Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disorder caused by mutations in the autoimmune regulator (AIRE) gene, including the distinctive R139X in Sardinia. Its rarity and great variability in manifestations/onset ages make early diagnosis difficult. To date, very few longitudinal studies of APS1 patients have been reported. Objective: The aim of this study was to describe the features and clinical course of APS1 and correlate them with AIRE and HLA class II genotypes in a large homogeneous cohort of Sardinian patients followed for up to 25 yr. Patients: Twenty-two pediatric APS1 patients were studied prospectively. Results: This Sardinian series(female/male ratio, 1.44; median current age, 30.7yr; range, 1.8-46yr) showed early disease onset (age range, 0.3-10 yr; median, 3.5 yr) and severe phenotype (on average, seven mani-festations per patient). Besides the classic triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease, autoimmune hepatitis was a serious and surprisingly common/early/presenting feature (27%; two deaths), with a 5: 1 female bias (median age, 6 yr; range, 2.5-11 yr). By contrast, type 1 diabetes was rare (one patient), and hypothyroidism was not seen. Additional disease components(several of them potentially life-threatening) appeared in adulthood. The major nonsense mutation, R139X, was found in 93% of the mutant AIRE alleles. High-titer interferon (IFN)-omega and IFN-alpha autoantibodies were detected in all patients tested, even preclinically at 4 months of age in one sibling. HLA alleles appear to influence the exact phenotype-the most interesting apparent association being between HLA-DRB1*0301-DQB1* 0201, liver-kidney microsome autoantibodies (anti-CYP1A2), and autoimmune hepatitis. Conclusion: APS1 in Sardinia is characterized by severe phenotype, marked clinical heterogeneity, and relative genetic homogeneity. The single AIRE mutation, R139X, and the anti-IFN-omega and IFN-alpha autoantibodies are helpful for earlier diagnosis, especially when APS1 presents unusually. HLA genotypes can modify the phenotype. (J Clin Endocrinol Metab 97: 1114-1124, 2012)