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

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.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

“…The management of APECED patients can be challenging due to the complex medical conditions that they develop, which are associated with poor quality of life and substantial psychosocial burden to both patients and their families ( 153 ). Mortality may exceed 30% even with best available medical treatment, driven by adrenal or hypocalcemic crises, end-organ failure (e.g., fulminant autoimmune hepatitis, pneumonitis-associated respiratory failure), malignancies (i.e., oral, esophageal and/or gastric), infections, or suicide ( 7 , 128 , 154 ). Therefore, a coordinated multidisciplinary approach that incorporates several medical and dental specialties is required to provide the best clinical care for the individual patient.…”

Monogenic Adult-Onset Inborn Errors of Immunity

“…It is essential to regulate self-tolerance and promotes the negative selection of autoreactive T cells, which can cause autoimmunity ( 122 ). AIRE deficiency patients reported in large cohorts from different countries ( 100 , 101 , 123 ) often have infancy onset symptoms, but are mostly diagnosed in later life when cumulative autoimmune phenomena alert physicians for monogenic causes. Autoimmune manifestations in adulthood in the context of recessive mutations is very rare and careful history for milder manifestations in infancy is important.…”

A Remarkable Case of Autoimmune Polyendocrinopathy, Candidiasis and Ectodermal Dystrophy Syndrome (APECED) misdiagnosed as Juvenile Idiopathic Arthritis on admission

“…A single-nucleotide polymorphism (SNP) that was strongly associated with APECED was identi ed in a largescale genome-wide cohort of patients with rheumatoid arthritis. Two SNPs in AIRE gene, rs2075876 and rs760426, showed strong association with rheumatoid arthritis risk suggesting that in addition to the key AIRE gene mutations, other genetic, environmental factors, SNPs may have an impact on the phenotypic expression of APECED (2). In addition, it is important to emphasize that a delay in diagnosis in a patient with arthritis may lead to poor prognostic outcomes.…”