Pathophysiology, Diagnosis, and Management of Autoimmune Polyglandular Syndromes in Childhood and Adolescence

The autoimmune polyglandular syndromes (APS) encompass a wide spectrum of multi-organ autoimmunity resulting from the disruption of immunological tolerance. The ability of the immune system to recognize “self” and “non-self” is of paramount importance to protect us from foreign antigens, whilst simultaneously avoiding an aberrant autoimmune response. The breakdown of immune tolerance, occurring “centrally,” “peripherally,” or at both sites, results in a broad clinical spectrum of polyautoimmunity with an evolving recognition of atypical, “non-classical” forms. Most of these conditions have a complex genetic etiology; however, there are a number of single gene disorders that tend to present in childhood. These will often point to a fundamental role of the transcribed protein on immune function. The best characterized monogenic APS subtypes are autoimmune polyendocrinopathy syndrome type 1 (APS-1) and immune dysregulatory, polyendocrinopathy, enteropathy, X-linked (IPEX). These diseases are caused by mutations in the autoimmune regulator (AIRE) and forkhead box protein 3 (FOXP3) genes, respectively. Monogenic “IPEX-like” phenotypes are increasingly being described and high-throughput sequencing continues to identify novel genes and mutations behind clinical syndromes, thereby expanding the spectrum of APS. Endocrine assessment and investigation is a key component of management in APS. Treatment of autoimmunity may need to be balanced against an increased risk of infection. Prognosis is variable and current treatment strategies and the associated immunological and clinical response will vary according to the underlying disease mechanism. Some of the monogenic autoimmune polyglandular disorders are potential candidates for gene therapy, and further research in this area could revolutionize the treatment of APS in the future.