Complement Hyperactivation, Angiopathic Thrombosis, And Protein-Losing Enteropathy

A number sign (#) is used with this entry because of evidence that complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is caused by homozygous mutation in the CD55 gene (125240) on chromosome 1q32.

Description

Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy 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).

Clinical Features

Sheba et al. (1968) and Shani et al. (1974) described a kindred from an inbred Christian Arab group living in Israel in which 8 of 28 children in 2 sibships had protein-losing enteropathy. The parents were in each case related as first cousins once removed, and the 2 affected sibships were first cousins through their mothers and second cousins through their fathers. Intestinal lymphangiectasia (see 152800) was initially suspected but was later shown not to be present. Affected children exhibited growth retardation, edema, clubbing, abdominal pain, and diarrhea, and all had iron-deficiency anemia and hypoproteinemia. Lymphocyte counts were normal. Ascites and death occurred in 4; autopsies in 2 of the deceased patients revealed hepatic vein stenosis with Budd-Chiari syndrome (see 600880).

Ozen et al. (2017) studied 11 patients and 2 deceased relatives with a history of protein-losing enteropathy from 8 families of Turkish, Moroccan, or Syrian descent. The disease was characterized by early-onset gastrointestinal symptoms, including abdominal pain, vomiting, and diarrhea, as well as edema, malnutrition, hypoalbuminemia, and hypogammaglobulinemia. Hypoproteinemia was always present, and was alleviated by albumin infusion. Chronic malabsorption caused micronutrient deficiencies as well as anemia and growth retardation. Histopathologic examination of intestinal tissue revealed extensive lymphangiectasia, verified by lymphatic endothelial markers; transmission electron microscopy of patient duodenal tissue showed lymphatic dilation but normal capillary architecture. Some of the patients underwent surgical removal of lymphangiectatic segments with amelioration of symptoms. Some patients also exhibited bowel inflammation, and radiologic examinations showed bowel-wall edema and/or thickening; the authors stated that protein-losing enteropathy and micronutrient deficiencies were probably caused by primary intestinal lymphangiectasia exacerbated by bowel inflammation. In addition, 5 patients had recurrent respiratory infections associated with hypogammaglobulinemia, and 3 patients had severe thrombotic vascular occlusion, with thrombi located in the mesenteric and hepatic veins, sometimes extending to the inferior vena cava and heart, resulting in pulmonary embolism. Analysis of patient T cells demonstrated increased C3 fragment deposition, and immunohistochemical study of duodenal biopsy tissue revealed terminal complement activation in submucosal arterioles. Elevated C5a production on patient cells was abrogated by coincubation with an experimental formulation of eculizumab, a complement-inhibitory therapeutic agent. Noting the variable expressivity of disease in their patients, Ozen et al. (2017) suggested that this might be attributable to background genetics, diet, microbiome composition, or other influences. The authors designated this disorder, comprising CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy, as 'CHAPLE' syndrome.

Kurolap et al. (2017) reported a large consanguineous Muslim-Arab family in which 6 individuals had protein-losing enteropathy associated with hypercoagulability. Disease onset was between 10 months and 3 years of age, and patients presented with generalized edema, severe hypoalbuminemia, diarrhea, and abdominal complications, with repeated thrombotic events in 3 of the patients; 2 of the patients died from disease complications. Membrane attack complex (MAC) deposition was significantly greater in white cells of patients than in those of age-matched controls, indicating abnormal complement activation.

Clinical Management

In a large consanguineous Muslim-Arab family with protein-losing enteropathy, hypercoagulability, and abnormal complement activation, Kurolap et al. (2017) treated 3 affected individuals with the terminal complement inhibitor eculizumab. Treated patients exhibited clinical and laboratory responses, including an approximately 60% decrease in complement activation, a continuous increase in serum albumin and total protein concentrations, and a decrease in number of stools as well as improvement in stool consistency. Noting the response to eculizumab therapy, Kurolap et al. (2017) suggested that high levels of MAC, possibly precipitating intestinal tissue damage, are involved in the pathogenesis of protein-losing enteropathy in these patients.

Molecular Genetics

In 11 patients with complement hyperactivity, angiopathic thrombosis, and protein-losing enteropathy from 8 consanguineous families of Turkish, Moroccan, or Syrian origin, Ozen et al. (2017) performed whole-exome sequencing and/or Sanger sequencing of CD55 and identified homozygosity for mutations in the CD55 gene (see, e.g., 125240.0004-125240.0007).

In a large consanguineous Muslim-Arab family with protein-losing enteropathy, hypercoagulability, and abnormal complement activation, Kurolap et al. (2017) identified homozygosity for a 1-bp deletion in the CD55 gene (125240.0008) that segregated fully with disease.