A number sign (#) is used with this entry because of evidence that megacystis-microcolon-intestinal hypoperistalsis syndrome-2 (MMIHS2) is caused by homozygous or compound heterozygous mutation in the MYH11 gene (160745) on chromosome 16p13.

Megacystis-microcolon-intestinal hypoperistalsis syndrome-2 (MMIHS2) is characterized by prenatal bladder enlargement, neonatal functional gastrointestinal obstruction, and chronic dependence on total parenteral nutrition and urinary catheterization. The majority of cases have a fatal outcome due to malnutrition and sepsis, followed by multiorgan failure (summary by Wang et al., 2019).

For a discussion of genetic heterogeneity of MMIHS, see 249210.

Gauthier et al. (2015) reported an Algerian boy who had megacystis and severe oligohydramnios observed on prenatal ultrasound. A classic prune belly phenotype (see 100100) was noted at birth, and he was anuric; ultrasound confirmed megacystis with normal wall thickness. He also had severe lung hypoplasia requiring assisted ventilation. The infant never passed meconium, and at 3 weeks, transit studies showed lack of opacification of the bowel distal to the duodenum; barium enema showed filiform opacification of the distal colon with no opacification of the cecum, consistent with microcolon. Echocardiogram was normal, and the ductus arteriosus closed spontaneously. The infant died following hemodynamic deterioration and multiorgan failure.

Yetman and Starr (2018) studied a male infant, born prematurely, who had MMIHS with the additional clinical features of congenital mydriasis and sensorineural hearing loss, lung disease, pulmonary hypertension, and mild aortic dilation. He lived to the age of 18 months, but showed no substantial improvement in bladder or bowel function. Prenatal ultrasound revealed a dilated bladder and anhydramnios. At birth, he had marked abdominal distention and was apneic, requiring high-frequency ventilation. Pupils were fixed and dilated. Chest radiograph did not suggest pulmonary hypoplasia. Initial echocardiogram showed bidirectional shunting across a large patent ductus arteriosus; follow-up at age 3 weeks showed that the ductus had closed, but pulmonary hypertension persisted. There was no aortic dilation at that time, but by age 15 months, mild aortic dilation was observed. Abdominal ultrasound showed marked distention of the bladder, dilated renal pelvises, and dilated ureters; no testes were visualized. The infant did not tolerate feeding, and upper gastrointestinal series showed failure of contrast to move past the stomach; he never passed meconium, and barium enema showed severe microcolon. Exploratory laparotomy at 2 months also showed numerous areas of ileal atresia. Esophagram at age 8 months showed a dilated and patulous esophagus, with disordered motility. The infant remained ventilator dependent; bronchoscopy at age 2 months revealed bilateral bronchomalacia, with near-occlusion of the left lower lobe. Brain MRI at 8 months showed no vascular anomalies, but there was enlargement of the lateral ventricles. He experienced recurrent infections, including bacterial and fungal septicemia, peritonitis, pyelonephritis, and pneumonias; at age 18 months his condition deteriorated and he developed multiorgan failure from which he ultimately died.

The transmission pattern of MMIHS2 in the Algerian family reported by Gauthier et al. (2015) was consistent with autosomal recessive inheritance.

Kloth et al. (2019) reported a 7-year-old girl, born of nonconsanguineous German and Hungarian parents, who had megacystis detected prenatally and confirmed postnatally, along with microcolon, establishing the diagnosis of MMIHS. Immunohistochemistry of intestinal tissue revealed generalized smooth muscle disarray, and relative hyperplasia of the tunica muscularis. The proband also had hyperopia, impaired tonic pupil reaction, and accommodation defect, as well as delayed motor development. Growth hormone deficiency and central hypothyroidism were detected at age 6 years, and at age 7 she showed proportionate short stature. Sequencing of the ACTG2 gene (102545) was negative, and subsequent sequencing of MYH11 revealed heterozygosity for a P127S missense variant, inherited from her unaffected father and not found in the NHLBI Exome Variant Server or the gnomAD database. The proband was also found to have a heterozygous 1.3-Mb deletion at chromosome 16p13.11, involving MHY11 and 14 other genes, that was inherited from her mother. In addition, a paternally inherited 1-Mb duplication at 16q24.1, encompassing 7 genes, was detected in the proband, which the authors deemed to be clinically irrelevant. The authors suggested that the father might be at increased risk for thoracic aortic aneurysm (see 132900) as a heterozygous carrier of the P127S missense variant, warranting regular cardiovascular follow-up.

In an Algerian infant who died with MMIHS, Gauthier et al. (2015) identified homozygosity for a nonsense mutation in the MYH11 gene (K1200X; 160745.0006). His unaffected consanguineous parents were heterozygous for the mutation, which was not found in 323 ethnically matched controls or in public variant databases. Analysis of the MYH11 sequence in 3 more patients with MMIHS and 20 patients with prune belly syndrome did not reveal any causative mutations. Heterozygous mutation in MYH11 had previously been associated with familial thoracic aortic aneurysm and patent ductus arteriosus (AAT4; 132900); the authors noted that the proband's parents and extended family were not known to have thoracic aneurysms or dissections, but were not available for echocardiographic studies.

In a male infant who died at 18 months of age with MMIHS, Yetman and Starr (2018) identified compound heterozygosity for frameshift mutations in the MYH11 gene (160745.0007 and 160745.0008). His unaffected parents, who were each heterozygous for one of the mutations, had normal echocardiograms and showed no evidence of mydriasis or other smooth muscle dysfunction.

In a Chinese family in which 3 male fetuses had progressive megacystis and oligohydramnios on prenatal ultrasound, Wang et al. (2019) identified compound heterozygosity for a missense mutation (R684H; 160745.0009) and a deletion/insertion (160745.0010) in the MYH11 gene. The unaffected parents, who showed no evidence of vascular smooth muscle disease, were each heterozygous for one of the mutations.

Maddirevula et al. (2019) searched their database of 799 research and 1,750 clinical exomes for homozygous variants that would otherwise qualify for pathogenic or likely pathogenic classification according to ACMG guidelines, except that the involved genes had only tentative links to disease. They identified homozygosity for a splicing mutation in the MYH11 gene (c.1033+1G-A) in a fetus (17-807) with massively dilated bladder with echogenic kidney and bilateral hydronephrosis. This was the fifth pregnancy in a 27-year-old mother who had previously experienced a spontaneous abortion at 2 months with her first pregnancy, terminated the second due to massively dilated bladder, had intrauterine fetal demise at 7 months with the third pregnancy, and terminated the fourth pregnancy at 15 weeks due to Potter sequence. The mutation was not found in the Saudi Human Genome Program or gnomAD databases.