Precocious presentation of autoimmune polyglandular syndrome type 2 associated with an AIRE mutation

Abstract

Autoimmune polyglandular syndrome type 2 (type 2 APS), or Schmidt's syndrome, is defined by the presence of Addison's disease in combination with type 1 diabetes and/or autoimmune thyroid disease. The estimated prevalence of this syndrome is 1.4-4.5 per 100,000 inhabitants and it is more frequent in middle-aged females, whilst it is quite rare in children. Type 2 APS, which shows a pattern of autosomal dominant inheritance with low penetrance, has been associated with HLA specific DR3/DQ2 and DR4/DQ8 haplotypes. However, it has been hypothesized that genetic variability in the AIRE gene, which causing type 1 APS, may play a role in more common organ-specific autoimmune conditions like type 1 diabetes, Hashimoto's disease and type 2 APS, among others. Here we present the case of an 8-year-old girl, with a past medical history of type 1 diabetes diagnosed at the age of 3. She was taken to the Emergency Department because she complained of abdominal pain, nausea and vomiting, and her blood analysis revealed a severe hyponatremia. She also had seizures as a consequence of the hyponatremia and frequent hypoglycemia. She was ultimately found to be suffering from autoimmune primary adrenal insufficiency. The combination of both mentioned conditions, type 1 diabetes and Addison's disease, in the absence of chronic mucocutaneous candidiasis, made a diagnosis of type 2 APS plausible in this girl. The genetic study showed two heterozygous variants: NM_000383.2:C.1411C>T (p. Arg471Cys) in exon 12 and IVS9+6G>A in intron 9 of the AIRE gene. The description of an uncommon case of type 2 APS with precocious presentation associated with an AIRE mutation in a very young girl could help to clarify the role of AIRE in the development of autoimmune diseases.

Autoimmune thyroid disease and type 1 diabetes mellitus: same pathogenesis; new perspective?

“… 50 In addition, single nucleotide polymorphisms (SNPs) in AIRE (rs74203920 and rs1800525) are reported to be associated with APS type 2 (APS-2) in patients with T1DM without AITD (where APS-2 was defined as the presence of Addison’s disease combined with T1DM, AITD, or both). 57 AIRE gene variations cause several autoimmune diseases, for example, G11107A polymorphism was demonstrated to be significantly related to AITD in patients with systemic sclerosis. 49 , 53 Furthermore, AIRE gene expression decreased in a mouse model of T1DM and in peripheral blood mononuclear cells of patients with T1DM, suggesting a role in T1DM pathogenesis.…”

A Case of Pediatric Adrenal Crisis, Not Just a Condition of Infancy

“…Approximately 40% to 50% of cases initially present with adrenal insufficiency, 30% to 40% present with thyroid dysfunction or diabetes, and the remainder present with concurrent endocrine dysfunction [6]. Common presenting symptoms include weakness, weight loss, nausea, vomiting, hypotension, hyperpigmentation, and mild hyponatremia and hyperkalemia [1][2][3]10]. While hypotension has been documented in adult patients, our patient's presentation with symptoms of shock is the first report of such a severe hemodynamic presentation of APS II in the pediatric age range [1,4].…”

Primary Amenorrhea Associated with Hyperprolactinemia in Polyglandular Autoimmune Syndrome Type II: A Case Report

“…3 However, some authors only consider the existence of the types I and II, including types III and IV as part of PGA-II type. 4,5 Polyglandular autoimmune syndromes type II is rare, with a prevalence of 1.4 to 2.0 cases per 100,000 individuals, and affects predominantly middle-aged women. 4,6,7 The syndrome expresses an autosomal dominance pattern with incomplete penetrance and has been associated with human leukocyte antigen (HLA)-DR3 and/or HLA-DR4 haplotypes that increase genetic susceptibility.…”

“…4,7,8 Polyglandular autoimmune syndromes type II (, or Schmidt syndrome, is characterized by the occurrence of Addison disease (100% of cases) along with diabetes mellitus type 1 and/or autoimmune thyroid disease. 5,7,9,10 In addition, PGA-II can be associated with less frequent manifestations (4-11% of cases), such as vitiligo, gastritis, hypogonadism, hepatitis, and alopecia areata. Rare autoimmune conditions (frequency < 1%) include myasthenia gravis, rheumatoid arthritis, and Sjögren syndrome.…”