Approach to the patient with APS-1/APECED.

Abstract

Autoimmune polyendocrine syndrome type 1 (APS-1), also known as Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a monogenic disorder of impaired central immune tolerance classically inherited in an autosomal recessive manner and caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene, leading to chronic mucocutaneous candidiasis (CMC) and multiorgan autoimmunity. Although hypoparathyroidism and adrenal insufficiency are among the most common and clinically consequential manifestations, it is increasingly recognized that several non-endocrine features - including autoimmune enteritis, urticarial eruption (termed APECED rash), enamel hypoplasia, autoimmune pneumonitis, and autoimmune hepatitis - often precede classical endocrinopathies, contributing to delayed diagnosis. Endocrinologists are often among the first specialists to encounter these patients and play a central role in early recognition and longitudinal care. Here we present five cases that illustrate the expanding clinical spectrum of APS-1, novel genetic mechanisms, key diagnostic challenges, and emerging therapeutic approaches. These cases highlight the importance of applying expanded clinical criteria and recognizing the limitations of standard genetic testing, including the need to consider deep intronic and dominant-negative AIRE variants. Finally, evolving mechanistic insights have established APS-1 as an interferon-γ (IFN-γ)-driven disease, providing a rationale for emerging targeted immunomodulatory therapies such as Janus kinase (JAK) inhibition with ruxolitinib. Early diagnosis enables proactive surveillance and may allow timely initiation of disease-modifying treatment.