The autoimmune polyendocrine syndromes (APS) comprise a constellation of disorders which are the result of dysfunction (sequential or simultaneous) of multiple endocrine or non-endocrine glands.

Autoimmune polyendocrine syndrome type 1 (APS-1) is also known as autoimmune polyglandular syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), and Whitaker syndrome. Although new features can emerge in adulthood, onset of features typically occur in childhood or adolescence. This type of APS is associated with symptoms such as intestinal malabsorption, diarrhea, hepatitis, juvenile-onset pernicious anemia, alopecia and primary hypogonadism (60% of females, which leads to premature ovarian failure). Many of these findings do not appear until adulthood, and specialists have recommended lifelong follow up for detection of new issues (Ahonen et al., 1990). In recent years, the spectrum of findings associated with this condition in children has expanded to include chronic lung disease, demyelinating polyneuropathy with progressive muscular weakness of arms and legs and sensory loss (Valenzise et al., 2016).

APS-1 is associated with pathogenic/likely pathogenic (P/LP) variants in the AIRE gene.  Although historically considered a recessive condition, recent evidence highlights that heterozygous P/LP variants in the AIRE gene can be associated with incomplete forms of APS-1 or increased susceptibility to autoimmune diseases (Oftedal et al., 2015).  Patients with heterozygous AIRE P/LP variants who have other immune diseases, or atypical or incomplete manifestations of APS-1 have also been described.

APS-1 is typically diagnosed by the presence of two of the following three major criteria: adrenal insufficiency (Addison disease),chronic mucocutaneous candidiasis, and hypoparathyroidism. However, individuals from some ethnic groups may only present with hypoparathyroidism with other manifestations not appearing until adulthood. Consensus diagnostic criteria do not exist, and some groups have proposed using a combination of major and minor criteria including family history or presence of an AIRE gene P/LP variant. Given the severity of some of the manifestations of the condition and the clinical heterogeneity at presentation in childhood, most endocrine groups agree that the presence of even minor criteria warrant careful investigation of other signs (Capalbo et al., 2013; Guo et al., 2018). Screening for interferon autoantibodies may be performed first, given that type 1 interferon autoantibodies are present in almost all patients with APS-1. However, this testing is not always clinically available, and genetic testing is a reasonable first-line test when needed to confirm the diagnosis of APS-1 (Husebye et al., 2018).

Management of APS-1 includes treatment of candidiasis if present, hormone replacement therapy, and immunosuppressive treatments (Guo et al., 2018). In addition, multisystem monitoring for associated findings is performed on a regular basis. A treatment, Rituximab, is also currently under investigation for use in specific clinical scenarios.