Necrotizing Enterocolitis in Two Siblings and an Unrelated Infant with Overlapping Chromosome 6q25 Deletions

Abstract

The pathogenesis of necrotizing enterocolitis (NEC) remains poorly understood but is thought to be multifactorial. There are no specific recurring chromosomal abnormalities previously associated with NEC. We report 3 cases of intestinal necrosis associated with large chromosome 6 deletions. The first patient was found to have a 7.9-Mb deletion of chromosome 6 encompassing over 40 genes, arr[GRCh37] 6q25.3q26(155699183_163554531)×1. The second patient had a 19.5-Mb deletion of chromosome 6 generated by an unbalanced translocation with chromosome 18, 46,XY,der(6)t (6;18)(q25.1;p11.23), arr[GRCh37] 6q25.1q27(151639526_ 171115067)×1, 18p11.32p11.23(131700_7694199)×3, which included the whole 7.9-Mb region deleted in the first patient. The third patient was the younger sibling of the second patient with an identical derivative chromosome 6. The shared abnormal chromosome 6 region includes multiple genes of interest, particularly EZR. Mouse models have demonstrated that Ezr is expressed in microvillar epithelium and helps regulate cell-cell adhesion in the gut. We hypothesize that deletion of this shared region of 6q leads to gastrointestinal vulnerability which may predispose patients to intestinal necrosis.

Keywords: Chromosome 6q deletion; EZR; Necrotizing enterocolitis.

Fig. 1

Abdominal radiographs. Patient 1: A Anteroposterior view showing diffusely dilated bowel with circumferential pneumatosis of the colon (red arrow) and branching portal venous gas in the liver (yellow arrow). B Left lateral decubitus view showing diffusely dilated bowel with air fluid levels, no free air, but linear pneumatosis (arrow) and portal venous gas. Patient 2: C Anteroposterior view showing extensive linear and circumferential pneumatosis (arrow) in the right lower quadrant. D Cross-table lateral view showing extensive linear and circumferential pneumatosis (arrow), but no free air. Patient 3: E Supine abdomen X-ray showing diffuse dilated small bowel and linear pneumatosis of the ascending colon (arrow) extending into cystic pneumatosis in the transverse colon.

Fig. 2

Intestinal pathology. Gut ischemic necrosis in 2 patients with chromosome 6q25 deletions. All samples show loss of villous and surface epithelium (red arrows). Pneumatosis is present in patient 1 (green arrows). Patient 1: stomach (A) and jejunum (B). Patient 2: small intestine (C, D). HE. ×40-100.

Fig. 3

A Chromosome 6 with arrows indicating the deleted region in patient 1. Chromosome images for patient 2 and 3 are unavailable. B Aligent array for chromosome 6 in patient 1 with deleted region highlighted and hg19 coordinates listed beneath. C View of UCSC genome browser for deleted area with candidate genes highlighted.