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, 30.7 yr; range, 1.8-46 yr) showed early disease onset (age range, 0.3-10 yr; median, 3.5 yr) and severe phenotype (on average, seven manifestations 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)-ω and IFN-α 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-ω and IFN-α autoantibodies are helpful for earlier diagnosis, especially when APS1 presents unusually. HLA genotypes can modify the phenotype.
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 APS1patients 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 APS1patients were studied prospectively. RESULTS: This Sardinian series (female/male ratio, 1.44; median current age, 30.7 yr; range, 1.8-46 yr) showed early disease onset (age range, 0.3-10 yr; median, 3.5 yr) and severe phenotype (on average, seven manifestations 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)-ω and IFN-α 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-ω and IFN-α autoantibodies are helpful for earlier diagnosis, especially when APS1 presents unusually. HLA genotypes can modify the phenotype.
Authors: Elise M N Ferré; Timothy J Break; Peter D Burbelo; Michael Allgäuer; David E Kleiner; Dakai Jin; Ziyue Xu; Les R Folio; Daniel J Mollura; Muthulekha Swamydas; Wenjuan Gu; Sally Hunsberger; Chyi-Chia R Lee; Anamaria Bondici; Kevin W Hoffman; Jean K Lim; Kerry Dobbs; Julie E Niemela; Thomas A Fleisher; Amy P Hsu; Laquita N Snow; Dirk N Darnell; Samar Ojaimi; Megan A Cooper; Martin Bozzola; Gary I Kleiner; Juan C Martinez; Robin R Deterding; Douglas B Kuhns; Theo Heller; Karen K Winer; Arun Rajan; Steven M Holland; Luigi D Notarangelo; Kevin P Fennelly; Kenneth N Olivier; Michail S Lionakis Journal: Sci Transl Med Date: 2019-06-05 Impact factor: 17.956
Authors: Elise M N Ferre; Stacey R Rose; Sergio D Rosenzweig; Peter D Burbelo; Kimberly R Romito; Julie E Niemela; Lindsey B Rosen; Timothy J Break; Wenjuan Gu; Sally Hunsberger; Sarah K Browne; Amy P Hsu; Shakuntala Rampertaap; Muthulekha Swamydas; Amanda L Collar; Heidi H Kong; Chyi-Chia Richard Lee; David Chascsa; Thomas Simcox; Angela Pham; Anamaria Bondici; Mukil Natarajan; Joseph Monsale; David E Kleiner; Martha Quezado; Ilias Alevizos; Niki M Moutsopoulos; Lynne Yockey; Cathleen Frein; Ariane Soldatos; Katherine R Calvo; Jennifer Adjemian; Morgan N Similuk; David M Lang; Kelly D Stone; Gulbu Uzel; Jeffrey B Kopp; Rachel J Bishop; Steven M Holland; Kenneth N Olivier; Thomas A Fleisher; Theo Heller; Karen K Winer; Michail S Lionakis Journal: JCI Insight Date: 2016-08-18
Authors: J Kärner; A Meager; M Laan; J Maslovskaja; M Pihlap; A Remm; E Juronen; A S B Wolff; E S Husebye; K T Podkrajšek; N Bratanic; T Battelino; N Willcox; P Peterson; K Kisand Journal: Clin Exp Immunol Date: 2013-03 Impact factor: 4.330