title: Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Clinica Pediatrica II and Dipartimento di Scienze Biomediche e Biotecnologie, Ospedale Microcitemico, Via Jenner s/n, 09121 Cagliari, Sardinia, Italy. ameloni@mcweb.unica.it
authors.forename: Antonella
authors.initials: A
authors.lastname: Meloni
authors.forename: Nick
authors.initials: N
authors.lastname: Willcox
authors.forename: Anthony
authors.initials: A
authors.lastname: Meager
authors.forename: Michela
authors.initials: M
authors.lastname: Atzeni
authors.forename: Anette S B
authors.initials: AS
authors.lastname: Wolff
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
authors.forename: Maria
authors.initials: M
authors.lastname: Furcas
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Rosatelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
authors.forename: Mauro
authors.initials: M
authors.lastname: Congia
mesh_terms: D001323:Autoantibodies / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D015331:Cohort Studies; D019388:Cytochrome P-450 CYP1A2; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D005260:Female; D005802:Genes, MHC Class II; D006720:Homozygote; D006801:Humans; D007223:Infant; D007372:Interferons / Q000037:antagonists & inhibitors; D007558:Italy; D008137:Longitudinal Studies; D008297:Male; D010375:Pedigree; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012720:Severity of Illness Index; D017678:Sex Distribution; D014157:Transcription Factors / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D001323:Autoantibodies; D018389:Codon, Nonsense; D019388:Cytochrome P-450 CYP1A2; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D007372:Interferons; D014157:Transcription Factors; D000096927:AIRE Protein; C504573:CYP1A2 protein, human