian insufficiency
  • Type 1 diabetes mellitus
  • Autoimmune thyroid disease

• Non-endocrine manifestations:

  • Dental enamel hypoplasia (very common)
  • Vitiligo
  • Alopecia
  • Autoimmune hepatitis
  • Malabsorption/intestinal dysfunction
  • Pernicious anemia
  • Asplenia
  • Pneumonitis
  • Nephritis 4, 3

Laboratory Diagnosis

1. Autoantibody testing:

   • Antibodies against interferon-omega and interferon-alpha: Highly sensitive and specific markers for APS-I 2, 5
   • Organ-specific autoantibodies (adrenal, parathyroid, gonadal)

2. Genetic testing:

   • AIRE gene mutational analysis: Diagnostic in >95% of cases 2
   • Common mutations include c.967_979del13 and c.769C>T 4, 5

3. Endocrine function tests:

   • Serum calcium, phosphate, and PTH for hypoparathyroidism
   • Cortisol and ACTH for adrenal insufficiency
   • Thyroid function tests
   • Glucose tolerance test

Disease Course and Prognosis

• Age of onset: Most patients present with first manifestations in childhood, but some may be delayed until adolescence or early adulthood 2
• Disease progression: With age, most patients develop three to five disease manifestations 4
• Mortality: Significant mortality reported (median age at death: 34 years in one study) 4
• Phenotypic variation: Enormous variation in presentation and phenotype, making diagnosis challenging 2

Management

1. Hormone replacement therapy:

   • Hydrocortisone (15-25 mg daily in split doses) for adrenal insufficiency
   • Fludrocortisone (50-200 μg daily) for mineralocorticoid replacement
   • Calcium and vitamin D analogs for hypoparathyroidism 1

2. Treatment of candidiasis:

   • Antifungal medications (topical or systemic)

3. Management of other manifestations:

   • Specific treatment for each autoimmune component

4. Patient education:

   • Steroid emergency cards and medical alert identification
   • Education about adrenal crisis prevention and management
   • Self-injection of parenteral hydrocortisone during emergencies 1

5. Follow-up:

   • Regular monitoring by multidisciplinary specialists
   • Annual assessment of endocrine function
   • Monitoring for development of new autoimmune manifestations 1, 4

Important Distinctions from Other APS Types

APS-I must be distinguished from other autoimmune polyendocrine syndromes:

• APS-II: Characterized by Addison's disease with autoimmune thyroid disease and/or type 1 diabetes; HLA-associated rather than monogenic; adult onset 6
• APS-III: Autoimmune thyroid disease with other autoimmune conditions (excluding Addison's disease and hypoparathyroidism) 6
• APS-IV: Other combinations of autoimmune diseases not fitting the above categories 6

Key Points for Clinicians

• Early diagnosis is crucial for preventing life-threatening complications
• Anti-interferon-omega antibodies appear very early in life and can help diagnose APS-I before clinical manifestations 5
• Genetic counseling is important for families with affected members
• Treatment is complex and requires collaboration between multiple specialists 2
• Structured follow-up should be performed in specialized centers 4