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Haas et al. (2012) reported a family of Ashkenazi Jewish descent with 2 of 3 children affected by congenital diarrhea. Both affected children presented 3 days af...

Haas et al. (2012) reported a family of Ashkenazi Jewish descent with 2 of 3 children affected by congenital diarrhea. Both affected children presented 3 days after birth with severe intractable diarrhea; 1 child died from complications at age 17 months. The second child showed marked improvement, with resolution of most symptoms at 10 to 12 months of age. The first affected child was a girl who had a normal birth weight of 3.18 kg. Three days after birth, she developed vomiting, colicky pain, and nonbloody watery diarrhea 8 to 10 times per day. She was treated with oral rehydration solution, and her formula was changed to soy-based formula from breast milk and cow's milk formula, but diarrhea continued. All cultures were negative. She exhibited protein-losing enteropathy and hypoalbuminemia, and required total parenteral nutrition (TPN). Stomach, duodenum, and colon biopsies were negative for chronic granulomatous disease (CGD), autoimmune enteropathy, food protein-induced enterocolitis, microvillous inclusion disease, and tufting enteropathy. Neuroendocrine cells were present in intestinal biopsies. There was no evidence of congenital lymphangiectasia by CT scan. There was evidence of dystrophic microvilli in the duodenum. The child had hyperlipidemia, with a fasting serum TG level of 325 at 1 month of age; her mother and father also had elevated fasting TG levels. At 14 months of age, the girl was below the first percentile for weight and had recurrent episodes of sepsis secondary to a venous catheter. She died at 17 months of age from complications of malnutrition and sepsis. The second affected child was a boy who weighed 3.7 kg at birth. He had a remarkably similar presentation to his sister, but he exhibited metabolic acidosis and hyponatremia at 6 days of age. He also had protein-losing enteropathy. Combined hyperlipidemia was treated with cholestyramine when the boy was 27 months of age, and fasting serum lipid levels decreased. He was thriving at 46 months of age on an unrestricted diet. Haas et al. (2012) showed villous atrophy and microvillous dystrophy in patchy areas next to normal morphology in jejunal biopsies.

▼ Molecular Genetics
Both patients in the family reported by Haas et al. (2012) were homozygous for a splice site mutation resulting in the skipping of exon 8 in the DGAT1 gene (604900.0001). Molecular analysis of the mutant allele indicated a total loss of function, with no detectable DGAT1 protein or activity produced. Both parents and an unaffected sib were heterozygous for the mutation. This variant was found in 3 individuals from 12,500 control exomes; Haas et al. (2012) estimated the probability of homozygosity to be 1 in approximately 50 to 100 million births.

Tags: 8q24.3