Megacystis microcolon intestinal hypoperistalsis syndrome

Other Names: MMIH syndrome; Berdon syndrome; MMIHS; Megacystis-microcolon-intestinal hypoperistalsis-hydronephrosis syndrome

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a severe disorder affecting the muscles that line the bladder and intestines. It is characterized by impairment of the muscle contractions that move food through the digestive tract (peristalsis) and empty the bladder.

Epidemiology

MMIHS is a rare disorder. More than 200 cases have been reported in the medical literature.

Cause

MMIHS can be caused by mutations in one of several genes, the most studied of which is ACTG2. The ACTG2 gene provides instructions for making a protein called gamma (γ)-2 actin. The γ-2 actin proteins organize into filaments that are important for the tensing of muscle fibers (muscle contraction), specifically contraction of smooth muscles of the urinary and intestinal tracts. These contractions empty urine from the bladder and move food through the intestines.

ACTG2 gene mutations lead to production of an altered γ-2 actin protein. These changes hinder the formation of actin filaments, which impairs the ability of smooth muscle in the bladder and intestines to contract. These problems with muscle contractions impair the release of urine and the movement of food through the intestines, leading to the key features of MMIHS.

Mutations in other genes have been found to cause rare cases of MMIHS. The proteins produced from these genes are also involved in smooth muscle contraction. Approximately 10 percent of people with MMIHS do not have a mutation in one of the identified genes. It is likely that additional genes that have not been identified are also involved in the disorder.

Inheritance

When caused by ACTG2 gene mutations, MMIHS follows an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. These cases result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. In these cases, affected individuals have no history of the disorder in their family.

When caused by mutations in other identified genes, MMIHS is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Some of the major features of MMIHS can be recognized before birth using ultrasound imaging. Affected fetuses have an enlarged bladder (megacystis) because it does not empty. In addition, the large intestine (colon) is abnormally narrow (microcolon) because of a shortage of functional muscle lining it. Intestinal and bladder problems persist throughout life.

After birth, the continued impairment of peristalsis (hypoperistalsis) often causes a digestive condition called intestinal pseudo-obstruction. This condition, which mimics a physical blockage (obstruction) of the intestines but without an actual blockage, leads to a buildup of partially digested food in the intestines. This buildup can cause abdominal swelling (distention) and pain, nausea, and vomiting. The vomit usually contains a green or yellow digestive fluid called bile. Because digestion is impeded and the body does not get the nutrients from food, nutritional support is usually needed, which is given through intravenous feedings (parenteral nutrition). While some affected individuals rely solely on intravenous feedings, others require it only on occasion. Long-term use of parenteral nutrition can lead to liver problems.

The reduced ability to pass urine also contributes to painful distention of the abdomen. Many people with MMIHS require placement of a tube (urinary catheter) to remove urine from the bladder.

Another abnormality in some people with MMIHS is intestinal malrotation, in which the intestines do not fold properly. Instead, they twist abnormally, often causing a blockage. Individuals with MMIHS can also develop problems with the kidneys or the ureters, which are the ducts that carry urine from the kidneys to the bladder.

The life expectancy of people with MMIHS is shorter than normal, often due to malnutrition, overwhelming infection (sepsis), or the failure of multiple organs.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abdominal distention(Abdominal bloating)
• Hypoperistalsis
• Megacystis
• Microcolon
• Nausea and vomiting

30%-79% of people have these symptoms

• Hydroureter
• Intestinal malrotation
• Multicystic kidney dysplasia
• Polyhydramnios(High levels of amniotic fluid)

5%-29% of people have these symptoms

• Cryptorchidism(Undescended testes)
• Death in infancy(Infantile death)
• Neoplasm of the heart(Heart tumor)
• Omphalocele
• Pancreatitis(Pancreatic inflammation)
• Sepsis(Infection in blood stream)
• Umbilical hernia

Diagnosis

Prenatal Imaging Features of MMIHS

• In a recent systematic review, prenatal diagnosis of MMIHS was suspected in 26% of individuals using prenatal ultrasound findings.
• Grossly dilated bladder with or without hydroureteronephrosis in the setting of normal or increased amniotic fluid volume may be found on the second trimester prenatal ultrasound . Prenatal bladder manifestations of megacystis with or without hydroureteronephrosis are an initial presenting finding in 88% of individuals .
• Gastrointestinal abnormalities on prenatal ultrasound are less common (24%) and include gastric distension (visible in the second trimester) and dilated bowel loops (visible in the third trimester) .

Dilated esophagus and microcolon have been reported using fetal MRI .

Imaging features 

• Abdominal radiograph shows gastric distension and dilation of small bowel loops with paucity of distal gas.
• Fluoroscopic upper-gastrointestinal series reveals dilated stomach and small intestine with associated malrotation
• Contrast enema demonstrates a small-caliber colon (microcolon) and may show an associated malrotation.
• Urologic findings on renal/bladder ultrasound and cystography include a dilated bladder with large capacity, hydroureteronephrosis, and vesicoureteral reflux (VUR) .

Physical examination. Dilated pupils (mydriasis) suggest MYL9-MMIHS. Dilated pupils (mydriasis) and vascular smooth muscle dysfunction (e.g., aortic aneurysm, aortic dissection) should raise concern for MYH11-MMIHS .

Treatment

Myopathic bladder dysfunction and associated urologic comorbidities. Clean intermittent catheterizations or vesicostomy to ensure bladder decompression and prevent renal scarring and failure

Bowel dysfunction, microcolon, intestinal dysmotility, and associated gastrointestinal comorbidities (malrotation, short bowel syndrome, recurrent non-mechanical bowel obstruction):

• Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression .
• Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression .
• Total parenteral nutrition(TPN) when appropriate for malnutrition due to intestinal failure from intestinal dysmotility
• Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN due to complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections).

Vascular smooth muscle dysfunction in individuals with MYH11 and ACTA2 pathogenic variants that cause concern for multisystemic smooth muscle dysfunction syndrome (MSMDS):

• Referral to cardiologist and monitoring for pulmonary hypertension, aortic dilation, patent ductus arteriosus
• Referral to neurologist for evaluation for abnormal cerebral vasculature.

Prognosis

Survival in MMIHS seems to have improved, thanks to more specialized care, innovations in parenteral nutrition, and introduction of multivisceral transplantation. Long-term survival usually requires total parenteral nutrition and urinary catheterization or diversion. Most long-term survivors have ileostomies. In families with an inherited MMIHS-causing mutation, some family members with a mutation have milder features, living into adolescence and early adulthood.

While there are reports of longer survival, the prognosis and life expectancy remains poor, and it is still fatal in many cases. The main causes of death include sepsis, malnutrition, or multiple organ failure.

• Megacystis microcolon intestinal hypoperistalsis syndrome at NIH's Office of Rare Diseases

• Online Mendelian Inheritance in Man (OMIM) Megacystis microcolon intestinal hypoperistalsis syndrome; MMIH syndrome; Berdon syndrome -249210

NIH genetic and rare disease info

• NIH info on Megacystis microcolon intestinal hypoperistalsis syndrome

Megacystis microcolon intestinal hypoperistalsis syndrome is a rare disease.

Megacystis microcolon intestinal hypoperistalsis syndrome Resources
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