Clinical Pearls & Morning Reports
Published September 21, 2022
Inborn errors of immunity, also known as primary immunodeficiencies, are disorders that stem from defects in immune regulation or tolerance and can mimic inflammatory bowel disease. These conditions can be fatal early in life. Read the NEJM Case Records of the Massachusetts General Hospital here.
Q: What is immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome?
A: IPEX syndrome is an immune dysregulatory disorder that typically develops in infancy. Patients with IPEX syndrome present with a classic triad of manifestations: autoimmune endocrinopathies (typically neonatal type 1 diabetes mellitus and thyroiditis), autoimmune enteropathy (associated with failure to thrive and severe chronic diarrhea), and eczematous dermatitis. IPEX syndrome is caused by loss-of-function variants in FOXP3, which is a master transcriptional regulator that is fundamental to the function of CD4+CD25+ regulatory T cells. Of note, FOXP3 variants have variable penetrance, with the same variant causing different clinical presentations across carriers, including family members.
Q: Do the endocrinopathies associated with autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) differ from those that occur in IPEX syndrome?
A: APECED, also known as autoimmune polyendocrine syndrome type 1 (APS-1), results from a defect in the autoimmune regulator gene that leads to a loss of central immune tolerance. Patients with APECED present with mucocutaneous candidiasis, ectodermal dystrophy, and multiple endocrine diseases. Hypoparathyroidism and adrenal insufficiency are the most common endocrine diseases; diabetes mellitus or hypothyroidism (or both) can also occur. APECED is often associated with underlying autoimmune enteropathy, and gastrointestinal manifestations can vary widely.
A: In addition to the classic triad of manifestations associated with IPEX syndrome, numerous other manifestations have been described, including neurologic abnormalities, hematologic disorders (e.g., immune-mediated cytopenias), pulmonary disease, hepatitis, renal disease, and infections. Allergic inflammation can include eczema, food allergies, eosinophilia, and an elevated total IgE level. Hemolytic anemia and nephritis have been described in patients with IPEX syndrome.
A: Immunosuppressive therapy is the mainstay of treatment. However, immunosuppression typically controls symptoms only transiently, without long-term remission. The rationale for the use of hematopoietic-cell transplantation (HCT) in treating patients with IPEX syndrome is straightforward: restoration of functional regulatory T cells should restore the normal immunologic balance, providing relief from autoimmune manifestations as well as obviating the need for continued immunosuppressive therapy. Multiple case reports and small series have shown success with the use of HCT in patients with IPEX syndrome. A large international series involving 96 patients with IPEX syndrome who were treated at 38 institutions has also been reported. Patients treated with medical therapy alone had lifelong manifestations and needed continued immunosuppressive therapy. Among the 58 patients who underwent HCT, overall survival was 73.2% with a median follow-up of 2.7 years. The extent and severity of organ involvement before HCT were predictive of outcomes after HCT.