Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is characterized by abdominal pain and diarrhea, primary intestinal lymphangiectasia, hypoproteinemic edema, and malabsorption. Some patients also exhibit bowel inflammation, recurrent infections associated with hypogammaglobulinemia, and/or angiopathic thromboembolic disease. Patient T lymphocytes show increased complement activation, causing surface deposition of complement and generating soluble C5a (Ozen et al., 2017).

Diarrhea-2 with microvillus atrophy, with or without cholestasis (DIAR2) is characterized by onset of intractable life-threatening watery diarrhea during infancy. Two forms are recognized: early-onset microvillus inclusion disease (MVID) with diarrhea beginning in the neonatal period, and late-onset, with first symptoms appearing after 3 or 4 months of life. Definite diagnosis is made by transmission electron microscopy demonstrating shortening or absence of apical microvilli with pathognomonic microvillus inclusions in mature enterocytes and peripheral accumulation of periodic acid-Schiff (PAS)-positive granules or vesicles in immature enterocytes (Muller et al., 2008). The natural course of MVID is often fatal, but partial or total weaning from parenteral nutrition has been described. For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (214700).

Immunodeficiency-17 (IMD17) is an autosomal recessive primary immunodeficiency characterized by highly variable clinical severity. Some patients have onset of severe recurrent infections in early infancy that may be lethal, whereas others may be only mildly affected or essentially asymptomatic into young adulthood. More severely affected patients may have evidence of autoimmune disease or enteropathy. The immunologic pattern is similar among patients, showing partial T-cell lymphopenia, particularly of cytotoxic CD8 (see 186910)-positive cells, decreased amounts of the CD3 complex, and impaired proliferative responses to T-cell receptor (TCR)-dependent stimuli. B cells, natural killer (NK) cells, and immunoglobulins are usually normal. Although thymic output of functional naive T cells early in life is decreased, polyclonal expansion of functional memory T cells is substantial. The phenotype in some patients is reminiscent of severe combined immunodeficiency (SCID) (summary by Timon et al. (1993) and Recio et al. (2007)).

Infantile-onset multisystem autoimmune disease-1 is characterized by early childhood onset of a spectrum of autoimmune disorders affecting multiple organs. Common manifestations include insulin-dependent diabetes mellitus and autoimmune enteropathy, or celiac disease, and autoimmune hematologic disorders. Other features include short stature and nonspecific dermatitis. More variable features include hypothyroidism, autoimmune arthritis, and delayed puberty. Some patients may show recurrent infections. The disorder results from an inborn error of cytokine signaling (summary by Flanagan et al., 2014 and Milner et al., 2015). Genetic Heterogeneity of Infantile-Onset Multisystem Autoimmune Disease See also ADMIO2 (617006), caused by mutation in the ZAP70 gene (176947) on chromosome 2q12, and ADMIO3 (620430), caused by mutation in the CBLB gene (604491) on chromosome 3q13.

Inflammatory bowel disease-30 (IBD30) is characterized by abdominal pain and watery or bloody diarrhea, with changes in the intestinal tract consistent with Crohn disease (Mao et al., 2018). For a general description and a discussion of genetic heterogeneity of inflammatory bowel disease, including Crohn disease (CD) and ulcerative colitis (UC), see IBD1 (266600).