A number sign (#) is used with this entry because of evidence that visceral myopathy-2 (VSCM2) is caused by heterozygous mutation in the MYH11 gene (160745) on chromosome 16p13.

Visceral myopathy-2 (VSCM2) is characterized by gastrointestinal symptoms resulting from intestinal dysmotility and paresis, including abdominal distention, pain, nausea, and vomiting. Some patients exhibit predominantly esophageal symptoms, with hiatal hernia and severe reflux resulting in esophagitis and stricture, whereas others experience chronic intestinal pseudoobstruction. Bladder involvement resulting in megacystis and megaureter has also been observed and may be evident at birth (Dong et al., 2019; Gilbert et al. (2020)).

Dong et al. (2019) studied a family (RQ6654) in which 13 members over 3 generations had chronic intestinal pseudoobstruction (CIPO). Limited clinical information was provided regarding the 7 living affected family members, of whom 5 had megacystis and 1 was dependent on parenteral nutrition. Major complications occurred in 3 family members, including bowel obstruction, rectal prolapse, and malrotation, respectively.

Gilbert et al. (2020) reported 2 unrelated families segregating an autosomal dominant smooth muscle dysmotility syndrome with severe esophageal, gastric, and intestinal disease. Family 1 consisted of a father and 4 children with primarily esophageal symptoms. The 54-year-old father was diagnosed with gastroesophageal reflux disease (GERD), hiatal hernia (HH), and reflux esophagitis in infancy. A 19-year-old female twin daughter was diagnosed with GERD at age 4 years and developed dysphagia for solids at age 6. Upper endoscopy revealed mild esophagitis, HH, and severe gastroparesis. She experienced progressive duodenal dilation, and an antroduodenal motility study showed low-amplitude duodenal and jejunal contractions. Colonic motility study demonstrated an absence of significant motor activity, suggesting colonic myopathy. The other twin daughter had HH and chronic reflux esophagitis resulting in a stricture at age 4 years. Antroduodenal motility studies showed low-amplitude duodenal and jejunal contractions. She also developed recurrent necrotizing enterocolitis, requiring partial colectomy. Both sisters had normal abdominal aortas by ultrasound at ages 15 and 19, respectively. The twins had 2 older brothers, aged 22 and 24, who had symptoms of dysphagia, HH, and GERD, with esophagitis and ulceration in childhood. Manometric studies, performed in 3 of the 4 children, showed normal amplitude and propagation of peristalsis in the proximal esophagus, which is composed almost exclusively of skeletal muscle, with absent or nearly absent muscle activity in the smooth muscle lining the mid- and distal esophagus. In family 2, the proband was a 30-year-old woman of Mexican and Arab descent who was diagnosed with constipation in infancy and had intestinal pseudoobstruction at age 11 years. She later experienced recurrent volvulus of the terminal ileum and episodic small bowel obstructions. Anal manometry at age 20 showed weak internal anal sphincter tone consistent with smooth muscle myopathy, and small bowel manometry results pointed to a neurogenic abnormality. Family history revealed 4 maternal family members spanning 3 generations who had chronic intestinal motility disorders, including recurrent colonic volvulus in her mother, recurrent intestinal obstruction in her maternal grandfather, and pseudoobstruction in a second cousin. In addition, several other maternal family members were reported as having lifelong gastrointestinal symptoms suggestive of a chronic motility disorder.

The transmission pattern of visceral myopathy in the families reported by Dong et al. (2019) and Gilbert et al. (2020) was consistent with autosomal dominant inheritance.

By whole-exome sequencing in a cohort of 23 unrelated families with CIPO, negative for mutation in the ACTG2 gene (102545), Dong et al. (2019) identified heterozygosity for a 1-bp deletion in the MYH11 gene (160745.0011) in a 3-generation family (RQ6654) with 7 living and 6 deceased affected members. The variant segregated fully with disease in the family and was present at a rare minor allele frequency in the gnomAD database (0.0000653). Noting that heterozygous mutation in MYH11 had previously been associated with familial thoracic aortic aneurysm and patent ductus arteriosus (AAT4; 132900), the authors stated that CT scan and MRA in the proband (122057) and his affected son (121911) showed normal aortas, and there was no family history of aneurysm.

In a father and 4 children (family 1) with predominantly esophageal symptoms due to gastrointestinal smooth muscle dysmotility, Gilbert et al. (2020) identified heterozygosity for a 2-bp insertion in the MYH11 gene (160745.0012) that was not found in 2 unaffected family members. In a 30-year-old woman of Mexican and Arab descent from a 4-generation family (family 2) with a chronic intestinal motility disorder, the authors identified heterozygosity for the previously identified 1-bp deletion in MYH11 (160745.0011). Other affected members of family 2 were unavailable for evaluation. The proband was also heterozygous for a L1555V missense mutation in MYH11 in a region that appeared to be tolerant to variation; the authors were not able to phase the deletion and missense variant, and stated that it was possible that they occurred on the same allele. Gilbert et al. (2020) noted that both the insertion and deletion are located within a polycytosine tract in the last coding exon of SM2 isoforms of MYH11 and do not affect the SM1 isoforms, and thus the associated phenotypes are isoform-specific.