Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

Area of Science:

• Immunology
• Genetics
• Endocrinology

Background:

• Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder.
• It is typically caused by homozygous autoimmune regulator (AIRE) mutations and classically presents with mucocutaneous candidiasis and endocrine autoimmunity.
• APECED is less defined in Western Hemisphere patients, with European cohorts showing fewer nonendocrine manifestations.

Purpose of the Study:

• To investigate the genetic, clinical, autoantibody, and immunological characteristics of American APECED patients.
• To compare the manifestation profile of APECED in American patients with that in European cohorts.
• To evaluate the diagnostic delay and identify early manifestations in American APECED cases.

Main Methods:

• A prospective observational natural history study enrolled 35 consecutive American APECED patients.
• Systematic examination of genetic, clinical, autoantibody, and immunological features.
• Analysis of AIRE mutations, presence of anti-IFN-ω autoantibodies, and clinical manifestations.

Main Results:

• Most American patients were compound heterozygous for AIRE mutations, with c.967_979del13 being most common.
• A high prevalence of nonendocrine manifestations (urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, Sjögren's-like syndrome) was observed (40%-80%).
• Diagnosis was delayed (mean 7.38 years), with 80% developing non-triad manifestations before the classic dyad; early signs included urticarial eruption, intestinal dysfunction, and enamel hypoplasia.

Conclusions:

• American APECED patients exhibit a diverse syndrome with a significant enrichment of early-onset, organ-specific nonendocrine manifestations compared to European patients.
• Incorporating these non-triad manifestations into diagnostic criteria could accelerate diagnosis by approximately 4 years.
• Earlier diagnosis has the potential to prevent life-threatening endocrine complications associated with APECED.