Summary
The purpose of this overview is to increase the awareness of clinicians regarding megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) and its genetic causes and management. The following are the goals of this overview.
1. Clinical Characteristics of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by megacystis (bladder distention in the absence of mechanical obstruction), microcolon, and intestinal hypoperistalsis (dysmotility). This rare disorder is associated with significant morbidity and mortality.
MMIHS may be suspected prenatally secondary to findings of fetal megacystis on prenatal ultrasound. Affected infants present shortly after birth with symptoms of bowel and bladder obstruction. The most common presenting symptom is abdominal distention that is secondary to a massively dilated bladder in the absence of mechanical obstruction with or without dilated bowel loops. Other symptoms include bilious emesis, failure to pass meconium, and inability to spontaneously void requiring catheterization [Puri & Shinkai 2005, Puri & Gosemann 2012, Soh et al 2015, Wymer et al 2016].
Infants and children with MMIHS have myopathic dysfunction of bladder and associated urologic comorbidities that include febrile urinary tract infections, vesicoureteral reflux (VUR), and hydronephrosis with resultant risk of renal failure [Wymer et al 2016, Hugar et al 2018]. Gastrointestinal complications of MMIHS include microcolon, intestinal dysmotility, and associated gastrointestinal comorbidities including malrotation and complications such as short bowel syndrome and recurrent symptomatic and radiographic evidence of bowel obstruction in the absence of mechanical obstruction, known as chronic intestinal pseudo-obstruction (CIPO).
Intestinal dysfunction ultimately leads to nutritional compromise and intestinal failure resulting in dependence on total parenteral nutrition (TPN). Subsequently individuals may develop complications from the TPN including central line infections, liver dysfunction, and liver failure. Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN as a result of liver failure or inability to maintain central venous access [Huang et al 2013, De Sousa et al 2016, Wymer et al 2016].
The prognosis for individuals with MMIHS, in light of its variable genetic causes, has not been well elucidated. Data on individuals prior to molecular diagnosis suggest a poor and often fatal prognosis especially within the first year of life.
Sepsis followed by multiorgan failure and malnutrition have been reported as the most frequent causes of death [Gosemann & Puri 2011].
Specialized centers with multidisciplinary care, multidisciplinary TPN management, and multivisceral transplantation have been credited for improving survival rates from 12.6% (1976-2004) to 55.6% (2004-2011) [Gosemann & Puri 2011, Puri & Gosemann 2012]. A recent Japanese nationwide survey reported five- and ten-year survival to be 63% and 57%, respectively [Soh et al 2015].
Establishing the Clinical Diagnosis of MMIHS
Prenatal Imaging Features of MMIHS
In a recent systematic review, prenatal diagnosis of MMIHS was suspected in 26% of individuals using prenatal ultrasound findings [Tuzovic et al 2014].
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 [Puri & Gosemann 2012, Tuzovic et al 2014, De Sousa et al 2016, Fontanella et al 2019]. Prenatal bladder manifestations of megacystis with or without hydroureteronephrosis are an initial presenting finding in 88% of individuals [Tuzovic et al 2014].
Gastrointestinal abnormalities on prenatal ultrasound are less common (24%) and include gastric distention (visible in the second trimester) and dilated bowel loops (visible in the third trimester) [Tuzovic et al 2014].
Dilated esophagus and microcolon have been reported using fetal MRI [Munch et al 2009].
Postnatal Clinical and Imaging Features of MMIHS
Clinical features include signs and symptoms of bowel and bladder obstruction [Gosemann & Puri 2011, Puri & Gosemann 2012]. The following are the most common:
Imaging features
Abdominal radiograph shows gastric distention and dilatation of small bowel loops with paucity of distal gas [
Ballisty et al 2013].
Fluoroscopic upper-gastrointestinal series reveals dilated stomach and small intestine with associated malrotation [
Ballisty et al 2013].
Urologic findings on renal/bladder ultrasound and cystography include a dilated bladder with large capacity, hydroureteronephrosis, and vesicoureteral reflux (VUR) [
Ballisty et al 2013].
Table 1.
Differential Diagnosis of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS)
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| Presenting Symptom in MMIHS | Differential Diagnosis | Distinguishing Clinical Features |
|---|
|
Fetal megacystis
| Lower urinary tract obstruction | Imaging or cystoscopy shows posterior urethral valves or urethral atresia/stenosis. |
Obstructive symptoms
(e.g., abdominal distention, bilious emesis, failure to pass meconium) | Hirschsprung disease | Absence of megacystis; rectal biopsy shows absence of ganglion cells |
| Small bowel atresia or colonic atresia | Absence of microcolon; isolated colonic atresia w/out megacystis |
| Anorectal malformation | Abnormal anal position/caliber; clinical features of VACTERL association |
| Meconium ileus/plug | Family history of cystic fibrosis; failure to thrive; pancreatic insufficiency |
| Hypothyroidism | Absence of megacystis & microcolon; laboratory evidence of hypothyroidism |
| Sepsis | Absence of megacystis & microcolon; laboratory evidence of sepsis |
| Prenatal & intrapartum medication exposure (e.g., magnesium sulfate, opioids) | Absence of megacystis & microcolon |
| Diabetic embryopathy | Absence of megacystis |
|
Fetal megacystis & obstructive symptoms
| Prune belly sequence 1 | Absence of microcolon |
| Multisystemic smooth muscle dysfunction syndrome (MSMDS) 1 | Mydriasis, vascular abnormalities, absence of microcolon |
- 1.
Isolated (without additional features of MMIHS)
2. Genetic Causes of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
Table 2.
Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: Genes and Distinguishing Clinical Features
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- 1.
Genes are listed alphabetically.
- 2.
Vascular smooth muscle dysfunction including aortic aneurysms or dissection has not been reported.
- 3.
3. Evaluation Strategy to Identify the Genetic Cause of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
Establishing a specific genetic cause of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS):
Can aid in discussions of prognosis (which are beyond the scope of this
GeneReview) and
genetic counseling;
Usually involves a medical history, physical examination, laboratory testing, family history, and
genomic/genetic testing.
Medical history
The following medical history should raise concern for MMIHS:
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 (see Table 2).
Family history. A three-generation family history should be taken, with attention to the following:
Manifestations of MMIHS, bowel/bladder dysfunction, chronic intestinal pseudo-obstruction (CIPO), and multisystemic smooth muscle dysfunction syndrome (MSMDS), as well as
familial forms of myopathy, neuropathy, mitochondrial diseases, and other conditions that affect the enteric nervous system or smooth muscle
Recurrent fetal loss
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.
A multigene panel that includes some or all of the genes listed in Table 1 is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 2).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Serial single-gene testing can be considered if clinical findings and/or family history indicate that pathogenic variants in a particular gene are most likely (see Table 2).
Comprehensive
genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
4. Genetic Counseling of Family Members of an Individual with Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) caused by pathogenic variants in ACTG2 is inherited in an autosomal dominant manner.
MMIHS caused by pathogenic variants in LMOD1, MYH11, MYL9, or MYLK is inherited in an autosomal recessive manner.
Autosomal Dominant Inheritance – Risk to Family Members
Parents of a proband
Some individuals diagnosed with MMIHS inherited an
ACTG2 pathogenic variant from a parent. The severity of clinical findings may vary within a family; a parent may be asymptomatic or have a milder
phenotype [
Wangler et al 2014].
The family history of some individuals diagnosed with MMIHS may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic expression, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or
molecular genetic testing has been performed on the parents of the
proband.
Note: If the parent is the individual in whom the
pathogenic variant first occurred, the parent may have
somatic mosaicism for the variant and may be mildly/minimally affected.
Sibs of a proband. The risk to sibs depends on the clinical/genetic status of a proband's parents:
If a parent of the
proband is affected and/or is known to have the
ACTG2 pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the parents have not been tested for the
ACTG2 pathogenic variant but are clinically unaffected, the risk to the sibs of a
proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for MMIHS because of the possibility of parental
germline mosaicism.
Depending on the specific
gene involved, clinical severity and
phenotype may differ between individuals with the same variant; thus, age of onset and/or progression may not be predictable.
Offspring of a proband. Each child of an individual with MMIHS has a 50% chance of inheriting the MMIHS-related pathogenic variant.
Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the ACTG2 pathogenic variant, the parent's family members may be at risk.
Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the causative variant identified in the proband or clinical evidence of the disorder, the variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.
Autosomal Recessive Inheritance – Risk to Family Members
Parents of a proband
Sibs of a proband
Offspring of a proband. The offspring of an individual with MMIHS are obligate heterozygotes (carriers of a MMIHS-related pathogenic variant).
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a MMIHS-related pathogenic variant.
Carrier detection. Carrier testing for at-risk relatives requires prior identification of the MMIHS-related pathogenic variants in the family.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
MMIHS Foundation
Children's Organ Transplant Association
Phone: 800-366-2682
Fax: 812-336-8885
Email: cota@cota.org
International Foundation for Functional Gastrointestinal Disorders (IFFGD)
PO Box 170864
Milwaukee WI 53217-8076
Phone: 888-964-2001 (toll-free); 414-964-1799
Fax: 414-964-7176
Email: iffgd@iffgd.org
International Foundation for Functional Gastrointestinal Disorders (IFFGD) - Pediatric
PO Box 170864
Milwaukee WI 53217-8076
Phone: 888-964-2001 (toll-free); 414-964-1799
Fax: 414-964-7176
Email: iffgd@iffgd.org
National Digestive Diseases Information Clearinghouse (NDDIC)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
31 Center Drive
Building 31, Room 9A06
MSC 2560
Bethesda MD 20892-2560
Phone: 301-496-3583
Prune Belly Syndrome Network
P.O. Box 16071
Philadelphia PA 19154
Phone: 855-ASK-PBSN
Pull-thru Network (PTN)
2312 Savoy Street
Hoover AL 35226-1528
Phone: 205-978-2930
Email: PTNmail@charter.net
The Oley Foundation
Phone: 518-262-5079
United Ostomy Associations of America, Inc.
Phone: 800-826-0826
5. Management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Urology
Urodynamic studies to evaluate the degree of bladder dysfunction (e.g., enlarged bladder capacity for age, detrusor acontractility with failure to empty) [
Wymer et al 2016]
Voiding cystourethrogram to evaluate for outlet obstruction, vesicoureteral reflux (VUR), and bladder capacity [
Wymer et al 2016]
Renal and bladder ultrasound to evaluate for hydronephrosis and renal parenchyma
Laboratory evaluation of renal function (BUN, creatinine, GFR, etc.) and electrolytes (potassium, phosphorus, calcium)
Gastroenterology
Bowel imaging: abdominal x-ray, contrast enema, and fluoroscopic upper gastrointestinal series. Computed tomography (CT) examination of the abdomen may be indicated to evaluate for a mechanical obstruction.
Laboratory monitoring of liver enzymes (AST, ALT, alkaline phosphatase), cholestasis (total and direct bilirubin), and liver function (PT, PTT, INR, albumin)
Laboratory evaluation of macronutrient (carbohydrates, fat, protein) and micronutrient (vitamins, minerals) deficiencies in the setting of intestinal dysfunction and progressive malabsorption
Nutrition evaluation and close monitoring of growth parameters
Cardiology. Cardiology evaluation with echocardiogram in individuals with MYH11 pathogenic variants that raise suspicion of multisystemic smooth muscle dysfunction syndrome (MSMDS) [Yetman & Starr 2018]
Genetic. Referral to a clinical geneticist and/or genetic counselor
Other. Ophthalmologic evaluation for mydriasis
Treatment of Manifestations
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):
Vascular smooth muscle dysfunction in individuals with MYH11 and ACTA2 pathogenic variants that cause concern for multisystemic smooth muscle dysfunction syndrome (MSMDS) [Yetman & Starr 2018]:
Surveillance
The prognosis for individuals with MMIHS in light of its variable genetic causes has not been well elucidated. Data on individuals prior to molecular diagnosis suggests a poor and often fatal prognosis within the first year of life with reported lifetime survival rates of 55.6% (2004-2011) [Puri & Gosemann 2012]. A Japanese nationwide survey reported five- and ten-year survival rates of 63% and 57%, respectively [Soh et al 2015].
The evaluation and management are primarily supportive. Specialized centers offer multidisciplinary medical and surgical models of care including comprehensive TPN management and multivisceral transplantation.
Goals of bladder management include bladder decompression and subsequent monitoring and prevention of renal failure.
Goals of bowel management include providing means of nutrition in the setting of intestinal dysmotility via enteral or parenteral means while monitoring for nutritional failure and TPN-associated complications (line infections, liver disease).
Agents/Circumstances to Avoid
Treatment/medications to be avoided or limited include those that diminish bowel and bladder motility.
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic younger at-risk relatives of an affected individual as early diagnosis may help prevent unnecessary surgery for symptoms of intestinal obstruction and may allow early evaluation of bladder function, the urinary tract (for evidence of dilatation), and renal function.
Evaluations can include:
Abdominal or bladder ultrasound and contrast enema if the
pathogenic variant(s) in the family are not known. Evidence of megacystis (on the abdominal or bladder ultrasound) and microcolon (on the contrast enema) are highly suggestive of MMIHS.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Chapter Notes
Author Notes
Author's web page
The author specializes in the diagnosis and management of individuals with gastroparesis, chronic intestinal pseudo-obstruction, achalasia, defecation disorders, and scleroderma. Her primary research involves the study of mechanisms of functional and organic fecal incontinence, spinal cord modulation of anorectal function, and the physiological relationship between the anorectum and the bladder.
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