Lessons From Prospective Longitudinal Follow-up of a French APECED Cohort.

Area of Science:

• Genetics and Immunology
• Rare Diseases
• Endocrinology

Background:

• Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is a rare genetic disorder caused by AIRE gene mutations.
• It typically presents with hypoparathyroidism, adrenal failure, and chronic mucocutaneous candidiasis (CMC), alongside nonendocrine manifestations.
• Understanding the molecular and immunological profile is crucial for comprehensive patient care.

Purpose of the Study:

• To determine the molecular profile of the AIRE gene in a French cohort of APECED patients.
• To investigate the prevalence of rare clinical manifestations associated with APECED.
• To characterize the immunological disturbances present in affected individuals.

Main Methods:

• A national, multicenter prospective observational study was conducted.
• Genetic, clinical, biological, and immunological data were collected from 25 patients across 23 families.
• The study utilized established protocols for data acquisition and analysis (NCT03751683).

Main Results:

• Eleven distinct AIRE variants were identified, including two novel variants (c.653-70G > A and c.1066del).
• The most frequent manifestations included the classic triad (19/25), ectodermal dystrophy (20/25), and significant nonendocrine issues like pulmonary involvement (8/13) and malabsorption (8/25).
• Immunological findings revealed natural killer cell lymphopenia, altered T and B lymphocyte populations, and autoantibodies against cytokines like interferon-α and IL-22.

Conclusions:

• The study highlights significant AIRE genotype variability and the high prevalence of nonendocrine manifestations in APECED.
• Age-dependent B-cell lymphopenia and nonendocrine issues may contribute to disease severity.
• Systematic screening for all APECED manifestations is recommended for earlier diagnosis, vaccination support, and targeted therapies.