JM2, encoding a fork head–related protein, is mutated in X-linked autoimmunity–allergic disregulation syndrome

Abstract

An X-linked recessive syndrome of autoimmunity, allergic disregulation, and diarrhea has been recognized in several families (1-6) (Mendelian Inheritance in Man entries 304930, 304790). This syndrome, referred to herein as XLAAD (for X-linked autoimmunity-allergic disregulation syndrome), presents early in life with autoimmunity, severe allergic inflammation, secretory diarrhea, and failure to thrive (1-6). Many affected males suffer from classical type 1 diabetes mellitus that frequently presents in the immediate postnatal period or early infancy. Type 1 diabetes mellitus in XLAAD is characterized by islet cell destruction by infiltrating T cells and, in some cases, by autoantibody formation (7). Patients with XLAAD also manifest a more general predilection to autoimmune diseases including autoimmune polyendocrinopathies (especially thyroiditis), hemolytic anemia, thrombocytopenia, and enteropathy. Severe allergic inflammation in XLAAD patients is reflected by the occurrence of eczema, food allergy, elevated IgE levels, and peripheral eosinophilia. Many patients suffer from persistent secretory diarrhea, which may be caused by both food allergy-associated eosinophilic gastroenteropathy and autoimmune enteropathy. Susceptibility to recurrent staphylococcal infections has been variably described in some XLAAD patients and may reflect the wellknown association of staphylococcal infections with severe eczema. XLAAD is frequently fatal, due to unrelenting diarrhea and wasting, difficult-to-treat diabetes, and/or superimposed infections.