Abstract
Context:Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse.Objective:To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996–2016).Patients:All known Norwegian patients with APS1.Results:Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes.Conclusions:Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.
Highlights
Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC)
Fifteen of the patients died during follow-up or were deceased siblings with a high probability of undisclosed APS1
Dental examination revealed that enamel hypoplasia was present in most patients and, together with CMC and hypoparathyroidism, is one of the three most common manifestations
Summary
Patients Patients were recruited from departments of medicine and pediatrics from hospitals in Norway and were included in our National Registry of Autoimmune Diseases initiated in 1996 [3]. All fulfilled the diagnostic criteria for APS1 given above. The Regional Committee for Medical and Health Research Ethics approved the study, and all participants gave informed consent. Definitions and clinical data The patients were assessed at least annually, including hormonal status and autoantibody profiles. All patients alive were screened for AIRE mutations. A dental and oral examination was performed in 31 patients, and most patients underwent esophagogastroduodenoscopy, chest x-ray, and imaging of the spleen and kidneys. Endocrinopathies were diagnosed as previously described [1]. The diagnostic criteria for other disease manifestations are given in Supplemental Table 1
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