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. 2021 Nov;44(11):2493-2510.
doi: 10.1007/s40618-021-01585-6. Epub 2021 May 18.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients

S Garelli #  1   2 , M Dalla Costa #  1   3 , C Sabbadin  1 , S Barollo  1 , B Rubin  1 , R Scarpa  1 , S Masiero  1 , A Fierabracci  4 , C Bizzarri  5 , A Crinò  5 , M Cappa  5 , M Valenzise  6 , A Meloni  7 , A M De Bellis  8 , C Giordano  9 , F Presotto  2 , R Perniola  10 , D Capalbo  11 , M C Salerno  12 , A Stigliano  13 , G Radetti  14 , V Camozzi  1 , N A Greggio  15 , F Bogazzi  16 , I Chiodini  17 , U Pagotto  18 , S K Black  19 , S Chen  19 , B Rees Smith  19 , J Furmaniak  19 , G Weber  20 , F Pigliaru  21 , L De Sanctis  22 , C Scaroni  1 , C Betterle  23
Affiliations

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients

S Garelli et al. J Endocrinol Invest. 2021 Nov.

Abstract

Background: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD).

Methods: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined.

Results: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases.

Conclusions: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Keywords: AIRE gene mutations; Addison’s disease; Autoimmune Polyglandular Syndrome type 1 (APS-1); Autoimmune-poly-endocrine-candidiasis-ectodermal-dystrophy (APECED); Chronic hypoparathyroidism; Chronic mucocutaneous candidiasis; Interferon autoantibodies.

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Conflict of interest statement

SC, BRS, JF, and SKB are employees of RSR Ltd. RSR Ltd is a developer of medical diagnostics including assays and/or kits for measuring 21-OH Abs, 17α-hydroxylase Abs, side-chain cleavage enzyme Abs, tryptophan hydroxylase Abs, interferon-ω Abs, aromatic-l-aminoacid-decarboxylase Abs, and TSH-Receptor Abs.

Figures

Fig. 1
Fig. 1
Clinical manifestations at the end of follow-up of APS-1 patients in Italy, presented as a percent of the total number of patients (n = 158). GH growth hormone
Fig. 2
Fig. 2
Mean age (in years) at the onset of different clinical manifestations in Italian patients with APS-1
Fig. 3
Fig. 3
Occurrence of CMC, CH and AD in patients with APS-1 from various Italian regions or macro-areas
Fig. 4
Fig. 4
Number of APS-1 patients in the Italian population who presented with 1–16 associated diseases
Fig. 5
Fig. 5
AIRE gene mutations in APS-1 patients in different macro-areas or regions of Italy
See this image and copyright information in PMC

References

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