Inborn errors of immunity (IEI) represent a rapidly expanding group of disorders characterized not only by susceptibility to infection but also by profound immune dysregulation affecting multiple organs. Among these manifestations, autoimmune endocrine diseases provide one of the most visible clinical consequences of failed immune tolerance. In many patients, endocrine abnormalities constitute an early and sometimes defining clue to an underlying IEI. The reported prevalence of endocrine involvement among IEI varies across cohorts but is estimated to range from approximately 5% to nearly 30%.
The association between immune dysfunction and endocrine disease has been recognized for nearly a century. Early descriptions of chronic mucocutaneous candidiasis accompanied by endocrine failure ultimately led to the concept of autoimmune polyendocrine syndromes. Identification of the AIRE gene subsequently established the molecular basis of autoimmune polyendocrine syndrome type 1 (APS-1), highlighting the central role of immune tolerance in endocrine homeostasis. Advances in human genetics have since revealed that many IEI affecting immune regulatory pathways frequently present with endocrine autoimmunity. Disorders characterized by regulatory T cell dysfunction—collectively termed Tregopathies—including IPEX syndrome, CTLA-4 haploinsufficiency, and LRBA deficiency, show particularly strong associations with endocrine diseases such as early-onset type 1 diabetes and autoimmune thyroiditis. In addition, dysregulation of key immune signaling pathways, including NF-κB signaling (e.g., A20 haploinsufficiency) and interferon signaling (e.g., STAT1 gain-of-function), further broadens the spectrum of IEI presenting with endocrine pathology. Despite their diverse genetic origins, emerging evidence suggests that many of these disorders may converge on shared immune effector mechanisms, particularly interferon-γ–dominant inflammatory responses contributing to organ-specific autoimmune damage in endocrine tissues.
Collectively, these observations highlight endocrine autoimmunity as a key clinical interface between immunology and endocrinology. Recognition of endocrine manifestations as potential indicators of IEI may facilitate earlier diagnosis and enable the application of emerging immunologically targeted therapies. Ultimately, these observations suggest that diverse IEI may converge on shared immune effector pathways contributing to endocrine autoimmunity, highlighting endocrine disease as a window into immune tolerance breakdown.
