Autoimmune polyendocrine syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autosomal recessive disorder primarily caused by mutations in the autoimmune regulator (AIRE) gene. It more commonly affects females and is characterized by mucocutaneous candidiasis, autoimmune hypoparathyroidism, and adrenal cortex insufficiency. Some patients may also present with hypogonadism, enamel hypoplasia, and other features.
Pathogenesis
The pathogenesis of APS-1 has yet to be fully elucidated. It is believed that APS-1 arises from mutations in the AIRE gene located on the short arm of chromosome 21. This gene encodes a transcriptional regulator involved in immune function, which is highly expressed in thymic antigen-presenting epithelial cells and lymphocytes. Mutations in the AIRE gene can lead to the escape of self-reactive antigen-specific T cells within the thymus. When these cells are activated in peripheral organs or tissues, they may trigger autoimmune destruction of specific tissues.
Clinical Manifestations
APS-1 can involve multiple organs or tissues, leading to various autoimmune diseases. The clinical manifestations are often related to the organs or tissues affected. Chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism, and primary adrenal insufficiency (Addison's disease) are the hallmark features, collectively termed the APS-1 triad. Most patients initially present with mucocutaneous candidiasis as the first symptom.
The onset age and the number of affected organs can vary widely among patients. Some may also develop autoimmune hypothyroidism, type 1 diabetes, and other conditions. Classic APS-1 often manifests in children with at least two components of the triad. Additional features may include chronic diarrhea or constipation, enamel hypoplasia, autoimmune hepatitis, cerebellar ataxia, and ocular complications such as keratitis, blepharitis, or retinitis. Female patients are also prone to developing primary ovarian insufficiency.
Chronic Recurrent Candidiasis
Individuals with APS-1 are predisposed to recurrent mucocutaneous candidiasis, which is associated with a deficiency in suppressive T lymphocytes. It commonly affects the oral mucosa and nails but is less frequent in the esophagus, gastrointestinal tract, or lungs. Chronic oral candidiasis significantly increases the risk of oral mucosal carcinoma in later stages.
Autoimmune Hypoparathyroidism
Autoimmune hypoparathyroidism in APS-1 often leads to symptoms such as hypocalcemic tetany, seizures, or convulsions. Some patients may also exhibit abnormalities in phosphate or magnesium metabolism.
Autoimmune Adrenal Cortex Insufficiency
Glucocorticoid deficiency is the primary feature in patients with adrenal insufficiency, though some may also experience aldosterone deficiency. Associated symptoms include fatigue, nausea, vomiting, and orthostatic hypotension. Severe cases may result in adrenal crises.
Other Autoimmune Diseases
When APS-1 affects multiple endocrine or non-endocrine organs, it is frequently accompanied by other autoimmune disorders.
Laboratory Tests
The clinical phenotypes of APS-1 are highly variable, and its diagnosis requires a comprehensive evaluation of family history, clinical symptoms, glandular function, and levels of autoantibodies. Genetic mutation analysis also plays a significant role in diagnosing and classifying APS-1.
Candida Testing
Candida testing is considered a routine laboratory screening method for APS-1. Tissue samples can typically be collected from oral or mucosal lesions, followed by smear preparation and microscopic examination. Biopsy for pathological analysis or tissue culture may be required in some cases. For deeper Candida infections, biopsy specimens from esophageal or gastrointestinal mucosal lesions obtained via endoscopy can provide valuable diagnostic information.
Hormone Measurement
In APS-1 patients with autoimmune-associated endocrine gland hypofunction, hormone levels and their metabolic byproducts can be measured directly. Hormone stimulation tests may be necessary for definitive diagnosis in particular cases.
Antibody Detection
APS-1 is primarily mediated by autoimmune responses that result in tissue or cellular destruction. Measuring autoantibody levels in tissues or plasma, such as antibodies against interferon-ω and interferon-α, can aid in diagnosis.
Treatment
The treatment of APS-1 primarily involves symptomatic management, antifungal therapy, and hormone replacement therapy.
Symptomatic Management
Symptoms such as mild diarrhea, constipation, nausea, fatigue, and water-electrolyte imbalances in APS-1 patients are managed symptomatically depending on specific clinical needs.
Antifungal Therapy
For patients with chronic Candida infections involving the oral cavity or mucocutaneous tissues, antifungal treatment is typically necessary. Topical or superficial infections of the skin and nails can be treated with antifungal agents such as itraconazole. For oral or deeper fungal infections, antifungal drugs including amphotericin B, nystatin, ketoconazole, or fluconazole are commonly used. Renal function and other potential adverse effects should be monitored during antifungal treatment.
Hormone Replacement Therapy
APS-1 patients with autoimmune-associated endocrine gland hypofunction and absolute hormone deficiencies require timely hormone replacement therapy. When multiple glandular deficiencies coexist, the sequence and dosage of hormone supplementation require careful attention, particularly in patients with adrenal cortex insufficiency.