Autoimmune polyendocrine syndrome type I in Slovakia: relevance of screening patients with autoimmune Addison's disease

Abstract

Background: Autoimmune polyendocrine syndrome type I (APS I) is a monogenic disease affecting endocrine glands and other organs due to mutations of the autoimmune regulator (AIRE) gene. There is a wide variability in clinical phenotypes in patients with APS I, which makes the diagnosis a challenge. Objective: To screen for APS I among Slovakian patients with sporadic Addison's disease and clinical features that raised the suspicion of APS I. Methods: All 14 exons and exon-intron boundaries of the AIRE gene were sequenced. In addition, autoantibodies specific for Addison's disease and polyendocrine syndromes were assayed. Results: Using clinical criteria we identified four patients with APS I in three families. Two patients had a novel missense mutation in exon 2 (c.274COT, p.R92W) and either the Finnish major mutation (c.769COT) or the common 13 bp deletion (c.967-979del13bp). APS I was diagnosed in a brother of the latter after his death due to an adrenal crisis. A fourth patient had primary adrenal failure and hypoparathyroidism without AIRE mutations or APS-I specific autoantibodies. Conclusions: Four patients with APS I were found in a Slovakian cohort of Addison patients, although the lack of detectable AIRE mutations and APS I-specific autoantibodies raises uncertainty regarding the pathogenesis in one of the patients. This study demonstrates the merits of screening patients with phenotypic features or autoantibody findings that could indicate APS I, even in adult patients. It is necessary to identify APS I patients in order to provide appropriate treatment and follow-up of the various components of APS I.

Autoantibodies against Type I Interferons as an Additional Diagnostic Criterion for Autoimmune Polyendocrine Syndrome Type I

“…In our previous studies (15,16,25), they were also present from the earliest sampling time onward; the single exceptional patient later became very strongly positive (16). In every informative case, titers have remained consistently high for up to about 30 yr (16).…”

“…They include five of the present Italian patients (four from family 1; Fig. 2) and several others reported recently (15,25). Although titers were strongly positive against IFN-in all of them, they were low or negative against IFN-␣2 in five of the 13 but high in the other eight (supplemental Table A).…”

“…We have now found anti-IFN antibodies in all 174 APS-I patients tested, including at least 47 without the full triad, two with only a single AIRE mutation detected, and another two with none found initially who later proved to be R257X homozygous (supplemental Table B). Notably, we found no anti-IFN antibodies in three final patients, each with just two of the APS-I triad and no AIRE mutations detected; there are other serious doubts about their APS-I diagnoses (supplemental Table B) (15,16,25).…”

Autoimmune Hepatitis as a Part of Polyglandular Autoimmune Syndrome Type II: Case Report and Literature Review

“…PAS type 1 is well defined and caused by a mutation in the autoimmune regulator gene AIRE [3][4][5]. Addison's disease occurring in PAS type 1 is associated with chronic mucocutaneous candidiasis and/or acquired hypoparathyroidism [6].…”

Detection of a complete autoimmune regulator gene deletion and two additional novel mutations in a cohort of patients with atypical phenotypic variants of autoimmune polyglandular syndrome type 1

“…To date, more than 70 different mutations of the AIRE gene have been described and are distributed throughout the gene. Fifty-nine of them are listed in Human Gene Mutation Database (http://www.hgmd.cf.ac.uk), and 13 additional mutations are described in the literature (6,(10)(11)(12)(13).…”