Enteropathy, Familial, With Villous Edema And Immunoglobulin G2 Deficiency

Clinical Features

In a large Mennonite kindred in Alberta, Canada, Smith et al. (1994) described a seemingly 'new' familial enteropathy manifested by recurrent acute, life-threatening secretory diarrhea associated with distinctive jejunal histologic changes and IgG2 subclass deficiency. Symptoms began abruptly with anorexia and vomiting, and progressed within hours to massive secretory diarrhea and shock with profound neutropenia and hypoproteinemia, including hypoalbuminemia and hypogammaglobulinemia. Affected survivors recovered quickly and thereafter grew and developed normally. Biopsy specimens obtained during remission from 3 adults and 11 children showed club-shaped jejunal villi broadened by edema and histiocytes with imbibed fluid; the overlying intestinal epithelium and brush border appeared normal, but the basement membrane was interrupted in some areas. No characteristic microorganisms had been identified in association with the syndrome. Clinical manifestations ceased in the second decade, but the abnormal jejunal histologic pattern persisted into adult life. Female and male patients were equally affected, although all fatal cases had been in female subjects. Affected individuals had a reduced serum concentration of IgG2. The pedigree published by Smith et al. (1994) showed 31 affected members. Four sibships were affected in the first of the 2 generations and 8 sibships in the second.

Inheritance

Smith et al. (1994) suggested that the disorder in the family they reported was autosomal dominant with incomplete penetrance. There were numerous examples of male-to-male transmission. One family member without a history of diarrhea had characteristic biopsy findings and another appeared to be an obligate carrier with normal biopsy findings.

Mapping

In the Mennonite kindred with a familial form of enteropathy reported by Smith et al. (1994), Johannes et al. (2007) found linkage of the disorder to chromosome 11q23 with a lod score of 6.2 at theta = zero. A higher-density microsatellite marker array refined the critical region to a 2-Mb interval between D11S4142 and D11S1364.

Molecular Genetics

By sequencing the open reading frames of 9 genes located within the critical region of chromosome 11q23 linked to the enteropathy in the Mennonite family reported by Smith et al. (1994), Johannes et al. (2007) identified a 198-bp in-frame duplication in the APOA4 gene (107690) that segregated with the disorder in the family. The mutation was not detected in 200 unrelated controls.