Mungan Syndrome

A number sign (#) is used with this entry because of evidence that Mungan syndrome (MGS) is caused by homozygous mutation in the RAD21 gene (606462) on chromosome 8q24. One such family has been reported.

Clinical Features

Mungan et al. (2003) reported a large consanguineous Turkish family segregating autosomal recessive chronic idiopathic intestinal pseudoobstruction (CIIP) in which 3 sibs had megaduodenum, long-segment Barrett esophagus, and different cardiac abnormalities. Two brothers and a sister, ages 26, 28, and 30 years, respectively, who had recurrent abdominal pain and pseudoobstruction from childhood, underwent upper endoscopy that revealed long-segment Barrett esophagus, hypomotility, and delayed gastric emptying. A biopsy of striated muscle in 1 of the brothers was normal. Esophageal manometry revealed aperistalsis and undetectable lower esophageal pressures, and barium small-bowel enema showed megaduodenum and delayed emptying. Cardiac murmurs were noted in all 3 sibs and echocardiography revealed 'trivial' supravalvular pulmonary stenosis and 2(+) pulmonary and tricuspid valve regurgitation in the 26-year-old proband, membranous ventricular septal defect in his brother, and 'trivial' pulmonic valve stenosis in their sister. Other findings in the sibs included epilepsy, glaucoma, and otosclerosis in the proband and bilateral ptosis in his brother. A male and female cousin, also born of consanguineous parents, were reported to have gastrointestinal complaints and died at 19 and 15 years of age, respectively.

Deglincerti et al. (2007) investigated the Turkish family previously reported by Mungan et al. (2003) and found that the female cousin who died at age 15 did in fact have clinical and radiologic evidence of chronic idiopathic intestinal pseudoobstruction, as well as renal hypoplasia, vesicoureteral reflux, ascites, and unspecified granulomatous hepatitis. The authors examined full-thickness intestinal biopsies from the proband and his brother and observed abnormalities of both the neural and muscular components, suggesting an underlying neuromyopathy.

Mapping

Deglincerti et al. (2007) performed homozygosity mapping in the large consanguineous Turkish family originally reported by Mungan et al. (2003) with autosomal recessive visceral neuromyopathy and obtained a maximum 2-point lod score of 3.97 and maximum multipoint lod score of 5.01 for a novel microsatellite marker between D8S199 and D8S514. The critical interval spans about 13 Mb between D8S1830 and D8S1799 on chromosome 8q23-q24.

Molecular Genetics

In the large consanguineous Turkish family originally reported by Mungan et al. (2003), with intestinal pseudoobstruction mapping to chromosome 8q23-q24, Bonora et al. (2015) performed whole-exome sequencing and identified a homozygous missense mutation in the RAD21 gene (A622T; 606462.0003) that segregated fully with disease in the family and was not found in 500 Turkish controls or in public variant databases. Screening of RAD21 in 21 Italian and 12 Swedish patients with pseudoobstruction did not reveal any mutations.