Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients

J Clin Endocrinol Metab. 2012 Apr;97(4):1114-24. doi: 10.1210/jc.2011-2461. Epub 2012 Feb 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / analysis
  • Child
  • Child, Preschool
  • Codon, Nonsense*
  • Cohort Studies
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Female
  • Genes, MHC Class II
  • Homozygote
  • Humans
  • Infant
  • Interferons / antagonists & inhibitors
  • Italy
  • Longitudinal Studies
  • Male
  • Pedigree
  • Polyendocrinopathies, Autoimmune / genetics*
  • Polyendocrinopathies, Autoimmune / immunology
  • Polyendocrinopathies, Autoimmune / physiopathology*
  • Polymorphism, Genetic
  • Prospective Studies
  • Severity of Illness Index
  • Sex Distribution
  • Transcription Factors / genetics*


  • APECED protein
  • Autoantibodies
  • Codon, Nonsense
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Transcription Factors
  • Interferons
  • CYP1A2 protein, human
  • Cytochrome P-450 CYP1A2

Supplementary concepts

  • Autoimmune polyendocrinopathy syndrome, type 1