Megacystis–microcolon–intestinal hypoperistalsis syndrome (MMIHS)

MMIHS typically manifests prenatally and is fully recognised in the neonatal period. Foetal megacystis, with or without hydronephrosis, is detected on antenatal ultrasound in 96% of cases; genitourinary and gastrointestinal involvement then dominates the clinical picture, with a massively dilated, poorly emptying bladder, defective intestinal peristalsis and, in a proportion of affected individuals, a reduced colon diameter. In one descriptive cohort, megacystis and defective intestinal peristalsis were present in 96% and 100% of affected individuals, respectively, while a microcolon was observed in 57%; absence of a microcolon does not exclude the diagnosis. Affected individuals present with marked abdominal distension, vomiting, and an inability to feed enterally and most rely at least intermittently on long-term parenteral nutrition. Clinical course and severity vary considerably, even within families carrying the same variant, and the condition is often fatal in childhood.

Due to insufficient data, no reliable statement on prevalence can currently be made.

Pathogenic germline variants in five genes encoding components of the visceral smooth-muscle contractile apparatus and cytoskeleton are known to cause MMIHS. ACTG2 is the most common causative gene, with pathogenic variants detected in approximately 79% of patients. Rarer causes include biallelic variants in MYH11, MYLK, LMOD1 and MYL9. The implicated genes encode smooth-muscle gamma-actin (ACTG2), smooth-muscle myosin heavy chain (MYH11), myosin light-chain kinase (MYLK), the regulatory myosin light chain (MYL9) and the actin-binding protein leiomodin-1 (LMOD1); disruption of any of these components impairs visceral smooth-muscle contraction and peristalsis.

MMIHS most commonly follows an autosomal dominant pattern; less frequently, autosomal recessive inheritance occurs, depending on the underlying causative gene. For autosomal dominant forms, each child of an affected individual has a 50% recurrence risk; for autosomal recessive forms, the recurrence risk is 25% when both parents are carriers. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of MMIHS is established primarily by molecular genetic testing. Prenatal ultrasound demonstrating foetal megacystis, with or without hydronephrosis, is the typical antenatal sign; postnatally, contrast studies demonstrate microcolon and absent or markedly reduced bowel peristalsis. Full-thickness intestinal biopsy may show smooth-muscle layer thinning, vacuolar changes, hypoganglionosis or immature ganglion cells.

Main differential diagnoses include:

• Chronic intestinal pseudo-obstruction (CIPO): postnatal-onset pseudo-obstructive symptoms without microcolon.
• : prenatal megacystis from obstructive uropathy without bowel hypoperistalsis.
• Multisystemic smooth muscle dysfunction syndrome (MSMDS): bladder hypotonicity with vascular and ciliary smooth-muscle involvement.

• Establishing the diagnosis through genetic testing confirms a clinical suspicion and provides a definitive basis for genetic counselling and reproductive planning.
• Identification of the underlying genetic cause is a prerequisite for targeted medical care; specific and individualised clinical management decisions rest with the treating physicians in consultation with the affected individual.
• Once a pathogenic variant has been identified in the index case, predictive testing of at-risk relatives becomes possible, allowing individualised risk assessment within the family.

• Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, et al. Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome Overview. PMID: .
• Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, et al. ACTG2 Visceral Myopathy. PMID: .
• Nham S, Nguyen ATM, Holland AJA. Paediatric intestinal pseudo-obstruction: a scoping review. European journal of pediatrics. 2022;181(7):2619-2632. doi: 10.1007/s00431-021-04365-9. PMID: . PMCID: PMC9192403.
• Hilberath J, Tsiflikas I, Sanders A, Lieber J, Luithle T, Haack TB, et al. Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study. Orphanet journal of rare diseases. 2025;21(1):19. doi: 10.1186/s13023-025-04154-9. PMID: . PMCID: PMC12817443.
• Geraghty RM, Orr S, Olinger E, Neatu R, Barroso-Gil M, Mabillard H, et al. Use of whole genome sequencing to determine the genetic basis of visceral myopathies including Prune Belly syndrome. Journal of rare diseases (Berlin, Germany). 2023;2(1):9. doi: 10.1007/s44162-023-00012-z. PMID: . PMCID: PMC10241726.