Autosomal Dominant Familial Intestinal Varicosis and Polyposis coli is associated with Pathogenic Variants in NKX2.3

Familial idiopathic intestinal varicosis (FIIV) is a rare entity, characterized by distention and elongation of submucosal veins of the small bowel and/or the colon. The symptoms include rectal bleeding, abdominal pain and diarrhea. Asymptomatic cases were also reported as incidental findings on screening colonoscopy, which likely renders underreporting. FIIV is characterized by colonic and intestinal varices in the absence of portal hypertension. Recently, a single family with dominant inheritance of FIIV associated with a pathogenic variant in NKX2-3 was reported. NKX2-3 is a homeobox containing transcription factor and essential for embryonic development and the maintenance of differentiated tissue functions, especially in the intestine.

Here we report a family affected by FIIV and the detection of a 29bp deletion causing a frameshift and premature stop codon predicted to result in a truncated NKX2-3 protein (NM_145285.2:c.899_927del, p.Gly300Aspfs*75). Investigation of the family members showed segregation of the endoscopic phenotype of intestinal varices with the novel dominant NKX2-3 mutation. The index patient presented with moderate abdominal bloating and intermittent diarrhea at the age of 38 years. On colonoscopy, colonic polyposis and large intestinal varices were found. Additional investigation of liver stiffness, ultrasound and magentic resonance imaging showed no signs of chronic liver disease or portal hypertension, and no esophageal varices were present on upper gastrointestinal endoscopy. Histological examination of the colonic polyps revealed normal epithelial cells and expansion of the lamina propria with marked proliferation of capillaries in most polyps. In few of the removed polyps low grade dysplasia was also present.

The present study shows an association between a truncating variant in NKX2-3 and colonic varicosis in a large family. This is the second variant reported in NKX2-3, and as the previous NKX2-3 variant, it is expected to result in haploinsufficiency. The co-occurrence of polyposis coli broadens the phenotypic spectrum of NKX2-3-associated disease.