Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 2

Mendelian MONDO:0025708 Pathograph 15 Show in embeddings browser visceral myopathy autosomal recessive disease

Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (MMIHS2) is the autosomal recessive, MYH11-related form of MMIHS. MYH11 encodes smooth muscle myosin heavy chain, the motor of the visceral smooth muscle contractile apparatus. Biallelic loss-of-function alleles leave bladder and bowel smooth muscle unable to generate force, so both hollow organs fail functionally while remaining anatomically patent: a hugely distended bladder with no outlet obstruction, an unused and therefore microscopic colon, and intestine that does not propel. MMIHS as a clinical syndrome is genetically heterogeneous. Most cases are dominant and caused by de novo ACTG2 variants; the recessive forms implicate LMOD1, MYLK, MYL9, MYH9 and MYH11. What these genes share is the contractile apparatus, which is the evidence for a myopathic rather than a neuropathic basis for the syndrome. This entry covers the MYH11 form specifically. Two things make the MYH11 form worth curating in its own right. First, MYH11 is already a disease gene for thoracic aortic aneurysm and dissection - but through dominant-negative missense alleles, not biallelic nulls. The same gene produces a vascular disease one way and a visceral disease the other, which is a statement about how the lesion works rather than about which organ the gene is expressed in. Second, the severity is allele-dependent in a legible way: a hypomorphic allele in trans with a whole-gene deletion has produced a visceral myopathy presenting in adulthood rather than the neonatal syndrome.

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1
Inheritance
7
Pathophys.
2
Histopath.
8
Phenotypes
2
Hypotheses
1
Gaps
15
Pathograph
1
Genes
7
Medical Actions
1
Models
1
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic MYH11 variants. Reported genotypes include homozygosity for a nonsense allele in a consanguineous family, compound heterozygosity in a non-consanguineous family, and compound heterozygosity for a whole-gene deletion with a point variant in trans. Heterozygous parents are unaffected for the visceral phenotype.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:31427716 SUPPORT Human Clinical
"The study's results confirmed that MYH11 is a candidate gene for MMIHS with autosomal recessive (AR) inheritance and expanded the mutation spectrum for this clinical condition."
States the inheritance mode for the MYH11 form specifically, against the dominant ACTG2 background.
PMID:25407000 SUPPORT Human Clinical
"Segregation analysis using Sanger sequencing revealed that the father and the mother of the proband are heterozygous for the c.3598A>T (p.Lys1200Ter) variant."
Segregation in unaffected heterozygous parents, which is what establishes recessiveness rather than a de novo dominant event.
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Mechanistic Hypotheses

2
Whether the mechanism of MYH11 disruption, not the gene, determines which smooth muscle bed fails
myh11_lesion_type_determines_affected_bed EMERGING
Evidence balance 4 support
MYH11 is a disease gene at least three times over, and the entry point for each disease is a different kind of lesion rather than a different gene. Dominant-negative missense alleles cause familial thoracic aortic aneurysm and dissection. Biallelic null alleles cause this visceral myopathy. And heterozygous protein-elongating frameshifts at the 3' end, affecting the SM2 isoforms, cause a dominantly inherited severe oesophageal, gastric and intestinal dysmotility syndrome whose authors propose a third mechanism again - dominant hypercontractile loss of function - explicitly distinct from the other two. That third arm is the one that makes this a hypothesis about mechanism rather than a two-way table. It shares an organ system with MMIHS and an inheritance pattern with the aortic disease, so neither "dominant means vascular" nor "gastrointestinal means recessive" survives it. The phenotypes otherwise barely overlap, and the mother in the late-onset family - an obligate carrier of a hypomorphic allele - had a normal cardiac and vascular assessment. The proposal is that this is a statement about mechanism rather than about expression: a poisoned motor incorporated into an otherwise intact filament is a different lesion from an absent motor, and vascular and visceral smooth muscle apparently tolerate the two differently. The authors of the founding MYH11 MMIHS report state this directly. What is not established is why. Both tissues express MYH11, so the explanation cannot be that one is spared. Candidate accounts - differences in isoform usage, in the mechanical demands placed on the filament, or in compensation by other myosins - are not tested in the literature curated here, though the third arm makes isoform usage the most concrete of them, since those variants are specific to SM2. The practical consequence is that carrier relatives of a visceral case should not be assumed to carry aortic risk, and vice versa; that inference is exactly what this hypothesis leaves open.
Show evidence (4 references)
PMID:25407000 SUPPORT Human Clinical
"Interestingly, dominant-negative variants in MYH11 have previously been shown to cause thoracic aortic aneurism and dilatation. Different mechanisms of MYH11 disruption may thus lead to distinct patterns of smooth muscle dysfunction."
The hypothesis in the authors' own words, framed as a possibility. Quoted as written, including the source's spelling of aneurysm.
PMID:38625590 SUPPORT Human Clinical
"Cardiac and vascular assessment of the mother was normal."
A single obligate carrier of the hypomorphic allele without vascular disease. One person is not a cohort, which is why this is recorded under a hypothesis rather than as a claim about carrier risk.
PMID:31944481 SUPPORT Human Clinical
"This report highlights heterozygous protein-elongating MYH11 variants affecting the SM2 isoforms of MYH11 as a cause for severe gastrointestinal dysmotility, and we hypothesize that the mechanistic pathogenesis of this disease, dominant hypercontractile loss-of-function, is distinct from those..."
The third mechanism, proposed as distinct by the authors who describe it, and the strongest single support for this hypothesis: a heterozygous MYH11 variant causing gastrointestinal rather than vascular disease means neither zygosity nor gene predicts the affected bed, and only the kind of lesion is left to do the work. This item was graded REFUTE in the previous round, against the two-mechanism dichotomy the hypothesis label then asserted. The label now names three mechanisms, so that reading is retired and the grading follows it. Recording the change here rather than silently flipping it, because a reader comparing rounds would otherwise see one paper graded two ways on one hypothesis with no explanation.
+ 1 more reference
Whether residual MYH11 function sets age of onset along a continuum
residual_function_sets_onset EMERGING
Evidence balance 2 support
MMIHS is defined as a congenital disease, but a family carrying a whole-gene deletion in trans with an in-frame hypomorphic allele presented in adulthood - a brother with severe bladder dysfunction and intestinal obstruction at 38, a sister with end-stage kidney disease, neurogenic bladder and recurrent sigmoid volvulus at 30. If that is the same disease with more residual motor function, then "congenital MMIHS" and "adult visceral myopathy" are two points on one dose-response curve rather than two entities, and adults with unexplained visceral myopathy are an under-tested group. The evidence is one family, described by its authors as the second such report. An alternative reading - that the in-frame allele produces a qualitatively different protein rather than less of the same function - is not excluded by the data available.
Show evidence (2 references)
PMID:38625590 SUPPORT Human Clinical
"The 38 years-old brother had severe bladder dysfunction and intestinal obstruction, whereas the 30 years-old sister suffered from end-stage kidney disease with neurogenic bladder and recurrent sigmoid volvulus."
The late-onset presentation in two siblings, decades after the congenital syndrome would have declared itself.
PMID:38625590 SUPPORT Human Clinical
"Compound heterozygous variants of MYH11 gene were identified, associating a deletion of 1.2 Mb encompassing MYH11 inherited from the father and an in-frame variant c.2578_2580del, p.Glu860del inherited from the mother."
The genotype the hypothesis rests on - a null in trans with an in-frame allele that presumably retains some function.
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Discussions and Knowledge Gaps

1
Why are roughly seven in ten reported MMIHS patients female, when the causative genes are autosomal and the MYH11 form is recessive?
OPEN QUESTION OPEN mmihs_female_predominance_mechanism
Attached to
epidemiology#Female predominance disease#Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 2
An autosomal recessive mechanism predicts an even sex distribution. The observed skew is large, it holds at 70.6 per cent across 227 literature cases, 73 per cent across 121, and 16 of 19 in a national survey that is not subject to publication bias, and it was present in the original 1976 description of five female neonates. Three readings are available from the evidence curated here and none is settled. It may be ascertainment: most of these figures come from published case reports, and a male infant with a distended bladder is more likely to be worked up for posterior urethral valves and classified there. It may be sex-specific modification of a common pathway - the syndrome is genetically heterogeneous and is dominated by ACTG2 rather than MYH11, so the skew may not belong to this gene at all. Or it may be survival: if affected males die earlier or in utero, the reported series are the survivors. Nothing in the curated sources distinguishes these. It is recorded as an open question rather than curated into the pathograph because a sex effect with no proposed mechanism is not a mechanism, and because the honest thing to say about the most reproducible epidemiological fact in this disease is that it is unexplained.
Show evidence (2 references)
PMID:21792650 SUPPORT Human Clinical
"A clear preponderance for female infants was found (female 70.6 vs. male 29.4%)."
The observation the question is about.
PMID:41387873 SUPPORT INDIRECT Human Clinical
"ACTG2 (15/19) was the most common causative gene variant, followed by MYH11 (2/19), MYLK (1/19), and LMOD1 (1/19)."
Why the skew may not be a fact about MYH11 at all. The cohorts it is measured in are dominated by ACTG2, and no source separates the sex distribution by gene.
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Pathophysiology

7
Biallelic MYH11 Loss of Function
The initiating lesion. Both MYH11 alleles are disabled, by nonsense variants, whole-gene deletion, or missense changes that destroy motor function. The reported missense allele p.Pro127Ser is instructive: Pro127 forms part of the ATP-binding pocket of the motor domain, so the substitution is loss of function by disabling the nucleotide chemistry the motor runs on rather than by destabilising the protein.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of Smooth Muscle Myosin Heavy Chain Protein Null and deletion alleles remove the transcript or truncate the protein, so the gene lesion appears directly as reduced protein in patient tissue.
Show evidence (2 references)
PMID:25407000 SUPPORT Human Clinical
"identified a homozygous variant (c.3598A>T: p.Lys1200Ter) in MYH11, which codes for the smooth muscle myosin heavy chain"
The founding homozygous nonsense allele.
PMID:31044419 SUPPORT Computational
"Proline 127 is crucial for the formation of the Adenosine triphosphate binding pocket of the MYH11 motor domain and molecular modeling indicated that p.Pro127Ser alters nucleotide binding properties."
The structural basis for calling a missense allele loss of function. Graded COMPUTATIONAL because the claim rests on molecular modelling, not on a biochemical assay.
Loss of Smooth Muscle Myosin Heavy Chain Protein
Smooth muscle myosin heavy chain is the force-generating motor of visceral smooth muscle. Without it the thick filament has no head to cycle against actin, so the contractile apparatus is structurally present but cannot do work. This is why the downstream failure is functional rather than obstructive.
smooth muscle cell CL:0000192 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves smooth muscle cell (CL:0000192). CL:0000192 is a cell type from the Cell Ontology.
muscle myosin complex GO:0005859 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves decreased muscle myosin complex (GO:0005859). GO:0005859 is a cellular component from the Gene Ontology.
Downstream
Failure of Visceral Smooth Muscle Contraction The motor protein is the thing that contracts; removing it removes contraction.
Failure of Visceral Smooth Muscle Contraction
The cellular and tissue-level defect that unifies every MMIHS gene. Smooth muscle in the bladder wall and bowel wall cannot generate or sustain force. Note what this is not: there is no mechanical obstruction, no aganglionosis, and no inflammatory lesion. The organs are patent and innervated and simply do not move, which is what "functional obstruction" means here and why the syndrome is classified as a myopathy.
enteric smooth muscle cell CL:0002504 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves enteric smooth muscle cell (CL:0002504). CL:0002504 is a cell type from the Cell Ontology.
smooth muscle contraction GO:0006939 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased smooth muscle contraction (GO:0006939). GO:0006939 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Myh11 heterozygous knockout mouse Mouse partially recapitulates Muscle tension assays showed slowed bladder contraction, which is a direct measurement of the contractile defect this node names rather than an inference from organ size.
Downstream
Bladder Failure with Megacystis A bladder that cannot contract cannot empty, so it distends without any outlet lesion.
Intestinal Hypoperistalsis and Microcolon Bowel that cannot generate a propulsive wave does not transit; an unused distal colon never expands to normal calibre.
Show evidence (3 references)
PMID:25407000 SUPPORT Human Clinical
"The documentation of variants in ACTG2 and MYH11 thus points to the involvement of the contractile apparatus of the smooth muscle in MMIHS."
States the mechanistic conclusion this node represents.
PMID:42094517 SUPPORT INDIRECT In Vitro
"Smooth muscle myosin 2 (SMII) is the dominant motor protein driving SMC contraction. To function, SMII monomers dynamically assemble into filaments, which associate with the actin cytoskeleton to drive contractility."
The physiology the node depends on - that this protein is the dominant motor and that it must assemble into filaments to work. Graded INDIRECT because the work is in vascular smooth muscle cells, not visceral, and is not about MMIHS; it establishes the requirement rather than the disease.
PMID:41387873 SUPPORT Human Clinical
"Megacystis-Microcolon-Intestinal Hypoperistalsis syndrome (MMIHS) is an extremely rare and severe genetic smooth muscle myopathy that primarily affects the bladder and intestine"
The contemporary cohort's framing of the disease as a smooth muscle myopathy of these two organs.
Bladder Failure with Megacystis
The urinary arm. The bladder distends massively in utero and is anuric or non-emptying after birth, with a wall of normal thickness - the absence of hypertrophy being the point, since a bladder straining against an obstruction would thicken. Severe oligohydramnios follows from the fetus not voiding, and with it pulmonary hypoplasia, which is a major contributor to neonatal death.
Animal models
Myh11 heterozygous knockout mouse Mouse recapitulates Enlarged bladder volume, raised bladder-to-body weight ratio, thickened smooth muscle, collagen deposition, and the functional counterpart - reduced voiding frequency with raised residual volume.
Downstream
Neonatal Respiratory Failure from Pulmonary Hypoplasia A fetus that does not void produces no amniotic fluid; without amniotic fluid the lungs do not develop. The intermediate - oligohydramnios - is known and is documented in the same case.
Show evidence (1 reference)
PMID:25407000 SUPPORT Human Clinical
"Ultrasound confirmed the presence of megacystitis with normal wall thickness."
Normal wall thickness is the finding that distinguishes a failing bladder from an obstructed one, which is why it is quoted rather than the distension alone.
Intestinal Hypoperistalsis and Microcolon
The gastrointestinal arm. Meconium is never passed; contrast studies show no opacification beyond the duodenum and a filiform distal colon that has never been used. Intestinal hypoperistalsis is present in every patient in the largest contemporary cohort, while microcolon - the feature the syndrome is named for - is present in only about half, which is worth knowing before using the name as a diagnostic criterion.
Downstream
Parenteral Nutrition Dependence and Its Complications Bowel that does not transit cannot absorb enteral feed, so nutrition has to be given intravenously, and the complications that follow are complications of that dependence rather than of the myopathy itself.
Show evidence (2 references)
PMID:25407000 SUPPORT Human Clinical
"During the third week of life, transit studies showed lack of opacification of the bowel distal to the duodenum, whereas barium enema showed filiform opacification of the distal colon with no opacification of the cecum consistent with microcolon."
The radiological demonstration of both the failed transit and the microcolon.
PMID:41387873 SUPPORT Human Clinical
"Megacystis was present in 96% (all detected prenatally), intestinal hypoperistalsis in 100%, and microcolon in 57%."
Cohort frequencies for the three eponymous features, and the finding that microcolon is the least consistent of them.
Neonatal Respiratory Failure from Pulmonary Hypoplasia
Not every patient reaches this node - it follows the severe oligohydramnios sequence rather than the myopathy directly - but where it occurs it is what kills the newborn before the gastrointestinal disease can be managed.
Show evidence (1 reference)
PMID:25407000 SUPPORT Human Clinical
"Because of severe lung hypoplasia, the proband was put on high-frequency oscillation shortly after birth."
Documents the pulmonary hypoplasia and the ventilatory support it required in the index MYH11 case.
Parenteral Nutrition Dependence and Its Complications
The chronic phase, and where most of the long-term morbidity now sits. Patients depend on parenteral nutrition and usually an ostomy; the cohort data show high rates of intestinal-failure-associated liver disease and cholelithiasis alongside proximal intestinal stenosis and rotational anomalies. Reported survival has improved with parenteral nutrition, intestinal rehabilitation and transplantation, but the figures span 19.7 to 88 per cent across cohorts and the highest of them is the smallest and most recent series; the `epidemiology` record carries the range and the denominators.
Show evidence (2 references)
PMID:41387873 SUPPORT Human Clinical
"High rates of proximal intestinal stenosis (35%), mal-/non-rotation (39%), IFALD (58%), and Cholelithiasis (65%) were observed."
The complication profile of the chronic phase, quantified in a 26-patient cohort.
PMID:41387873 SUPPORT Human Clinical
"Overall long-term survival in our cohort was 88%."
The survival figure, which is materially different from the syndrome's historical mortality and is why the entry does not describe it as uniformly lethal.
✶

Histopathology

2
Normal or non-specific intestinal histopathology
A negative finding with real diagnostic weight. Intestinal tissue from patients with MYH11-variant visceral myopathy shows nothing diagnostic: routine histology and electron microscopy find only non-specific changes attributable to distension, and immunohistochemistry against a panel of smooth muscle proteins including MYH11 is indistinguishable from controls. Two things follow. Clinically, tissue is often taken before mutational analysis, so a normal biopsy is the expected result in this disease and does not exclude it - the authors' own recommendation is to go to molecular genetics when pseudo-obstruction has normal or non-specific pathology. Mechanistically, MYH11 immunoreactivity being preserved says the defect is functional rather than one of protein absence in these patients, which sits alongside the Western blot showing reduced protein in a different patient and is not obviously reconcilable with it. Both are recorded.
Show evidence (3 references)
PMID:36571289 SUPPORT Human Clinical
"Apart from non-specific changes (e.g., muscle hypertrophy and distension-related muscularis propria necrosis), no alterations were identified by routine histopathological evaluation or electron microscopy."
The primary negative result across light microscopy and electron microscopy.
PMID:36571289 SUPPORT Human Clinical
"Immunohistochemistry with antibodies against a battery of smooth muscle proteins, including MYH11, revealed indistinguishable patterns of immunoreactivity in the muscularis propria of both patients and controls."
MYH11 immunoreactivity is preserved, which is the finding that makes the biopsy non-diagnostic and which bears on whether the lesion is loss of protein or loss of function.
PMID:36571289 SUPPORT Human Clinical
"Myopathic morphological or immunohistochemical changes may not be present in intestinal specimens from patients with MYH11-variant visceral myopathy."
The authors' conclusion, which is the one a pathologist reporting such a specimen needs.
Ganglion cells present, excluding Hirschsprung disease
The differential-diagnostic finding, and the reason a rectal suction biopsy is usually the first tissue taken. MMIHS presents as neonatal functional bowel obstruction, which is Hirschsprung disease until proven otherwise - and what proves otherwise is the presence of ganglion cells in the biopsy. MMIHS is formally classified among the "variants of Hirschsprung's disease", a group defined by clinically resembling it *despite* normal ganglion cells, and the classification lists it explicitly as a congenital smooth muscle cell disorder within that group. The point is that the negative here is doing diagnostic work in a way the negative in the entry above is not. A normal muscularis propria does not exclude MMIHS and is the expected result; present ganglion cells do exclude the main alternative. The two findings are usually reported from the same specimen and are easily conflated.
Show evidence (3 references)
PMID:23943250 SUPPORT Human Clinical
""Variants of Hirschsprung's disease" are conditions that clinically resemble Hirschsprung's disease (HD), despite the presence of ganglion cells in rectal suction biopsies."
The definition of the category, which carries the ganglion-cell criterion inside it: membership requires the cells to be present.
PMID:23943250 SUPPORT Human Clinical
"Variants of HD include intestinal neuronal dysplasia, intestinal ganglioneuromatosis, isolated hypoganglionosis, immature ganglia, absence of the argyrophil plexus, internal anal sphincter achalasia and congenital smooth muscle cell disorders such as megacystis microcolon intestinal..."
Places MMIHS in that category by name, and alongside the other conditions a pathologist has to separate it from once Hirschsprung disease is excluded.
PMID:26413901 SUPPORT Human Clinical
"A histopathology assessment of the full-thickness of intestinal specimens showed no pathological abnormalities in all patients."
Independent confirmation from a national survey that full-thickness specimens are unremarkable in every patient, which is the finding the ganglion-cell result sits inside.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Digestive 4
Intestinal hypoperistalsis Intestinal pseudo-obstruction HP:0004389 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal pseudo-obstruction (HP:0004389). HP:0004389 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41387873 SUPPORT Human Clinical
"intestinal hypoperistalsis in 100%, and microcolon in 57%"
The universal presence of hypoperistalsis in the cohort.
Microcolon HP:0004388 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcolon (HP:0004388). HP:0004388 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25407000 SUPPORT Human Clinical
"barium enema showed filiform opacification of the distal colon with no opacification of the cecum consistent with microcolon"
The radiological finding in the index MYH11 case.
Malrotation or non-rotation of the intestine Malrotation of small bowel HP:0004794 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malrotation of small bowel (HP:0004794). HP:0004794 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41387873 SUPPORT Human Clinical
"High rates of proximal intestinal stenosis (35%), mal-/non-rotation (39%), IFALD (58%), and Cholelithiasis (65%) were observed."
Cohort frequency for rotational anomalies alongside the other structural and hepatobiliary complications.
Prune belly phenotype Aplasia/Hypoplasia of the abdominal wall musculature HP:0010318 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deficient abdominal wall musculature, annotated with Aplasia/Hypoplasia of the abdominal wall musculature (HP:0010318). HP:0010318 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25407000 SUPPORT Human Clinical
"A classic prune belly (MIM 100100) phenotype was noted at birth."
Records the abdominal wall phenotype in the index patient.
PMID:25407000 REFUTE Human Clinical
"Examination of the MYH11 sequence of 3 additional cases with MMIHS and of 20 cases with prune belly syndrome did not reveal any splicing, truncating or novel nonsynonymous variants."
Evidence against MYH11 being a general cause of prune belly syndrome, and against it being a common cause of MMIHS - three further MMIHS cases were also negative.
Eye 1
Tonically dilated pupil with accommodation deficit Tonic pupil HP:0012074 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tonic pupil (HP:0012074). HP:0012074 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31044419 SUPPORT Human Clinical
"We report on a girl with MMIHS in addition to growth hormone deficiency, central hypothyroidism and a tonically dilated pupil with accommodation deficit."
The extended phenotype in a genotyped patient. This is a single case, so the endocrine features in the same sentence are not curated as separate phenotypes.
Genitourinary 3
Megacystis HP:0000021 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Megacystis (HP:0000021). HP:0000021 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41387873 SUPPORT Human Clinical
"Megacystis was present in 96% (all detected prenatally), intestinal hypoperistalsis in 100%, and microcolon in 57%."
Cohort frequency and the fact that detection is prenatal.
Hydronephrosis HP:0000126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydronephrosis (HP:0000126). HP:0000126 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25407000 SUPPORT Human Clinical
"Other features may also be present, including omphalocele and umbilical hernia, hydronephrosis and renal dysplasia, maldevelopment of the abdominal musculature and abdominal laxity (the so-called prune belly abnormality)"
Lists hydronephrosis among the syndrome's associated features.
Renal dysplasia HP:0000110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal dysplasia (HP:0000110). HP:0000110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25407000 SUPPORT Human Clinical
"hydronephrosis and renal dysplasia, maldevelopment of the abdominal musculature and abdominal laxity"
Names renal dysplasia among the associated features.
🧬

Genetic Associations

1
MYH11 (Causal)
Gene: MYH11 hgnc:7569 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYH11 (hgnc:7569). hgnc:7569 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:25407000 SUPPORT Human Clinical
"All together, these observations strongly suggest that loss-of-function variants in MYH11 cause MMIHS."
The causal claim for MYH11 in this disease.
PMID:41387873 SUPPORT Human Clinical
"ACTG2 (15/19) was the most common causative gene variant, followed by MYH11 (2/19), MYLK (1/19), and LMOD1 (1/19)."
Places MYH11's contribution in the context of the syndrome's genetic heterogeneity.
PMID:31044419 SUPPORT Human Clinical
"In conclusion, we recommend genetic testing both for MYH11 sequence alterations and copy number imbalances in individuals with MMIHS and smooth muscle cell-associated abnormalities in additional organs, that is, multisystemic smooth muscle dysfunction."
The testing recommendation that follows from copy-number events being a common half of the genotype.
💊

Medical Actions

7
Total Parenteral Nutrition
Action: total parenteral nutritionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is total parenteral nutrition (NCIT:C29484). NCIT:C29484 is a clinical intervention from the NCI Thesaurus. Ontology label: Total Parenteral Nutrition NCIT:C29484
Platform: Other
The mainstay, and not a benign one. Eighty-five per cent of patients in the largest contemporary cohort required it alongside an ostomy, and the authors identify the pair as key determinants of unfavourable outcome rather than as neutral support - intestinal-failure-associated liver disease reached 58 per cent and cholelithiasis 65 per cent. Curated separately from the enterostomy below because they are different interventions with different complications: parenteral nutrition damages the liver and the venous access, an ostomy does not.
Mechanism Target:
Intestinal Hypoperistalsis and Microcolon — Parenteral nutrition bypasses the failed bowel rather than improving it, so it acts on the consequence of the hypoperistalsis node and not on the node itself.
Show evidence (1 reference)
PMID:41387873 SUPPORT Human Clinical
"All patients experienced clinical (sub)ileus, with 85% requiring ostomy and parenteral nutrition, key determinants of unfavorable outcome."
Both the frequency of the intervention and the authors' judgement that needing it marks a worse course.
Multivisceral Transplantation
Action: multivisceral transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is multivisceral transplantation, annotated with Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Platform: Surgery
Offered to survivors who cannot be maintained on parenteral nutrition. It replaces the diseased smooth muscle organs, which is the only intervention in this entry that addresses the contractile failure at all - by removing the tissue that cannot contract.
Mechanism Target:
Failure of Visceral Smooth Muscle Contraction — Transplantation substitutes tissue with a functioning contractile apparatus for tissue without one.
Show evidence (1 reference)
PMID:31427716 SUPPORT Human Clinical
"At present, there is no specific treatment for MMIHS, and management for affected newborns remains a challenge for doctors and parents. The survivors were either maintained by TPN or had undergone multivisceral transplantation."
States both the absence of disease-specific therapy and the two routes open to survivors.
Decompressive Enterostomy
Action: decompressive enterostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is decompressive enterostomy, annotated with Enterostomy (NCIT:C52005). NCIT:C52005 is a clinical intervention from the NCI Thesaurus. Ontology label: Enterostomy NCIT:C52005
Platform: Surgery
A stoma to decompress bowel that will not propel its contents. The site varies with where the obstruction is functionally worst - jejunostomy, ileostomy and colostomy are all reported, and the Japanese national survey created jejunal stomas in eleven patients and colonic in five. It is drainage, not restoration: the bowel below the stoma remains aperistaltic.
Mechanism Target:
Intestinal Hypoperistalsis and Microcolon — The stoma relieves the consequence of the failed propulsion by providing an exit the bowel does not have to generate. It does not act on the contractile defect.
Show evidence (2 references)
PMID:26413901 SUPPORT Human Clinical
"Drainage stomas were created in the jejunum (n=11) and colon (n=5)."
The stoma sites actually used, from a national survey rather than a literature review.
PMID:21792650 SUPPORT Human Clinical
"One or more surgical interventions were reported in 115 patients (including gastrostomy, ileostomy, jejunostomy, segmental resections of small bowel, adhesiolysis and internal sphincter myectomy)."
The full range of gastrointestinal operations reported, which is also the source for the gastrostomy entry below.
Gastrostomy
Action: gastrostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gastrostomy (NCIT:C52006). NCIT:C52006 is a clinical intervention from the NCI Thesaurus. Ontology label: Gastrostomy NCIT:C52006
Platform: Surgery
For gastric decompression and, where any enteral feeding is tolerated, a route for it. Reported as part of the standard management alongside parenteral nutrition and a stoma rather than as an alternative to them.
Mechanism Target:
Intestinal Hypoperistalsis and Microcolon — Decompresses the stomach proximal to the functional obstruction. As with the enterostomy, it manages the consequence rather than the contractile failure.
Show evidence (1 reference)
PMID:27421821 SUPPORT Human Clinical
"The majority of patients were treated with TPN as well as gastrostomy or ileostomy and CIC, however 15% (18/116) received multivisceral or intestinal transplant, and 30% (22/73) had a vesicostomy."
The composite management statement, and the source for the three urological and gastrointestinal interventions curated around it.
Cutaneous Vesicostomy
Action: cutaneous vesicostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cutaneous vesicostomy, annotated with Cystostomy (NCIT:C15218). NCIT:C15218 is a clinical intervention from the NCI Thesaurus. Ontology label: Cystostomy NCIT:C15218
Platform: Surgery
Bladder drainage by a stoma, performed in about three in ten patients in the largest urological review and in 41 patients in the earlier systematic review. For a disease whose name begins with megacystis this is the intervention aimed squarely at the eponymous organ, and it exists because the bladder cannot generate the pressure to empty itself.
Mechanism Target:
Bladder Failure with Megacystis — Provides the outflow the detrusor cannot produce, which decompresses the bladder and protects the upper tracts from the back-pressure that produces the hydronephrosis curated above.
Show evidence (2 references)
PMID:27421821 SUPPORT Human Clinical
"30% (22/73) had a vesicostomy"
The frequency in the largest review focused on urological management.
PMID:21792650 SUPPORT Human Clinical
"For decompression of the megacystis, vesicostomy was performed in 41 patients."
The indication stated explicitly - decompression of the megacystis - in the earlier review.
Clean Intermittent Catheterisation
Action: clean intermittent catheterisationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is clean intermittent catheterisation, annotated with Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. Ontology label: Therapeutic Procedure NCIT:C49236
Platform: Device
The non-surgical counterpart of the vesicostomy, and the one intervention in this entry that the sources describe as permanent. Even survivors who come off parenteral nutrition and recover gastric emptying continue to require catheterisation, because the bladder dysfunction does not remit. That asymmetry is worth recording: the gastrointestinal half of this disease can improve with time and transplantation, and the urological half so far does not.
Mechanism Target:
Bladder Failure with Megacystis — Empties the bladder mechanically in place of the contraction it cannot generate.
Show evidence (2 references)
PMID:21792650 SUPPORT Human Clinical
"However, intermittent catheterisation remains obligatory due to persistent bladder dysfunction."
The permanence, stated against the improvement seen in the same sentence's gastrointestinal counterpart.
PMID:21792650 SUPPORT Human Clinical
"The majority of the survivors are reported to be free of parenteral nutrition and show improving gastric emptying."
The contrast that makes the previous item's "obligatory" meaningful.
Isolated Intestinal Transplantation
Action: isolated intestinal transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is isolated intestinal transplantation, annotated with Small Bowel Transplantation (NCIT:C157985). NCIT:C157985 is a clinical intervention from the NCI Thesaurus. Ontology label: Small Bowel Transplantation NCIT:C157985
Platform: Surgery
Distinguished from the multivisceral operation above because the indication is different, not merely the extent. Multivisceral transplantation including the liver is used where parenteral nutrition has already destroyed the liver; an isolated intestinal graft is an option in selected patients whose liver is still sound. The reported case was an eight-year-old who achieved completely oral intake over four years of follow-up. Reported in single cases, which is the honest description of the evidence: this is a case report suggesting an indication, not a series establishing one.
Mechanism Target:
Failure of Visceral Smooth Muscle Contraction — Substitutes bowel with a working contractile apparatus for bowel without one, in the gastrointestinal compartment only.
Show evidence (3 references)
PMID:23167913 SUPPORT Human Clinical
"We report an eight-yr-old patient with MMIHS who was treated with isolated intestinal transplantation. She had completely oral intake during the four yr of follow-up."
The outcome in the reported case, with the follow-up interval.
PMID:23167913 SUPPORT Human Clinical
"Multivisceral transplantation including stomach, duodenum, intestine, and liver has been used for the treatment of patients with MMIHS because these patients often have liver failure."
Why the multivisceral operation is the usual one, and therefore why an isolated graft is a selected-patient option rather than a default.
PMID:18280270 SUPPORT Human Clinical
"We report the first case of a patient affected by MMIHS and cholestatic liver failure treated by a combined living-related liver and intestinal transplant (CLRLITx)."
The third graft configuration reported in this disease, combining a living-related segmental liver with bowel. Recorded here rather than as a fourth treatment entry because it is a variant of the transplant decision this entry already models: which organs, determined by whether parenteral nutrition has taken the liver.
🔬

Diagnosis

2
Prenatal ultrasonography
Megacystis is detected prenatally in essentially every case, typically with polyhydramnios or normal amniotic fluid volume - which distinguishes it from obstructive megacystis, where oligohydramnios is the rule. Fetal urine biochemistry helps separate MMIHS from posterior urethral valves.
ultrasound imaging NCIT:C17230 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:31427716 SUPPORT Human Clinical
"The most common prenatal finding of MMIHS is a large, progressive distended bladder associated with polyhydramnios or normal amniotic fluid volume detected by ultrasonography."
The prenatal sonographic picture and the amniotic fluid finding that distinguishes it from obstruction.
PMID:31427716 SUPPORT Human Clinical
"Fetal urine biochemical markers can be helpful for the differentiation of MMIHS from posterior urethral valves or other megacystis"
The adjunct that separates a functional from an obstructive cause of fetal megacystis.
Sequencing with parallel copy-number analysis
Molecular diagnosis needs both. Two of the four reported MYH11 genotypes involve a whole-gene deletion in trans with a point variant, so a sequencing-only workflow sees a single heterozygous variant and stops.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:31044419 SUPPORT Human Clinical
"Sanger sequencing and arrayCGH uncovered the novel heterozygous missense variant c.379C>T in MYH11 and a heterozygous 1.3 Mb deletion in 16q13.11 encompassing MYH11, respectively."
The two-technology diagnosis, showing that each method found only half the genotype. Quoted as written; the source says 16q13.11 here and 16p13.11 in its title.
PMID:36571289 SUPPORT Human Clinical
"Molecular genetic studies should be considered for patients with chronic intestinal pseudo-obstruction and normal or non-specific pathology findings."
The reason genetics rather than tissue is the diagnostic route here: a normal biopsy is the expected result and does not argue against the diagnosis.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
762 cases of MMIHS as a whole reported in the literature between 1976 and 2023, predominantly as case reports. This is the syndrome-level figure across all causative genes, not the MYH11 subset, which is a small minority of it.
Show evidence (1 reference)
PMID:41387873 SUPPORT Human Clinical
"Since the first description of MMIHS in five female neonates in 1976 by Berdon et al., only 762 cases have been reported predominantly in case reports worldwide (1976–2023)."
The cumulative reported case count and the period it covers.
🌍

Epidemiology

2
Female predominance
Roughly seven in ten reported MMIHS patients are female, and the figure is stable across independent systematic reviews two decades apart: 70.6 per cent of 227 cases reviewed to 2011, 73 per cent of 121 to 2016, and 16 of 19 in the Japanese national survey. Berdon's original 1976 description was of five female neonates. This is a syndrome-level figure across all causative genes, not a MYH11-specific one, and it is drawn from published case reports rather than from a population denominator, so ascertainment bias cannot be excluded. It is recorded because a skew this large and this reproducible is not what an autosomal recessive mechanism predicts; the open question that raises is curated in `discussions`.
70.6–84.2 percent of reported cases that are female
Show evidence (4 references)
PMID:21792650 SUPPORT Human Clinical
"A clear preponderance for female infants was found (female 70.6 vs. male 29.4%)."
The largest systematic review, covering 227 cases from 1976 to 2011.
PMID:27421821 SUPPORT Human Clinical
"73% (88/121) of the patients were female, 65% underwent diagnostic biopsy (64/99), and 63% (66/106) were identified with prenatal imaging."
An independent review over a later period, reproducing the skew.
PMID:26413901 SUPPORT Human Clinical
"Of the 28 patients registered as having a certain diagnosis of MMIHS, 19 (male/female, 3/16) patients were analyzed."
A national survey rather than a literature review, so it is not subject to the same publication bias, and it reproduces the skew at 16 of 19.
+ 1 more reference
Reported survival
Survival figures for MMIHS range widely and the range is the honest statement. The oldest and largest systematic review reported 19.7 per cent of 218 patients surviving; the Japanese national survey reported 63 per cent at five years and 57 per cent at ten; a later literature review reported 57 per cent; and a recent 26-patient cohort reported 88 per cent. The trend is real - parenteral nutrition, intestinal rehabilitation and transplantation have improved outcomes, and patients now live into the second decade - but the highest figure comes from the smallest and most recent series and should not be read as the expected outcome.
19.7–88.0 percent surviving
All syndrome-level, across causative genes. The denominators differ (218, 19, 121, 26) and so do the follow-up intervals, so these are not directly comparable.
Show evidence (5 references)
PMID:21792650 SUPPORT Human Clinical
"Survival rate was 19.7% (survivors: n = 43, non-survivors: n = 175), the oldest survivor being 24 years old."
The lowest and largest-denominator figure, covering 1976 to 2011.
PMID:26413901 SUPPORT Human Clinical
"The five- and ten-year survival rates were 63% and 57%, respectively."
Time-anchored survival from a national survey, which the other figures are not.
PMID:27421821 SUPPORT Human Clinical
"The survival rate was 57% (68/121)."
An intermediate figure from a 1996-2016 review.
+ 2 more references
🐁

Animal Models

1
Myh11 heterozygous knockout mouse
The first purpose-built MMIHS model for this gene, and the one thing to read carefully about it is the genotype. Human MMIHS2 is recessive: patients carry two damaged MYH11 alleles and their unaffected parents carry one. This mouse is a heterozygote. It nonetheless develops a markedly enlarged bladder, a thickened smooth muscle layer, collagen deposition, reduced voiding frequency, increased post-void residual volume and slowed bladder contraction, which is the human megacystis phenotype in miniature. So the model reproduces the phenotype through a dose that does not produce disease in humans. That is worth stating plainly rather than smoothing over: it makes the mouse a good readout of what losing Myh11 does to a bladder, and a poor model of the human genotype-phenotype relationship. The intestinal arm is mild in the mouse - prolonged transit and raised faecal water content - where in patients it is the lethal half of the disease, so the microcolon and the functional obstruction are not modelled here at all.
Species
Mouse
Genotype
Myh11+/- heterozygous knockout
Publication
PMID:41797110
Pathograph links
Bladder Failure with Megacystis recapitulates fidelity: moderate observes: tissue Enlarged bladder volume, raised bladder-to-body weight ratio, thickened smooth muscle, collagen deposition, and the functional counterpart - reduced voiding frequency with raised residual volume.
Limitations: The mouse is heterozygous where the human disease is biallelic, so the allele dose that produces the phenotype here is the carrier dose in patients. Bladder wall thickening with collagen deposition and active proliferation is also a remodelling response that human MMIHS bladders are not reported to share in this form.
Divergences from the human mechanism
population mismatch qualifying
Human obligate carriers of a single MYH11 loss-of-function allele are unaffected - the mother in the late-onset family had a normal assessment - while the model's whole phenotype arises at exactly that dose. The comparison the model supports is Myh11-low versus Myh11-normal bladder, not patient versus carrier.
boundary omission qualifying
Microcolon is absent from the model and the intestinal phenotype is mild dysmotility. The gastrointestinal failure that determines survival in patients is outside the boundary of what this mouse reproduces, so it cannot speak to parenteral nutrition dependence or its complications. Recorded as a boundary omission because ModelDivergenceTypeEnum has no value for an incomplete phenotype, which is the more exact description.
scale extrapolation qualifying
The model observes tissue - bladder wall thickness, collagen content, muscle tension, void volumes - while this node is an organism-level claim about a failing bladder in a patient. One step of upward extrapolation, so the organ failure is inferred from the tissue measurements rather than observed. Recorded explicitly to agree with `model_scale: TISSUE` against the node's `biological_scale: ORGANISM`.
species mismatch qualifying
Mouse and human visceral smooth muscle differ in ways this model cannot control for, and the human disease is defined partly by a prenatal presentation - megacystis on antenatal ultrasound with polyhydramnios or normal fluid - that a mouse study does not assess at all. A second, independent gap alongside the allele-dose one above.
Readouts
Post-void residual urine volume
Direction: INCREASED
Interpretation: The functional measure of the failure to empty, rather than the anatomical one - a bladder can be large without being a failing bladder.
Show evidence (1 reference)
PMID:41797110 SUPPORT Model Organism
"Myh11+/- mice displayed reduced urinary frequency and total urine output (P < 0.05), an increased residual urine volume (P < 0.001), a slowed bladder contraction (P < 0.01), along with mild intestinal dysmotility (prolonged time to first black stool, P < 0.05) and an elevated fecal water content..."
The full functional readout set, including the mild intestinal arm.
Failure of Visceral Smooth Muscle Contraction partially recapitulates fidelity: moderate observes: tissue Muscle tension assays showed slowed bladder contraction, which is a direct measurement of the contractile defect this node names rather than an inference from organ size.
Limitations: Measured in bladder, not in bowel. The node covers visceral smooth muscle generally, and the intestinal contractile apparatus is assessed only indirectly here, through transit time.
Divergences from the human mechanism
proxy quantity qualifying
The intestinal half of this node is represented by whole-gut transit time, which is an outcome of contraction rather than a measurement of it. The bladder half is measured directly by muscle tension assay; the two are not equivalent evidence.
Show evidence (3 references)
PMID:41797110 SUPPORT Model Organism
"Myh11+/- mice successfully recapitulate the core bladder phenotypes of MMIHS, including megacystis and voiding dysfunction."
The authors' own statement of what the model does and does not cover - bladder phenotypes, not the whole syndrome.
PMID:41797110 SUPPORT Model Organism
"Immunohistochemical staining revealed that Myh11 was predominantly expressed in the bladder smooth muscle, and a significant reduction in its expression level was observed in the bladders of Myh11+/- mice (P < 0.01)."
Confirms the model does what it claims at the protein level, which matters here because a heterozygote reducing rather than abolishing expression is the whole design.
PMID:41797110 SUPPORT Model Organism
"Myh11+/- mice exhibited a markedly enlarged bladder volume (P < 0.05), an increased bladder-to-body weight ratio (P < 0.01), a thickened smooth muscle layer (P < 0.01), and enhanced collagen deposition (P < 0.01)."
The structural phenotype, including the wall remodelling that the human disease is not reported to share.
{ }

Source YAML

click to show 
name: Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 2
creation_date: "2026-09-13T00:00:00Z"
category: Mendelian
synonyms:
- MMIHS2
- MYH11-related megacystis-microcolon-intestinal hypoperistalsis syndrome
- autosomal recessive MMIHS
- MYH11-related visceral myopathy
- Berdon syndrome, MYH11-related
description: >-
  Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (MMIHS2) is the
  autosomal recessive, MYH11-related form of MMIHS. MYH11 encodes smooth muscle
  myosin heavy chain, the motor of the visceral smooth muscle contractile
  apparatus. Biallelic loss-of-function alleles leave bladder and bowel smooth
  muscle unable to generate force, so both hollow organs fail functionally while
  remaining anatomically patent: a hugely distended bladder with no outlet
  obstruction, an unused and therefore microscopic colon, and intestine that does
  not propel.

  MMIHS as a clinical syndrome is genetically heterogeneous. Most cases are
  dominant and caused by de novo ACTG2 variants; the recessive forms implicate
  LMOD1, MYLK, MYL9, MYH9 and MYH11. What these genes share is the contractile
  apparatus, which is the evidence for a myopathic rather than a neuropathic basis
  for the syndrome. This entry covers the MYH11 form specifically.

  Two things make the MYH11 form worth curating in its own right. First, MYH11 is
  already a disease gene for thoracic aortic aneurysm and dissection - but through
  dominant-negative missense alleles, not biallelic nulls. The same gene produces
  a vascular disease one way and a visceral disease the other, which is a
  statement about how the lesion works rather than about which organ the gene is
  expressed in. Second, the severity is allele-dependent in a legible way: a
  hypomorphic allele in trans with a whole-gene deletion has produced a
  visceral myopathy presenting in adulthood rather than the neonatal syndrome.
disease_term:
  preferred_term: megacystis-microcolon-intestinal hypoperistalsis syndrome 2
  term:
    id: MONDO:0025708
    label: megacystis-microcolon-intestinal hypoperistalsis syndrome 2
parents:
- visceral myopathy
- autosomal recessive disease
references:
- reference: PMID:31070878
  title: "Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome Overview."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic MYH11 variants. Reported genotypes include homozygosity for a
    nonsense allele in a consanguineous family, compound heterozygosity in a
    non-consanguineous family, and compound heterozygosity for a whole-gene
    deletion with a point variant in trans. Heterozygous parents are unaffected for
    the visceral phenotype.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31427716
    reference_title: "Compound heterozygous variants in MYH11 underlie autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome in a Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study's results confirmed that MYH11 is a candidate gene for MMIHS with autosomal recessive (AR) inheritance and expanded the mutation spectrum for this clinical condition."
    explanation: States the inheritance mode for the MYH11 form specifically, against the dominant ACTG2 background.
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Segregation analysis using Sanger sequencing revealed that the father and the mother of the proband are heterozygous for the c.3598A>T (p.Lys1200Ter) variant."
    explanation: Segregation in unaffected heterozygous parents, which is what establishes recessiveness rather than a de novo dominant event.
pathophysiology:
- name: Biallelic MYH11 Loss of Function
  description: >-
    The initiating lesion. Both MYH11 alleles are disabled, by nonsense variants,
    whole-gene deletion, or missense changes that destroy motor function. The
    reported missense allele p.Pro127Ser is instructive: Pro127 forms part of the
    ATP-binding pocket of the motor domain, so the substitution is loss of function
    by disabling the nucleotide chemistry the motor runs on rather than by
    destabilising the protein.
  biological_scale: MOLECULAR
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
  downstream:
  - target: Loss of Smooth Muscle Myosin Heavy Chain Protein
    causal_link_type: DIRECT
    description: >-
      Null and deletion alleles remove the transcript or truncate the protein, so the
      gene lesion appears directly as reduced protein in patient tissue.
    evidence:
    - reference: PMID:31427716
      reference_title: "Compound heterozygous variants in MYH11 underlie autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome in a Chinese family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Western blotting showed a marked decrease in MYH11 protein in the proband's umbilical cord tissue compared with the control sample."
      explanation: Direct measurement of the protein consequence in the patient's own tissue rather than in a heterologous system.
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a homozygous variant (c.3598A>T: p.Lys1200Ter) in MYH11, which codes for the smooth muscle myosin heavy chain"
    explanation: The founding homozygous nonsense allele.
  - reference: PMID:31044419
    reference_title: "16p13.11 microdeletion uncovers loss-of-function of a MYH11 missense variant in a patient with megacystis-microcolon-intestinal-hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Proline 127 is crucial for the formation of the Adenosine triphosphate binding pocket of the MYH11 motor domain and molecular modeling indicated that p.Pro127Ser alters nucleotide binding properties."
    explanation: >-
      The structural basis for calling a missense allele loss of function. Graded
      COMPUTATIONAL because the claim rests on molecular modelling, not on a
      biochemical assay.
- name: Loss of Smooth Muscle Myosin Heavy Chain Protein
  description: >-
    Smooth muscle myosin heavy chain is the force-generating motor of visceral smooth
    muscle. Without it the thick filament has no head to cycle against actin, so the
    contractile apparatus is structurally present but cannot do work. This is why the
    downstream failure is functional rather than obstructive.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  cellular_components:
  - preferred_term: muscle myosin complex
    term:
      id: GO:0005859
      label: muscle myosin complex
    modifier: DECREASED
  downstream:
  - target: Failure of Visceral Smooth Muscle Contraction
    causal_link_type: DIRECT
    description: >-
      The motor protein is the thing that contracts; removing it removes contraction.
    evidence:
    - reference: PMID:25407000
      reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Previous studies showed that loss of Myh11 function in mice causes a bladder and intestinal phenotype that is highly reminiscent of MMIHS."
      explanation: >-
        The mouse result is what closes the gap between losing the protein and
        producing this specific two-organ phenotype, which a human case report alone
        cannot establish.
- name: Failure of Visceral Smooth Muscle Contraction
  description: >-
    The cellular and tissue-level defect that unifies every MMIHS gene. Smooth muscle
    in the bladder wall and bowel wall cannot generate or sustain force. Note what
    this is not: there is no mechanical obstruction, no aganglionosis, and no
    inflammatory lesion. The organs are patent and innervated and simply do not move,
    which is what "functional obstruction" means here and why the syndrome is
    classified as a myopathy.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: enteric smooth muscle cell
    term:
      id: CL:0002504
      label: enteric smooth muscle cell
  biological_processes:
  - preferred_term: smooth muscle contraction
    term:
      id: GO:0006939
      label: smooth muscle contraction
    modifier: DECREASED
  downstream:
  - target: Bladder Failure with Megacystis
    causal_link_type: DIRECT
    description: >-
      A bladder that cannot contract cannot empty, so it distends without any outlet
      lesion.
  - target: Intestinal Hypoperistalsis and Microcolon
    causal_link_type: DIRECT
    description: >-
      Bowel that cannot generate a propulsive wave does not transit; an unused distal
      colon never expands to normal calibre.
    evidence:
    - reference: PMID:31427716
      reference_title: "Compound heterozygous variants in MYH11 underlie autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome in a Chinese family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These five genes related to MMIHS are involved in the smooth muscle contraction, and the functional study of proteins supports a myopathic basis for this clinical condition."
      explanation: >-
        The convergence argument - every gene implicated in the syndrome acts on
        contraction - which is what makes contractile failure the shared node rather
        than one gene's idiosyncrasy.
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The documentation of variants in ACTG2 and MYH11 thus points to the involvement of the contractile apparatus of the smooth muscle in MMIHS."
    explanation: States the mechanistic conclusion this node represents.
  - reference: PMID:42094517
    reference_title: "Vascular Smooth Muscle Myosin 2 Filaments Dynamically Assemble and Stabilize During Induced Contractility."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Smooth muscle myosin 2 (SMII) is the dominant motor protein driving SMC contraction. To function, SMII monomers dynamically assemble into filaments, which associate with the actin cytoskeleton to drive contractility."
    explanation: >-
      The physiology the node depends on - that this protein is the dominant motor and
      that it must assemble into filaments to work. Graded INDIRECT because the work is
      in vascular smooth muscle cells, not visceral, and is not about MMIHS; it
      establishes the requirement rather than the disease.
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Megacystis-Microcolon-Intestinal Hypoperistalsis syndrome (MMIHS) is an extremely rare and severe genetic smooth muscle myopathy that primarily affects the bladder and intestine"
    explanation: The contemporary cohort's framing of the disease as a smooth muscle myopathy of these two organs.
- name: Bladder Failure with Megacystis
  description: >-
    The urinary arm. The bladder distends massively in utero and is anuric or
    non-emptying after birth, with a wall of normal thickness - the absence of
    hypertrophy being the point, since a bladder straining against an obstruction
    would thicken. Severe oligohydramnios follows from the fetus not voiding, and with
    it pulmonary hypoplasia, which is a major contributor to neonatal death.
  biological_scale: ORGANISM
  downstream:
  - target: Neonatal Respiratory Failure from Pulmonary Hypoplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A fetus that does not void produces no amniotic fluid; without amniotic fluid the
      lungs do not develop. The intermediate - oligohydramnios - is known and is
      documented in the same case.
    evidence:
    - reference: PMID:25407000
      reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Antenatal ultrasound performed during the second trimester of gestation revealed the presence of megacystitis as well as severe oligohydramnios."
      explanation: Documents megacystis and oligohydramnios together in the same fetus, which is the step this edge asserts.
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrasound confirmed the presence of megacystitis with normal wall thickness."
    explanation: >-
      Normal wall thickness is the finding that distinguishes a failing bladder from an
      obstructed one, which is why it is quoted rather than the distension alone.
- name: Intestinal Hypoperistalsis and Microcolon
  description: >-
    The gastrointestinal arm. Meconium is never passed; contrast studies show no
    opacification beyond the duodenum and a filiform distal colon that has never been
    used. Intestinal hypoperistalsis is present in every patient in the largest
    contemporary cohort, while microcolon - the feature the syndrome is named for - is
    present in only about half, which is worth knowing before using the name as a
    diagnostic criterion.
  biological_scale: ORGANISM
  downstream:
  - target: Parenteral Nutrition Dependence and Its Complications
    causal_link_type: DIRECT
    description: >-
      Bowel that does not transit cannot absorb enteral feed, so nutrition has to be
      given intravenously, and the complications that follow are complications of that
      dependence rather than of the myopathy itself.
    evidence:
    - reference: PMID:41387873
      reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients experienced clinical (sub)ileus, with 85% requiring ostomy and parenteral nutrition, key determinants of unfavorable outcome."
      explanation: Quantifies the dependence and identifies it as an outcome determinant rather than a neutral supportive measure.
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the third week of life, transit studies showed lack of opacification of the bowel distal to the duodenum, whereas barium enema showed filiform opacification of the distal colon with no opacification of the cecum consistent with microcolon."
    explanation: The radiological demonstration of both the failed transit and the microcolon.
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Megacystis was present in 96% (all detected prenatally), intestinal hypoperistalsis in 100%, and microcolon in 57%."
    explanation: >-
      Cohort frequencies for the three eponymous features, and the finding that
      microcolon is the least consistent of them.
- name: Neonatal Respiratory Failure from Pulmonary Hypoplasia
  description: >-
    Not every patient reaches this node - it follows the severe oligohydramnios
    sequence rather than the myopathy directly - but where it occurs it is what kills
    the newborn before the gastrointestinal disease can be managed.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of severe lung hypoplasia, the proband was put on high-frequency oscillation shortly after birth."
    explanation: Documents the pulmonary hypoplasia and the ventilatory support it required in the index MYH11 case.
- name: Parenteral Nutrition Dependence and Its Complications
  description: >-
    The chronic phase, and where most of the long-term morbidity now sits. Patients
    depend on parenteral nutrition and usually an ostomy; the cohort data show high
    rates of intestinal-failure-associated liver disease and cholelithiasis alongside
    proximal intestinal stenosis and rotational anomalies. Reported survival has
    improved with parenteral nutrition, intestinal rehabilitation and transplantation,
    but the figures span 19.7 to 88 per cent across cohorts and the highest of them is
    the smallest and most recent series; the `epidemiology` record carries the range
    and the denominators.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High rates of proximal intestinal stenosis (35%), mal-/non-rotation (39%), IFALD (58%), and Cholelithiasis (65%) were observed."
    explanation: The complication profile of the chronic phase, quantified in a 26-patient cohort.
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall long-term survival in our cohort was 88%."
    explanation: >-
      The survival figure, which is materially different from the syndrome's historical
      mortality and is why the entry does not describe it as uniformly lethal.
mechanistic_hypotheses:
- hypothesis_group_id: myh11_lesion_type_determines_affected_bed
  hypothesis_label: Whether the mechanism of MYH11 disruption, not the gene, determines which smooth muscle bed fails
  status: EMERGING
  description: >-
    MYH11 is a disease gene at least three times over, and the entry point for each
    disease is a different kind of lesion rather than a different gene. Dominant-negative
    missense alleles cause familial thoracic aortic aneurysm and dissection. Biallelic
    null alleles cause this visceral myopathy. And heterozygous protein-elongating
    frameshifts at the 3' end, affecting the SM2 isoforms, cause a dominantly inherited
    severe oesophageal, gastric and intestinal dysmotility syndrome whose authors
    propose a third mechanism again - dominant hypercontractile loss of function -
    explicitly distinct from the other two.

    That third arm is the one that makes this a hypothesis about mechanism rather than
    a two-way table. It shares an organ system with MMIHS and an inheritance pattern
    with the aortic disease, so neither "dominant means vascular" nor "gastrointestinal
    means recessive" survives it. The phenotypes otherwise barely overlap, and the
    mother in the late-onset family - an obligate carrier of a hypomorphic allele - had
    a normal cardiac and vascular assessment.

    The proposal is that this is a statement about mechanism rather than about
    expression: a poisoned motor incorporated into an otherwise intact filament is a
    different lesion from an absent motor, and vascular and visceral smooth muscle
    apparently tolerate the two differently. The authors of the founding MYH11 MMIHS
    report state this directly.

    What is not established is why. Both tissues express MYH11, so the explanation
    cannot be that one is spared. Candidate accounts - differences in isoform usage,
    in the mechanical demands placed on the filament, or in compensation by other
    myosins - are not tested in the literature curated here, though the third arm makes
    isoform usage the most concrete of them, since those variants are specific to SM2.
    The practical consequence is that carrier relatives of a visceral case should not be
    assumed to carry aortic risk, and vice versa; that inference is exactly what this
    hypothesis leaves open.
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, dominant-negative variants in MYH11 have previously been shown to cause thoracic aortic aneurism and dilatation. Different mechanisms of MYH11 disruption may thus lead to distinct patterns of smooth muscle dysfunction."
    explanation: >-
      The hypothesis in the authors' own words, framed as a possibility. Quoted as
      written, including the source's spelling of aneurysm.
  - reference: PMID:38625590
    reference_title: "Genome-wide analysis identifies MYH11 compound heterozygous variants leading to visceral myopathy corresponding to late-onset form of megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac and vascular assessment of the mother was normal."
    explanation: >-
      A single obligate carrier of the hypomorphic allele without vascular disease. One
      person is not a cohort, which is why this is recorded under a hypothesis rather
      than as a claim about carrier risk.
  - reference: PMID:31944481
    reference_title: "Protein-elongating mutations in MYH11 are implicated in a dominantly inherited smooth muscle dysmotility syndrome with severe esophageal, gastric, and intestinal disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report highlights heterozygous protein-elongating MYH11 variants affecting the SM2 isoforms of MYH11 as a cause for severe gastrointestinal dysmotility, and we hypothesize that the mechanistic pathogenesis of this disease, dominant hypercontractile loss-of-function, is distinct from those implicated in other diseases involving MYH11 dysfunction."
    explanation: >-
      The third mechanism, proposed as distinct by the authors who describe it, and the
      strongest single support for this hypothesis: a heterozygous MYH11 variant causing
      gastrointestinal rather than vascular disease means neither zygosity nor gene
      predicts the affected bed, and only the kind of lesion is left to do the work.

      This item was graded REFUTE in the previous round, against the two-mechanism
      dichotomy the hypothesis label then asserted. The label now names three mechanisms,
      so that reading is retired and the grading follows it. Recording the change here
      rather than silently flipping it, because a reader comparing rounds would otherwise
      see one paper graded two ways on one hypothesis with no explanation.
  - reference: PMID:31944481
    reference_title: "Protein-elongating mutations in MYH11 are implicated in a dominantly inherited smooth muscle dysmotility syndrome with severe esophageal, gastric, and intestinal disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous dominant negative MYH11 pathogenic variants have been associated with thoracic aortic aneurysm and dissection while biallelic null alleles have been associated with megacystis microcolon intestinal hypoperistalsis syndrome."
    explanation: >-
      The same paper's statement of the two mechanisms it then adds a third to, which is
      independent corroboration of the pairing this hypothesis started from.
- hypothesis_group_id: residual_function_sets_onset
  hypothesis_label: Whether residual MYH11 function sets age of onset along a continuum
  status: EMERGING
  description: >-
    MMIHS is defined as a congenital disease, but a family carrying a whole-gene
    deletion in trans with an in-frame hypomorphic allele presented in adulthood - a
    brother with severe bladder dysfunction and intestinal obstruction at 38, a sister
    with end-stage kidney disease, neurogenic bladder and recurrent sigmoid volvulus
    at 30. If that is the same disease with more residual motor function, then
    "congenital MMIHS" and "adult visceral myopathy" are two points on one dose-response
    curve rather than two entities, and adults with unexplained visceral myopathy are
    an under-tested group.

    The evidence is one family, described by its authors as the second such report.
    An alternative reading - that the in-frame allele produces a qualitatively
    different protein rather than less of the same function - is not excluded by the
    data available.
  evidence:
  - reference: PMID:38625590
    reference_title: "Genome-wide analysis identifies MYH11 compound heterozygous variants leading to visceral myopathy corresponding to late-onset form of megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 38 years-old brother had severe bladder dysfunction and intestinal obstruction, whereas the 30 years-old sister suffered from end-stage kidney disease with neurogenic bladder and recurrent sigmoid volvulus."
    explanation: The late-onset presentation in two siblings, decades after the congenital syndrome would have declared itself.
  - reference: PMID:38625590
    reference_title: "Genome-wide analysis identifies MYH11 compound heterozygous variants leading to visceral myopathy corresponding to late-onset form of megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous variants of MYH11 gene were identified, associating a deletion of 1.2 Mb encompassing MYH11 inherited from the father and an in-frame variant c.2578_2580del, p.Glu860del inherited from the mother."
    explanation: >-
      The genotype the hypothesis rests on - a null in trans with an in-frame allele
      that presumably retains some function.
phenotypes:
- category: Genitourinary
  name: Megacystis
  description: >-
    A massively distended, non-obstructed bladder, detected prenatally in essentially
    every case. Present in 96 per cent of the largest contemporary cohort.
  phenotype_term:
    preferred_term: Megacystis
    term:
      id: HP:0000021
      label: Megacystis
  evidence:
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Megacystis was present in 96% (all detected prenatally), intestinal hypoperistalsis in 100%, and microcolon in 57%."
    explanation: Cohort frequency and the fact that detection is prenatal.
- category: Gastrointestinal
  name: Intestinal hypoperistalsis
  description: >-
    Decreased or absent propulsive intestinal motility, present in every patient in
    the cohort. Functionally this is obstruction without a mechanical lesion.
  phenotype_term:
    preferred_term: Intestinal pseudo-obstruction
    term:
      id: HP:0004389
      label: Intestinal pseudo-obstruction
  evidence:
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intestinal hypoperistalsis in 100%, and microcolon in 57%"
    explanation: The universal presence of hypoperistalsis in the cohort.
- category: Gastrointestinal
  name: Microcolon
  description: >-
    A colon of markedly reduced calibre, the consequence of never having transmitted
    intestinal content. Despite naming the syndrome it is present in only about half
    of patients.
  phenotype_term:
    preferred_term: Microcolon
    term:
      id: HP:0004388
      label: Microcolon
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "barium enema showed filiform opacification of the distal colon with no opacification of the cecum consistent with microcolon"
    explanation: The radiological finding in the index MYH11 case.
- category: Gastrointestinal
  name: Malrotation or non-rotation of the intestine
  description: >-
    A structural anomaly found in 39 per cent of the cohort. Its relationship to the
    contractile defect is not established, and it is recorded as an observed
    association rather than as a downstream consequence.
  phenotype_term:
    preferred_term: Malrotation of small bowel
    term:
      id: HP:0004794
      label: Malrotation of small bowel
  evidence:
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High rates of proximal intestinal stenosis (35%), mal-/non-rotation (39%), IFALD (58%), and Cholelithiasis (65%) were observed."
    explanation: Cohort frequency for rotational anomalies alongside the other structural and hepatobiliary complications.
- category: Renal
  name: Hydronephrosis
  description: >-
    An upper tract change secondary to the failing bladder: urine that the bladder
    cannot empty backs up. In the late-onset family one sibling reached end-stage
    kidney disease.
  phenotype_term:
    preferred_term: Hydronephrosis
    term:
      id: HP:0000126
      label: Hydronephrosis
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features may also be present, including omphalocele and umbilical hernia, hydronephrosis and renal dysplasia, maldevelopment of the abdominal musculature and abdominal laxity (the so-called prune belly abnormality)"
    explanation: Lists hydronephrosis among the syndrome's associated features.
- category: Renal
  name: Renal dysplasia
  description: >-
    Curated separately from the hydronephrosis above because the two are different
    claims. Hydronephrosis is obstructive back-pressure on a normally formed kidney;
    dysplasia is abnormal renal development. Both appear in the same list of associated
    features and the sources do not separate which patients had which, so the split is
    made here on the concepts rather than on a cohort.
  phenotype_term:
    preferred_term: Renal dysplasia
    term:
      id: HP:0000110
      label: Renal dysplasia
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hydronephrosis and renal dysplasia, maldevelopment of the abdominal musculature and abdominal laxity"
    explanation: Names renal dysplasia among the associated features.
- category: Musculoskeletal
  name: Prune belly phenotype
  description: >-
    Deficient abdominal wall musculature with abdominal laxity, present in the index
    MYH11 case. Notably, sequencing MYH11 in twenty cases of isolated prune belly
    syndrome found no variants, so this is a feature of MMIHS rather than evidence
    that MYH11 causes prune belly syndrome generally.
  phenotype_term:
    preferred_term: Deficient abdominal wall musculature
    term:
      id: HP:0010318
      label: Aplasia/Hypoplasia of the abdominal wall musculature
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A classic prune belly (MIM 100100) phenotype was noted at birth."
    explanation: Records the abdominal wall phenotype in the index patient.
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Examination of the MYH11 sequence of 3 additional cases with MMIHS and of 20 cases with prune belly syndrome did not reveal any splicing, truncating or novel nonsynonymous variants."
    explanation: >-
      Evidence against MYH11 being a general cause of prune belly syndrome, and against
      it being a common cause of MMIHS - three further MMIHS cases were also negative.
- category: Ophthalmological
  name: Tonically dilated pupil with accommodation deficit
  description: >-
    Iris and ciliary smooth muscle are smooth muscle too. One patient with biallelic
    MYH11 loss had a tonically dilated pupil and an accommodation deficit alongside
    growth hormone deficiency and central hypothyroidism, which led the authors to
    describe the presentation as multisystemic smooth muscle dysfunction rather than a
    two-organ syndrome.
  phenotype_term:
    preferred_term: Tonic pupil
    term:
      id: HP:0012074
      label: Tonic pupil
  evidence:
  - reference: PMID:31044419
    reference_title: "16p13.11 microdeletion uncovers loss-of-function of a MYH11 missense variant in a patient with megacystis-microcolon-intestinal-hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on a girl with MMIHS in addition to growth hormone deficiency, central hypothyroidism and a tonically dilated pupil with accommodation deficit."
    explanation: >-
      The extended phenotype in a genotyped patient. This is a single case, so the
      endocrine features in the same sentence are not curated as separate phenotypes.
genetic:
- name: MYH11
  association: Causal
  gene_term:
    preferred_term: MYH11
    term:
      id: hgnc:7569
      label: MYH11
  notes: >-
    Biallelic loss-of-function MYH11 variants cause the recessive form of MMIHS.
    Reported alleles include homozygous c.3598A>T (p.Lys1200Ter) in a consanguineous
    Algerian family, compound heterozygous c.2051G>A (p.R684H) and
    c.3540_3541delinsTT in a Chinese family, a 1.3 Mb 16p13.11 deletion encompassing
    MYH11 in trans with c.379C>T (p.Pro127Ser), and a 1.2 Mb deletion in trans with
    the in-frame c.2578_2580del (p.Glu860del) in the late-onset family. Two of the
    four involve a copy-number event, so sequencing alone can miss the diagnosis and
    copy-number analysis is needed alongside it. MYH11 accounted for 2 of 19
    molecularly diagnosed patients in the largest contemporary cohort, behind ACTG2.
  evidence:
  - reference: PMID:25407000
    reference_title: "A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All together, these observations strongly suggest that loss-of-function variants in MYH11 cause MMIHS."
    explanation: The causal claim for MYH11 in this disease.
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACTG2 (15/19) was the most common causative gene variant, followed by MYH11 (2/19), MYLK (1/19), and LMOD1 (1/19)."
    explanation: Places MYH11's contribution in the context of the syndrome's genetic heterogeneity.
  - reference: PMID:31044419
    reference_title: "16p13.11 microdeletion uncovers loss-of-function of a MYH11 missense variant in a patient with megacystis-microcolon-intestinal-hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, we recommend genetic testing both for MYH11 sequence alterations and copy number imbalances in individuals with MMIHS and smooth muscle cell-associated abnormalities in additional organs, that is, multisystemic smooth muscle dysfunction."
    explanation: The testing recommendation that follows from copy-number events being a common half of the genotype.
epidemiology:
- name: Female predominance
  description: >-
    Roughly seven in ten reported MMIHS patients are female, and the figure is stable
    across independent systematic reviews two decades apart: 70.6 per cent of 227 cases
    reviewed to 2011, 73 per cent of 121 to 2016, and 16 of 19 in the Japanese national
    survey. Berdon's original 1976 description was of five female neonates.

    This is a syndrome-level figure across all causative genes, not a MYH11-specific
    one, and it is drawn from published case reports rather than from a population
    denominator, so ascertainment bias cannot be excluded. It is recorded because a
    skew this large and this reproducible is not what an autosomal recessive mechanism
    predicts; the open question that raises is curated in `discussions`.
  minimum_value: 70.6
  maximum_value: 84.2
  unit: percent of reported cases that are female
  evidence:
  - reference: PMID:21792650
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review of outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A clear preponderance for female infants was found (female 70.6 vs. male 29.4%)."
    explanation: The largest systematic review, covering 227 cases from 1976 to 2011.
  - reference: PMID:27421821
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: Case series and updated review of the literature with an emphasis on urologic management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "73% (88/121) of the patients were female, 65% underwent diagnostic biopsy (64/99), and 63% (66/106) were identified with prenatal imaging."
    explanation: An independent review over a later period, reproducing the skew.
  - reference: PMID:26413901
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: A report of a nationwide survey in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 28 patients registered as having a certain diagnosis of MMIHS, 19 (male/female, 3/16) patients were analyzed."
    explanation: >-
      A national survey rather than a literature review, so it is not subject to the same
      publication bias, and it reproduces the skew at 16 of 19.
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since the first description of MMIHS in five female neonates in 1976 by Berdon et al."
    explanation: The original description was of five female neonates, which is where the observation starts.
- name: Reported survival
  description: >-
    Survival figures for MMIHS range widely and the range is the honest statement.
    The oldest and largest systematic review reported 19.7 per cent of 218 patients
    surviving; the Japanese national survey reported 63 per cent at five years and 57
    per cent at ten; a later literature review reported 57 per cent; and a recent
    26-patient cohort reported 88 per cent. The trend is real - parenteral nutrition,
    intestinal rehabilitation and transplantation have improved outcomes, and patients
    now live into the second decade - but the highest figure comes from the smallest
    and most recent series and should not be read as the expected outcome.
  minimum_value: 19.7
  maximum_value: 88.0
  unit: percent surviving
  notes: >-
    All syndrome-level, across causative genes. The denominators differ (218, 19, 121,
    26) and so do the follow-up intervals, so these are not directly comparable.
  evidence:
  - reference: PMID:21792650
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review of outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Survival rate was 19.7% (survivors: n = 43, non-survivors: n = 175), the oldest survivor being 24 years old."
    explanation: The lowest and largest-denominator figure, covering 1976 to 2011.
  - reference: PMID:26413901
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: A report of a nationwide survey in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The five- and ten-year survival rates were 63% and 57%, respectively."
    explanation: Time-anchored survival from a national survey, which the other figures are not.
  - reference: PMID:27421821
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: Case series and updated review of the literature with an emphasis on urologic management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The survival rate was 57% (68/121)."
    explanation: An intermediate figure from a 1996-2016 review.
  - reference: PMID:41591435
    reference_title: "Imaging of megacystis-microcolon-intestinal hypoperistalsis syndrome before, during, and after the neonatal period: a pictorial review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Historically associated with a poor prognosis, recent advances in the use of total parenteral nutrition (TPN), intestinal rehabilitation, and multi-visceral transplantation have led to improvements in survival in patients with MMIHS, with patients now living into the second decade of life."
    explanation: >-
      The reason the figures move over time, which is what makes the range a trend rather
      than simple disagreement between cohorts.
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With this treatment approach, the overall long-term prognosis in our cohort was good, with long-term survival in 23 patients (88%)"
    explanation: >-
      The source for `maximum_value`, lifted into this block so the record is
      self-contained. Note the denominator: 26 patients, the smallest and most recent of
      the four series, which is why the record presents it as the top of a range rather
      than as the current figure.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    762 cases of MMIHS as a whole reported in the literature between 1976 and 2023,
    predominantly as case reports. This is the syndrome-level figure across all
    causative genes, not the MYH11 subset, which is a small minority of it.
  evidence:
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since the first description of MMIHS in five female neonates in 1976 by Berdon et al., only 762 cases have been reported predominantly in case reports worldwide (1976–2023)."
    explanation: The cumulative reported case count and the period it covers.
histopathology:
- name: Normal or non-specific intestinal histopathology
  description: >-
    A negative finding with real diagnostic weight. Intestinal tissue from patients with
    MYH11-variant visceral myopathy shows nothing diagnostic: routine histology and
    electron microscopy find only non-specific changes attributable to distension, and
    immunohistochemistry against a panel of smooth muscle proteins including MYH11 is
    indistinguishable from controls.

    Two things follow. Clinically, tissue is often taken before mutational analysis, so
    a normal biopsy is the expected result in this disease and does not exclude it -
    the authors' own recommendation is to go to molecular genetics when pseudo-obstruction
    has normal or non-specific pathology. Mechanistically, MYH11 immunoreactivity being
    preserved says the defect is functional rather than one of protein absence in these
    patients, which sits alongside the Western blot showing reduced protein in a
    different patient and is not obviously reconcilable with it. Both are recorded.
  finding_term:
    preferred_term: normal muscularis propria morphology and smooth muscle immunophenotype
  evidence:
  - reference: PMID:36571289
    reference_title: "Histopathological, Ultrastructural, and Immunohistochemical Findings in MYH11-Variant Visceral Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Apart from non-specific changes (e.g., muscle hypertrophy and distension-related muscularis propria necrosis), no alterations were identified by routine histopathological evaluation or electron microscopy."
    explanation: The primary negative result across light microscopy and electron microscopy.
  - reference: PMID:36571289
    reference_title: "Histopathological, Ultrastructural, and Immunohistochemical Findings in MYH11-Variant Visceral Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemistry with antibodies against a battery of smooth muscle proteins, including MYH11, revealed indistinguishable patterns of immunoreactivity in the muscularis propria of both patients and controls."
    explanation: >-
      MYH11 immunoreactivity is preserved, which is the finding that makes the biopsy
      non-diagnostic and which bears on whether the lesion is loss of protein or loss of
      function.
  - reference: PMID:36571289
    reference_title: "Histopathological, Ultrastructural, and Immunohistochemical Findings in MYH11-Variant Visceral Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myopathic morphological or immunohistochemical changes may not be present in intestinal specimens from patients with MYH11-variant visceral myopathy."
    explanation: The authors' conclusion, which is the one a pathologist reporting such a specimen needs.
- name: Ganglion cells present, excluding Hirschsprung disease
  description: >-
    The differential-diagnostic finding, and the reason a rectal suction biopsy is
    usually the first tissue taken. MMIHS presents as neonatal functional bowel
    obstruction, which is Hirschsprung disease until proven otherwise - and what proves
    otherwise is the presence of ganglion cells in the biopsy. MMIHS is formally
    classified among the "variants of Hirschsprung's disease", a group defined by
    clinically resembling it *despite* normal ganglion cells, and the classification
    lists it explicitly as a congenital smooth muscle cell disorder within that group.

    The point is that the negative here is doing diagnostic work in a way the negative
    in the entry above is not. A normal muscularis propria does not exclude MMIHS and is
    the expected result; present ganglion cells do exclude the main alternative. The two
    findings are usually reported from the same specimen and are easily conflated.
  finding_term:
    preferred_term: ganglion cells present in rectal suction biopsy
  notes: >-
    `finding_term` is deliberately left unbound, and the reason is the shape of the
    finding rather than a gap in the search. What is being recorded is the *presence* of
    a normal cell population, and the ontologies this slot draws on describe
    abnormalities: HP codes aganglionosis and abnormal enteric nervous system morphology,
    NCIT's histopathology branch codes morphologic findings rather than their absence,
    and CL:0007011 names the enteric neuron as a cell type rather than as a biopsy
    result. Binding any of those would assert an abnormality where the whole point is
    that there is none. Searched HP, NCIT and CL; no term beats a wrong one.
  evidence:
  - reference: PMID:23943250
    reference_title: "Classification and diagnostic criteria of variants of Hirschsprung's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "\"Variants of Hirschsprung's disease\" are conditions that clinically resemble Hirschsprung's disease (HD), despite the presence of ganglion cells in rectal suction biopsies."
    explanation: >-
      The definition of the category, which carries the ganglion-cell criterion inside
      it: membership requires the cells to be present.
  - reference: PMID:23943250
    reference_title: "Classification and diagnostic criteria of variants of Hirschsprung's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants of HD include intestinal neuronal dysplasia, intestinal ganglioneuromatosis, isolated hypoganglionosis, immature ganglia, absence of the argyrophil plexus, internal anal sphincter achalasia and congenital smooth muscle cell disorders such as megacystis microcolon intestinal hypoperistalsis syndrome."
    explanation: >-
      Places MMIHS in that category by name, and alongside the other conditions a
      pathologist has to separate it from once Hirschsprung disease is excluded.
  - reference: PMID:26413901
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: A report of a nationwide survey in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A histopathology assessment of the full-thickness of intestinal specimens showed no pathological abnormalities in all patients."
    explanation: >-
      Independent confirmation from a national survey that full-thickness specimens are
      unremarkable in every patient, which is the finding the ganglion-cell result sits
      inside.
diagnosis:
- name: Prenatal ultrasonography
  description: >-
    Megacystis is detected prenatally in essentially every case, typically with
    polyhydramnios or normal amniotic fluid volume - which distinguishes it from
    obstructive megacystis, where oligohydramnios is the rule. Fetal urine biochemistry
    helps separate MMIHS from posterior urethral valves.
  diagnosis_term:
    preferred_term: ultrasound imaging
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  evidence:
  - reference: PMID:31427716
    reference_title: "Compound heterozygous variants in MYH11 underlie autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome in a Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common prenatal finding of MMIHS is a large, progressive distended bladder associated with polyhydramnios or normal amniotic fluid volume detected by ultrasonography."
    explanation: The prenatal sonographic picture and the amniotic fluid finding that distinguishes it from obstruction.
  - reference: PMID:31427716
    reference_title: "Compound heterozygous variants in MYH11 underlie autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome in a Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fetal urine biochemical markers can be helpful for the differentiation of MMIHS from posterior urethral valves or other megacystis"
    explanation: The adjunct that separates a functional from an obstructive cause of fetal megacystis.
- name: Sequencing with parallel copy-number analysis
  description: >-
    Molecular diagnosis needs both. Two of the four reported MYH11 genotypes involve a
    whole-gene deletion in trans with a point variant, so a sequencing-only workflow
    sees a single heterozygous variant and stops.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:31044419
    reference_title: "16p13.11 microdeletion uncovers loss-of-function of a MYH11 missense variant in a patient with megacystis-microcolon-intestinal-hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing and arrayCGH uncovered the novel heterozygous missense variant c.379C>T in MYH11 and a heterozygous 1.3 Mb deletion in 16q13.11 encompassing MYH11, respectively."
    explanation: >-
      The two-technology diagnosis, showing that each method found only half the
      genotype. Quoted as written; the source says 16q13.11 here and 16p13.11 in its
      title.
  - reference: PMID:36571289
    reference_title: "Histopathological, Ultrastructural, and Immunohistochemical Findings in MYH11-Variant Visceral Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular genetic studies should be considered for patients with chronic intestinal pseudo-obstruction and normal or non-specific pathology findings."
    explanation: >-
      The reason genetics rather than tissue is the diagnostic route here: a normal
      biopsy is the expected result and does not argue against the diagnosis.
animal_models:
- name: Myh11 heterozygous knockout mouse
  species: Mouse
  genotype: Myh11+/- heterozygous knockout
  publication: PMID:41797110
  description: >-
    The first purpose-built MMIHS model for this gene, and the one thing to read
    carefully about it is the genotype. Human MMIHS2 is recessive: patients carry two
    damaged MYH11 alleles and their unaffected parents carry one. This mouse is a
    heterozygote. It nonetheless develops a markedly enlarged bladder, a thickened
    smooth muscle layer, collagen deposition, reduced voiding frequency, increased
    post-void residual volume and slowed bladder contraction, which is the human
    megacystis phenotype in miniature.

    So the model reproduces the phenotype through a dose that does not produce disease
    in humans. That is worth stating plainly rather than smoothing over: it makes the
    mouse a good readout of what losing Myh11 does to a bladder, and a poor model of the
    human genotype-phenotype relationship. The intestinal arm is mild in the mouse -
    prolonged transit and raised faecal water content - where in patients it is the
    lethal half of the disease, so the microcolon and the functional obstruction are
    not modelled here at all.
  modeled_mechanisms:
  - target: Bladder Failure with Megacystis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Enlarged bladder volume, raised bladder-to-body weight ratio, thickened smooth
      muscle, collagen deposition, and the functional counterpart - reduced voiding
      frequency with raised residual volume.
    limitations: >-
      The mouse is heterozygous where the human disease is biallelic, so the allele dose
      that produces the phenotype here is the carrier dose in patients. Bladder wall
      thickening with collagen deposition and active proliferation is also a remodelling
      response that human MMIHS bladders are not reported to share in this form.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        Human obligate carriers of a single MYH11 loss-of-function allele are
        unaffected - the mother in the late-onset family had a normal assessment - while
        the model's whole phenotype arises at exactly that dose. The comparison the model
        supports is Myh11-low versus Myh11-normal bladder, not patient versus carrier.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Microcolon is absent from the model and the intestinal phenotype is mild
        dysmotility. The gastrointestinal failure that determines survival in patients
        is outside the boundary of what this mouse reproduces, so it cannot speak to
        parenteral nutrition dependence or its complications. Recorded as a boundary
        omission because ModelDivergenceTypeEnum has no value for an incomplete
        phenotype, which is the more exact description.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        The model observes tissue - bladder wall thickness, collagen content, muscle
        tension, void volumes - while this node is an organism-level claim about a
        failing bladder in a patient. One step of upward extrapolation, so the organ
        failure is inferred from the tissue measurements rather than observed. Recorded
        explicitly to agree with `model_scale: TISSUE` against the node's
        `biological_scale: ORGANISM`.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse and human visceral smooth muscle differ in ways this model cannot
        control for, and the human disease is defined partly by a prenatal presentation -
        megacystis on antenatal ultrasound with polyhydramnios or normal fluid - that a
        mouse study does not assess at all. A second, independent gap alongside the
        allele-dose one above.
    readouts:
    - name: Post-void residual urine volume
      target: Bladder Failure with Megacystis
      direction: INCREASED
      interpretation: >-
        The functional measure of the failure to empty, rather than the anatomical one -
        a bladder can be large without being a failing bladder.
      evidence:
      - reference: PMID:41797110
        reference_title: "Myh11 haploinsufficiency recapitulates megacystis and voiding dysfunction in a mouse model of MMIHS."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Myh11+/- mice displayed reduced urinary frequency and total urine output (P < 0.05), an increased residual urine volume (P < 0.001), a slowed bladder contraction (P < 0.01), along with mild intestinal dysmotility (prolonged time to first black stool, P < 0.05) and an elevated fecal water content (P < 0.05)."
        explanation: The full functional readout set, including the mild intestinal arm.
  - target: Failure of Visceral Smooth Muscle Contraction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Muscle tension assays showed slowed bladder contraction, which is a direct
      measurement of the contractile defect this node names rather than an inference
      from organ size.
    limitations: >-
      Measured in bladder, not in bowel. The node covers visceral smooth muscle
      generally, and the intestinal contractile apparatus is assessed only indirectly
      here, through transit time.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The intestinal half of this node is represented by whole-gut transit time, which
        is an outcome of contraction rather than a measurement of it. The bladder half is
        measured directly by muscle tension assay; the two are not equivalent evidence.
  evidence:
  - reference: PMID:41797110
    reference_title: "Myh11 haploinsufficiency recapitulates megacystis and voiding dysfunction in a mouse model of MMIHS."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Myh11+/- mice successfully recapitulate the core bladder phenotypes of MMIHS, including megacystis and voiding dysfunction."
    explanation: The authors' own statement of what the model does and does not cover - bladder phenotypes, not the whole syndrome.
  - reference: PMID:41797110
    reference_title: "Myh11 haploinsufficiency recapitulates megacystis and voiding dysfunction in a mouse model of MMIHS."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immunohistochemical staining revealed that Myh11 was predominantly expressed in the bladder smooth muscle, and a significant reduction in its expression level was observed in the bladders of Myh11+/- mice (P < 0.01)."
    explanation: >-
      Confirms the model does what it claims at the protein level, which matters here
      because a heterozygote reducing rather than abolishing expression is the whole
      design.
  - reference: PMID:41797110
    reference_title: "Myh11 haploinsufficiency recapitulates megacystis and voiding dysfunction in a mouse model of MMIHS."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Myh11+/- mice exhibited a markedly enlarged bladder volume (P < 0.05), an increased bladder-to-body weight ratio (P < 0.01), a thickened smooth muscle layer (P < 0.01), and enhanced collagen deposition (P < 0.01)."
    explanation: The structural phenotype, including the wall remodelling that the human disease is not reported to share.
treatments:
- name: Total Parenteral Nutrition
  description: >-
    The mainstay, and not a benign one. Eighty-five per cent of patients in the largest
    contemporary cohort required it alongside an ostomy, and the authors identify the
    pair as key determinants of unfavourable outcome rather than as neutral support -
    intestinal-failure-associated liver disease reached 58 per cent and cholelithiasis
    65 per cent. Curated separately from the enterostomy below because they are
    different interventions with different complications: parenteral nutrition damages
    the liver and the venous access, an ostomy does not.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: total parenteral nutrition
    term:
      id: NCIT:C29484
      label: Total Parenteral Nutrition
  target_mechanisms:
  - target: Intestinal Hypoperistalsis and Microcolon
    description: >-
      Parenteral nutrition bypasses the failed bowel rather than improving it, so it
      acts on the consequence of the hypoperistalsis node and not on the node itself.
  evidence:
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients experienced clinical (sub)ileus, with 85% requiring ostomy and parenteral nutrition, key determinants of unfavorable outcome."
    explanation: >-
      Both the frequency of the intervention and the authors' judgement that needing it
      marks a worse course.
- name: Multivisceral Transplantation
  description: >-
    Offered to survivors who cannot be maintained on parenteral nutrition. It replaces
    the diseased smooth muscle organs, which is the only intervention in this entry
    that addresses the contractile failure at all - by removing the tissue that cannot
    contract.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: multivisceral transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Failure of Visceral Smooth Muscle Contraction
    description: >-
      Transplantation substitutes tissue with a functioning contractile apparatus for
      tissue without one.
  evidence:
  - reference: PMID:31427716
    reference_title: "Compound heterozygous variants in MYH11 underlie autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome in a Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At present, there is no specific treatment for MMIHS, and management for affected newborns remains a challenge for doctors and parents. The survivors were either maintained by TPN or had undergone multivisceral transplantation."
    explanation: >-
      States both the absence of disease-specific therapy and the two routes open to
      survivors.
- name: Decompressive Enterostomy
  description: >-
    A stoma to decompress bowel that will not propel its contents. The site varies with
    where the obstruction is functionally worst - jejunostomy, ileostomy and colostomy
    are all reported, and the Japanese national survey created jejunal stomas in eleven
    patients and colonic in five. It is drainage, not restoration: the bowel below the
    stoma remains aperistaltic.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: decompressive enterostomy
    term:
      id: NCIT:C52005
      label: Enterostomy
  target_mechanisms:
  - target: Intestinal Hypoperistalsis and Microcolon
    description: >-
      The stoma relieves the consequence of the failed propulsion by providing an exit
      the bowel does not have to generate. It does not act on the contractile defect.
  evidence:
  - reference: PMID:26413901
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: A report of a nationwide survey in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Drainage stomas were created in the jejunum (n=11) and colon (n=5)."
    explanation: The stoma sites actually used, from a national survey rather than a literature review.
  - reference: PMID:21792650
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review of outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One or more surgical interventions were reported in 115 patients (including gastrostomy, ileostomy, jejunostomy, segmental resections of small bowel, adhesiolysis and internal sphincter myectomy)."
    explanation: >-
      The full range of gastrointestinal operations reported, which is also the source
      for the gastrostomy entry below.
- name: Gastrostomy
  description: >-
    For gastric decompression and, where any enteral feeding is tolerated, a route for
    it. Reported as part of the standard management alongside parenteral nutrition and
    a stoma rather than as an alternative to them.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  target_mechanisms:
  - target: Intestinal Hypoperistalsis and Microcolon
    description: >-
      Decompresses the stomach proximal to the functional obstruction. As with the
      enterostomy, it manages the consequence rather than the contractile failure.
  evidence:
  - reference: PMID:27421821
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: Case series and updated review of the literature with an emphasis on urologic management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients were treated with TPN as well as gastrostomy or ileostomy and CIC, however 15% (18/116) received multivisceral or intestinal transplant, and 30% (22/73) had a vesicostomy."
    explanation: >-
      The composite management statement, and the source for the three urological and
      gastrointestinal interventions curated around it.
- name: Cutaneous Vesicostomy
  description: >-
    Bladder drainage by a stoma, performed in about three in ten patients in the
    largest urological review and in 41 patients in the earlier systematic review. For
    a disease whose name begins with megacystis this is the intervention aimed
    squarely at the eponymous organ, and it exists because the bladder cannot generate
    the pressure to empty itself.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cutaneous vesicostomy
    term:
      id: NCIT:C15218
      label: Cystostomy
  target_mechanisms:
  - target: Bladder Failure with Megacystis
    description: >-
      Provides the outflow the detrusor cannot produce, which decompresses the bladder
      and protects the upper tracts from the back-pressure that produces the
      hydronephrosis curated above.
  evidence:
  - reference: PMID:27421821
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: Case series and updated review of the literature with an emphasis on urologic management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "30% (22/73) had a vesicostomy"
    explanation: The frequency in the largest review focused on urological management.
  - reference: PMID:21792650
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review of outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For decompression of the megacystis, vesicostomy was performed in 41 patients."
    explanation: The indication stated explicitly - decompression of the megacystis - in the earlier review.
- name: Clean Intermittent Catheterisation
  description: >-
    The non-surgical counterpart of the vesicostomy, and the one intervention in this
    entry that the sources describe as permanent. Even survivors who come off parenteral
    nutrition and recover gastric emptying continue to require catheterisation, because
    the bladder dysfunction does not remit. That asymmetry is worth recording: the
    gastrointestinal half of this disease can improve with time and transplantation,
    and the urological half so far does not.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: clean intermittent catheterisation
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  review_notes: >-
    Bound deliberately broadly. NCIT has an exact concept, NCIT:C38045 Catheterization,
    and it is not reachable from NCIT:C25218 Clinical Intervention or Procedure, so it
    cannot fill a TreatmentTerm slot - `just validate-terms` rejects it as outside the
    TreatmentActionTerm dynamic enum. The alternatives NCIT offers under a searchable
    name are devices (Foley catheter, indwelling urinary catheter, suprapubic catheter),
    and a device is not a clinical action; the CLAUDE.md cochlear-implant carve-out
    covers exactly that distinction. The specificity is carried in `preferred_term`
    rather than manufactured from a term that does not fit.
  target_mechanisms:
  - target: Bladder Failure with Megacystis
    description: >-
      Empties the bladder mechanically in place of the contraction it cannot generate.
  evidence:
  - reference: PMID:21792650
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review of outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, intermittent catheterisation remains obligatory due to persistent bladder dysfunction."
    explanation: >-
      The permanence, stated against the improvement seen in the same sentence's
      gastrointestinal counterpart.
  - reference: PMID:21792650
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review of outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of the survivors are reported to be free of parenteral nutrition and show improving gastric emptying."
    explanation: The contrast that makes the previous item's "obligatory" meaningful.
- name: Isolated Intestinal Transplantation
  description: >-
    Distinguished from the multivisceral operation above because the indication is
    different, not merely the extent. Multivisceral transplantation including the liver
    is used where parenteral nutrition has already destroyed the liver; an isolated
    intestinal graft is an option in selected patients whose liver is still sound. The
    reported case was an eight-year-old who achieved completely oral intake over four
    years of follow-up.

    Reported in single cases, which is the honest description of the evidence: this is a
    case report suggesting an indication, not a series establishing one.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: isolated intestinal transplantation
    term:
      id: NCIT:C157985
      label: Small Bowel Transplantation
  target_mechanisms:
  - target: Failure of Visceral Smooth Muscle Contraction
    description: >-
      Substitutes bowel with a working contractile apparatus for bowel without one, in
      the gastrointestinal compartment only.
  evidence:
  - reference: PMID:23167913
    reference_title: "Isolated intestinal transplantation for megacystis microcolon intestinal hypoperistalsis syndrome: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report an eight-yr-old patient with MMIHS who was treated with isolated intestinal transplantation. She had completely oral intake during the four yr of follow-up."
    explanation: The outcome in the reported case, with the follow-up interval.
  - reference: PMID:23167913
    reference_title: "Isolated intestinal transplantation for megacystis microcolon intestinal hypoperistalsis syndrome: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multivisceral transplantation including stomach, duodenum, intestine, and liver has been used for the treatment of patients with MMIHS because these patients often have liver failure."
    explanation: >-
      Why the multivisceral operation is the usual one, and therefore why an isolated
      graft is a selected-patient option rather than a default.
  - reference: PMID:18280270
    reference_title: "Combined living-related segmental liver and bowel transplantation for megacystis-microcolon-intestinal hypoperistalsis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the first case of a patient affected by MMIHS and cholestatic liver failure treated by a combined living-related liver and intestinal transplant (CLRLITx)."
    explanation: >-
      The third graft configuration reported in this disease, combining a living-related
      segmental liver with bowel. Recorded here rather than as a fourth treatment entry
      because it is a variant of the transplant decision this entry already models: which
      organs, determined by whether parenteral nutrition has taken the liver.
discussions:
- discussion_id: mmihs_female_predominance_mechanism
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - epidemiology#Female predominance
  - disease#Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 2
  prompt: >-
    Why are roughly seven in ten reported MMIHS patients female, when the causative
    genes are autosomal and the MYH11 form is recessive?
  rationale: >-
    An autosomal recessive mechanism predicts an even sex distribution. The observed
    skew is large, it holds at 70.6 per cent across 227 literature cases, 73 per cent
    across 121, and 16 of 19 in a national survey that is not subject to publication
    bias, and it was present in the original 1976 description of five female neonates.

    Three readings are available from the evidence curated here and none is settled.
    It may be ascertainment: most of these figures come from published case reports,
    and a male infant with a distended bladder is more likely to be worked up for
    posterior urethral valves and classified there. It may be sex-specific modification
    of a common pathway - the syndrome is genetically heterogeneous and is dominated by
    ACTG2 rather than MYH11, so the skew may not belong to this gene at all. Or it may
    be survival: if affected males die earlier or in utero, the reported series are the
    survivors.

    Nothing in the curated sources distinguishes these. It is recorded as an open
    question rather than curated into the pathograph because a sex effect with no
    proposed mechanism is not a mechanism, and because the honest thing to say about
    the most reproducible epidemiological fact in this disease is that it is unexplained.
  evidence:
  - reference: PMID:21792650
    reference_title: "Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review of outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A clear preponderance for female infants was found (female 70.6 vs. male 29.4%)."
    explanation: The observation the question is about.
  - reference: PMID:41387873
    reference_title: "Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACTG2 (15/19) was the most common causative gene variant, followed by MYH11 (2/19), MYLK (1/19), and LMOD1 (1/19)."
    explanation: >-
      Why the skew may not be a fact about MYH11 at all. The cohorts it is measured in
      are dominated by ACTG2, and no source separates the sex distribution by gene.
notes: >-
  On gnomAD constraint. The deep-research report gives MYH11 constraint metrics -
  pLI approximately 1.0, observed/expected LoF 0.32, LOEUF approximately 0.39, LoF Z
  of 9.0, missense Z of 3.29 - and they would sit naturally in the genetic section.
  They are not curated, because there is no way to cite them here. gnomAD is not a
  reference prefix this repository can fetch, so a constraint figure can only be
  entered as an uncited number in prose, which is the failure mode the evidence SOP
  exists to prevent. The claim they support - that MYH11 is strongly intolerant of
  loss of function, which is why one damaged allele is enough for the aortic phenotype
  and two are needed for this one - is made in the mechanistic_hypotheses block from
  cited sources instead.

  Scope. This entry covers the MYH11 form of MMIHS, which is what MONDO:0025708
  names. MMIHS as a clinical syndrome is genetically heterogeneous - dominant ACTG2
  accounts for most cases, with recessive LMOD1, MYLK, MYL9, MYH9 and MYH11 making up
  the rest - and several statements curated here (cohort frequencies, the 762 reported
  cases, the management data) are syndrome-level rather than MYH11-specific. Each is
  flagged as such in its own notes or explanation. The mechanistic chain, by contrast,
  is MYH11-specific from the gene lesion down to the contractile failure node, where
  it converges with the other genes.

  Relationship to the MYH11 aortic entries. MYH11 appears on main in
  Familial_Thoracic_Aortic_Aneurysm_and_Aortic_Dissection and related entries, and as
  the fusion partner in CBFB-MYH11 acute myeloid leukemia. None of those is the same
  disease as this one, and the first is the subject of a mechanistic_hypotheses block
  here because the allelic mechanism dichotomy between them is a substantive open
  question rather than a curation artefact.

  On copy-number variants. Two of the four reported MYH11 genotypes pair a point
  variant with a whole-gene deletion. Any diagnostic workflow that does not look for
  copy-number change will report these patients as heterozygous carriers, which is the
  practical reason the diagnosis section carries a separate entry for it.
📚

References & Deep Research

References

1
PMID:31070878
Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome Overview.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

On gnomAD constraint. The deep-research report gives MYH11 constraint metrics - pLI approximately 1.0, observed/expected LoF 0.32, LOEUF approximately 0.39, LoF Z of 9.0, missense Z of 3.29 - and they would sit naturally in the genetic section. They are not curated, because there is no way to cite them here. gnomAD is not a reference prefix this repository can fetch, so a constraint figure can only be entered as an uncited number in prose, which is the failure mode the evidence SOP exists to prevent. The claim they support - that MYH11 is strongly intolerant of loss of function, which is why one damaged allele is enough for the aortic phenotype and two are needed for this one - is made in the mechanistic_hypotheses block from cited sources instead. Scope. This entry covers the MYH11 form of MMIHS, which is what MONDO:0025708 names. MMIHS as a clinical syndrome is genetically heterogeneous - dominant ACTG2 accounts for most cases, with recessive LMOD1, MYLK, MYL9, MYH9 and MYH11 making up the rest - and several statements curated here (cohort frequencies, the 762 reported cases, the management data) are syndrome-level rather than MYH11-specific. Each is flagged as such in its own notes or explanation. The mechanistic chain, by contrast, is MYH11-specific from the gene lesion down to the contractile failure node, where it converges with the other genes. Relationship to the MYH11 aortic entries. MYH11 appears on main in Familial_Thoracic_Aortic_Aneurysm_and_Aortic_Dissection and related entries, and as the fusion partner in CBFB-MYH11 acute myeloid leukemia. None of those is the same disease as this one, and the first is the subject of a mechanistic_hypotheses block here because the allelic mechanism dichotomy between them is a substantive open question rather than a curation artefact. On copy-number variants. Two of the four reported MYH11 genotypes pair a point variant with a whole-gene deletion. Any diagnostic workflow that does not look for copy-number change will report these patients as heterozygous carriers, which is the practical reason the diagnosis section carries a separate entry for it.

Create: Megacystis-Microcolon-Intestinal_Hypoperistalsis_Syndrome_2 (MONDO:0025708) · 2026-09-13T21:52:02Z · View source

De novo curation of MMIHS2, the MYH11 form of megacystis-microcolon-intestinal hypoperistalsis syndrome. Deep research: one openscientist report, committed alongside. Report reference validation resolved 22/22 citations with confabulation_rate 0.0 and 1/1 quotes valid; term validation returned needs_review: true with 9 label mismatches, all table-parsing artefacts. GeneReviews baseline: PMID:31070878 (MMIHS Overview) fetched and tagged. just preflight-dr returns WARN for two reasons, both checked. First, ACTG2 is mentioned 14 times; that is correct rather than a second disease entity, since ACTG2 is the dominant MMIHS gene and the report covers the syndrome's genetic heterogeneity. Second, the report cites OMIM 155310 and 160745 where MONDO:0025708 xrefs 619351; 155310 is the syndrome-level Berdon entry and 160745 is the MYH11 gene, so the report is pitched at MMIHS generally rather than at MMIHS2 specifically. That drift is real and the entry handles it explicitly: a scope note names which statements are syndrome-level rather than MYH11-specific, and the cohort frequencies, the 762 reported cases and the management data are each flagged as such in their own notes. No OMIM identifier is recorded in the entry. The report also supplied the histopathology section, which is a negative finding with diagnostic weight: MYH11-variant visceral myopathy shows no diagnostic change on light microscopy, electron microscopy or MYH11 immunohistochemistry, so a normal biopsy does not exclude the diagnosis and molecular genetics is the route. That preserved MYH11 immunoreactivity also sits awkwardly beside the Western blot showing reduced protein in a different patient, and both are recorded rather than reconciled. Two mechanistic_hypotheses blocks: whether the mechanism of MYH11 disruption rather than the gene determines vascular versus visceral disease, and whether residual function sets age of onset along a continuum. Validation: schema, term and reference checks pass with 43/43 snippets verified; all five offline gates pass.

OpenScientist ▸
Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 2 (MMIHS2): A Comprehensive Disease Characteristics Report
openscientist-autonomous 22 citations 2026-09-13T21:23:19.939282

Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 2 (MMIHS2): A Comprehensive Disease Characteristics Report

Disease: Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 2 MONDO ID: MONDO:0025708 | OMIM: 619431 | Causal gene: MYH11 (HGNC:7569) Category: Mendelian (autosomal recessive)

Evidence source note: This report is compiled from aggregated disease-level resources (OMIM, Orphanet, HGNC/Ensembl/UniProt/gnomAD) and primary literature (human clinical case series/cohorts, mouse models, in vitro/immunohistochemical studies, and computational constraint data). Because MMIHS2 is ultra-rare, most human evidence derives from case reports and small cohorts; MMIHS-wide cohort statistics (which are dominated by ACTG2 cases) are used where MYH11-specific numbers are unavailable and are flagged as such.

Summary

Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome 2 (MMIHS2) is a rare, severe congenital visceral myopathy caused by autosomal-recessive biallelic loss-of-function (LOF) variants in MYH11, the gene encoding smooth-muscle myosin heavy chain (SM myosin II) — the dominant motor protein that drives smooth-muscle-cell contraction. Loss of functional SM myosin abolishes contractility in the smooth muscle of the urinary bladder and gastrointestinal tract, producing the defining triad from birth: a massively distended, non-obstructed urinary bladder (megacystis), an unused, small-caliber microcolon, and intestinal hypo- or aperistalsis causing a functional (non-mechanical) intestinal obstruction. MMIHS2 is the MYH11-linked subtype within the broader MMIHS family, which also includes the more common ACTG2-related form (MMIHS type 1, OMIM 155310) and rarer recessive forms caused by LMOD1, MYLK, MYL9, and the candidate gene PDCL3.

Mechanistically, MMIHS2 is a "contractile apparatus" disease: all confirmed MMIHS genes encode components of the smooth-muscle thin/thick filament and the myosin-light-chain-kinase (MLCK) phosphorylation axis. Biallelic MYH11 null alleles remove or drastically reduce the myosin motor itself, so the smooth muscle cannot generate force despite the presence of normal enteric ganglion cells and interstitial cells of Cajal. This distinguishes MMIHS from Hirschsprung disease (a neuropathic aganglionosis) and classifies it among the "variants of Hirschsprung's disease" — congenital smooth-muscle-cell disorders. Notably, routine histopathology and electron microscopy of MYH11 visceral myopathy are often near-normal, underscoring that the defect is functional rather than grossly structural.

Clinically, MMIHS shows a striking female preponderance (~70–73%), is frequently detected on prenatal ultrasound (megacystis ± polyhydramnios), and historically carried a very poor prognosis (survival <20% in older series). Modern management — total parenteral nutrition (TPN), intestinal rehabilitation, bladder catheterization/vesicostomy, enteric stomas, and isolated-intestinal or multivisceral (± liver) transplantation — has raised survival to roughly 55–65%, with patients now living into the second and third decades of life. There is no effective disease-specific pharmacotherapy; treatment is entirely supportive/surgical, with transplantation the only definitive option once TPN-associated liver failure develops. This report synthesizes 9 confirmed findings across 26 reviewed papers into a complete disease-characteristics knowledge-base entry.

Section 1. Disease Information

Overview. MMIHS (Berdon syndrome) is a congenital disorder of impaired smooth-muscle contractility producing functional obstruction of the bladder and bowel. MMIHS2 designates the subtype caused by biallelic MYH11 variants. It is the most severe form of functional intestinal obstruction in the newborn (PMID: 18280270).

Key identifiers.

Resource Identifier
OMIM (MMIHS2) 619431
OMIM (MMIHS1, ACTG2) 155310
MONDO MONDO:0025708
Orphanet (MMIHS) ORPHA:2241
Gene-OMIM (MYH11) 160745
HGNC HGNC:7569
NCBI Gene 4629
Ensembl ENSG00000133392
UniProt P35749
Cytoband 16p13.11 (GRCh38 chr16:15,703,135–15,858,438, minus strand)

Synonyms / alternative names. Berdon syndrome; Berdon's syndrome; MMIHS; congenital visceral myopathy (MMIHS subtype); megacystis–microcolon–intestinal hypoperistalsis syndrome type 2.

Information source. Content here is derived from aggregated disease-level resources (OMIM, Orphanet, HGNC/Ensembl/UniProt) plus individual-patient and small-cohort clinical reports and systematic reviews. It is not derived from a large EHR/population registry, reflecting the disease's rarity.

Section 2. Etiology

Primary cause — genetic. MMIHS2 is caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in MYH11 (Finding F001). This is a monogenic Mendelian cause; there is no established environmental, infectious, or acquired etiology.

Evidence: - A homozygous nonsense variant c.3598A>T (p.Lys1200Ter) was identified by exome sequencing in a newborn with MMIHS and prune-belly phenotype from consanguineous parents (PMID: 25407000): "We performed exome sequencing in a newborn with MMIHS and prune belly phenotype whose parents are consanguineous and identified a homozygous variant (c.3598A>T: p.Lys1200Ter) in MYH11, which codes for the smooth muscle myosin heavy chain." - Compound heterozygous variants c.2051G>A (p.R684H) and c.3540_3541delinsTT (p.(E1180D,Q1181Ter)) were found in a Chinese family, with a marked decrease in MYH11 protein on Western blot (PMID: 31427716): "Trio-targeted exome sequencing identified compound heterozygous variants, c.2051 G > A (p.R684H) and c.3540_3541delinsTT (p.(E1180D, Q1181Ter)), in MYH11." - A 16p13.11 microdeletion encompassing MYH11 unmasked a missense p.Pro127Ser variant on the other allele, confirming a biallelic null mechanism (PMID: 31044419): "Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), a rare condition that affects smooth muscle cells, is caused by biallelic null alleles in MYH11."

Genetic risk factors. The causal variants are the risk factor. Consanguinity is a major contributor (multiple index cases arose from consanguineous unions), consistent with an autosomal-recessive rare-allele architecture. MYH11 is highly intolerant to LOF in the general population (Finding F008): gnomAD constraint pLI ≈ 1.0; observed/expected LoF = 80/246.6 (o/e = 0.32, 90% CI 0.27–0.39; LOEUF ≈ 0.39); LoF Z = 9.0; missense Z = 3.29 — i.e., strong depletion of both LoF and missense variants. This intolerance explains the dual disease architecture of MYH11: heterozygous dominant-negative or protein-elongating variants cause thoracic aortic aneurysm/dissection and a dominant dysmotility syndrome, while biallelic null alleles cause recessive MMIHS2.

Environmental risk factors / protective factors / gene–environment interactions. Not applicable / none identified. As a fully penetrant Mendelian disorder driven by biallelic null alleles, no environmental risk factors, protective factors, lifestyle exposures, or gene–environment interactions have been described. Sex is a phenotype-modifying factor (female predominance and worse outcomes in girls) rather than a causal risk factor.

Section 3. Phenotypes

All phenotypes are congenital/neonatal in onset, severe, and stable-to-progressive (organ damage accrues secondary to chronic obstruction and TPN). HPO terms below were verified against EBI OLS4/HPO (Finding F009).

Phenotype Type HPO term Onset Frequency / notes
Megacystis (massively distended non-obstructed bladder) Physical/imaging sign HP:0000021 (Fetal megacystis HP:0010956) Congenital/prenatal Defining; detectable prenatally
Microcolon Physical/imaging sign HP:0004388 Congenital Defining; girls > boys (ACTG2 data)
Intestinal pseudo-obstruction / hypoperistalsis Clinical sign HP:0004389 Neonatal Defining
Gastrointestinal dysmotility Clinical sign HP:0002579 Neonatal Universal
Abdominal distention Clinical sign HP:0003270 Neonatal Very frequent
Hydronephrosis Imaging sign HP:0000126 Congenital Common (upper-tract effects of megacystis)
Hydroureter Imaging sign HP:0000072 Congenital Common
Intestinal malrotation Structural HP:0002566 Congenital Frequent
Polyhydramnios Prenatal sign HP:0001561 Prenatal Common
Feeding difficulties Symptom HP:0011968 Neonatal Universal (leads to TPN dependence)

Important negative: Aganglionic megacolon / Hirschsprung disease (HP:0002251) is NOT a feature — enteric ganglia are present in MMIHS2 (Finding F009). This is a key differential-diagnostic point.

Quality-of-life impact. Profound. Affected individuals are typically dependent on parenteral nutrition and require bladder drainage (intermittent catheterization or vesicostomy) and enteric stomas from birth. Chronic complications include TPN-associated cholestatic liver disease, recurrent sepsis, and chronic kidney disease (PMID: 41591435). Disease-specific formal QoL instrument data (EQ-5D/SF-36/PROMIS) are not available for this ultra-rare condition.

Section 4. Genetic / Molecular Information

Causal gene. MYH11 — "myosin heavy chain 11" (smooth muscle) — HGNC:7569, NCBI Gene 4629, Ensembl ENSG00000133392, UniProt P35749, gene-OMIM 160745, located at 16p13.11 (Finding F007).

Pathogenic variants (MMIHS2 = recessive, biallelic).

Variant (cDNA / protein) Type Zygosity Evidence
c.3598A>T (p.Lys1200Ter) Nonsense Homozygous PMID: 25407000
c.2051G>A (p.R684H) + c.3540_3541delinsTT (p.(E1180D,Q1181Ter)) Missense + delins/nonsense Compound het PMID: 31427716
p.Pro127Ser + 16p13.11 microdeletion (whole-gene) Missense unmasked by deletion Compound (point + CNV) PMID: 31044419
  • Classification: Pathogenic/likely pathogenic per ACMG (nonsense/frameshift LOF; missense-unmasked-by-deletion). All are exceedingly rare in population databases.
  • Variant types: Nonsense, frameshift/delins, missense, and whole-gene deletion (CNV) — all converging on a loss-of-function / biallelic-null mechanism.
  • Allele frequency: All variants are ultra-rare; MYH11 is strongly LoF-constrained in gnomAD (Finding F008), so these alleles are essentially private/family-specific.
  • Origin: Germline, inherited from carrier (often consanguineous) parents.
  • Functional consequence: Loss of function — absent or markedly reduced SM myosin heavy chain (confirmed by Western blot in PMID: 31427716).

Contrast — dominant MYH11 variants (NOT MMIHS2). Heterozygous dominant-negative MYH11 variants cause familial thoracic aortic aneurysm/dissection, and protein-elongating heterozygous variants (e.g., c.5819_5820insCA p.Gln1941Asnfs91; c.5819del p.Pro1940Hisfs91) cause a dominant severe smooth-muscle dysmotility syndrome via a distinct "dominant hypercontractile loss-of-function" mechanism (PMID: 31944481). MMIHS2 specifically requires biallelic null alleles.

Genetic heterogeneity of MMIHS (related genes). ACTG2 (dominant, most common), and recessive LMOD1, MYLK, MYL9, plus candidate PDCL3 (PMID: 28602422, PMID: 29453416, PMID: 32621347, PMID: 38461165). Approximately 10% of cases lack a variant in known genes, implying further loci.

Modifier genes / epigenetics / chromosomal abnormalities. No specific modifier genes are established for MMIHS2. Sex acts as a phenotype modifier (see Sections 3, 9, 11). No disease-specific epigenetic mechanism is described. A 16p13.11 microdeletion encompassing MYH11 is a relevant structural abnormality that can contribute one null allele (PMID: 31044419).

Section 5. Environmental Information

Not applicable. MMIHS2 is a monogenic recessive disorder. No environmental factors, toxins, radiation, occupational exposures, lifestyle factors, or infectious agents are known to cause or trigger it. (Recurrent bacterial sepsis occurs as a complication of chronic TPN/central lines and bacterial translocation, not as an etiologic agent — see Sections 11–12.)

Section 6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function variants in MYH11 (nonsense, frameshift, missense-over-deletion; germline, recessive) lead to absent or markedly reduced smooth-muscle myosin heavy chain (SM myosin II) protein. (Demonstrated — homozygous/compound-het LOF; Western blot shows reduced protein.)
  2. Loss of SM myosin II results in failure to assemble functional thick filaments in the smooth-muscle contractile apparatus, so myosin cannot engage actin thin filaments to generate force. (Inferred from protein function; SMII is "the dominant motor protein driving SMC contraction.")
  3. Absent myosin motor activity leads to loss of smooth-muscle contraction in the detrusor (bladder) and intestinal muscularis propria. (Demonstrated functionally; mechanistically inferred.) 4a. Bladder branch: Detrusor failure results in a non-contractile, massively distended bladder (megacystis) → leads to upstream hydroureter and hydronephrosis, and (chronically) chronic kidney disease. (Demonstrated clinically/radiologically.) 4b. Intestinal branch: Muscularis failure results in intestinal hypo-/aperistalsis (intestinal pseudo-obstruction) → the unused distal bowel remains small-caliber (microcolon) and the proximal bowel distends (abdominal distention). (Demonstrated.)
  4. Functional intestinal obstruction leads to inability to feed enterally → TPN dependence → TPN-associated cholestatic liver disease, sepsis, and multi-organ failure, the principal causes of death. (Demonstrated clinically.)

Key qualifier: enteric ganglion cells are present and normal, and routine histology/EM of MYH11 visceral myopathy is often near-normal with preserved MYH11 immunostaining — the lesion is functional (motor deficit) rather than a gross structural loss of smooth muscle (PMID: 36571289): "Apart from non-specific changes (e.g., muscle hypertrophy and distension-related muscularis propria necrosis), no alterations were identified by routine histopathological evaluation or electron microscopy."

Mechanistic detail

Molecular pathway / contractile apparatus (Finding F004). MYH11 encodes SM myosin II, described as "the dominant motor protein driving SMC contraction" (PMID: 42094517). The MMIHS gene set — ACTG2, MYH11, LMOD1, MYLK, MYL9 — collectively encodes proteins of the thin/thick-filament and MLCK-phosphorylation axis; "MYLK, LMOD1, MYL9, and MYH11 encode for various proteins within smooth muscle cells; abnormalities within these proteins lead to abnormal intestinal smooth muscle contractions" (PMID: 31848803). The physiologic contraction cascade is: Ca²⁺/calmodulin → MLCK (MYLK) phosphorylates regulatory myosin light chain (MYL9) → activated SM myosin (MYH11) cross-bridges with γ-smooth-muscle actin (ACTG2), stabilized by leiomodin (LMOD1). MMIHS2 removes the motor itself.

Cellular process. Failure of smooth-muscle-cell contraction (the core defect). Downstream, chronic distension produces non-specific muscle hypertrophy and distension-related muscularis propria necrosis (PMID: 36571289).

Protein dysfunction. Loss of function of SM myosin heavy chain — reduced/absent protein rather than a toxic aggregate. (Contrast: dominant MYH11 disease uses dominant-negative or hypercontractile mechanisms — PMID: 31944481.)

Immune involvement. None primary. Recurrent sepsis is secondary to catheters/TPN and bacterial translocation.

Tissue-damage mechanisms. Mechanical over-distension → ischemia/necrosis of muscularis; secondary uropathy (hydronephrosis → CKD) and TPN-associated cholestatic hepatopathy.

Suggested ontology terms. - GO biological process: smooth muscle contraction (GO:0006939); regulation of smooth muscle contraction (GO:0006940); myosin filament assembly (GO:0031034); muscle filament sliding (GO:0030049). - GO molecular function: microfilament motor activity (GO:0000146); actin binding (GO:0003779). - GO cellular component: myosin filament (GO:0032982); contractile fiber (GO:0043292); myosin II complex (GO:0016460). - CL cell types: smooth muscle cell (CL:0000192); smooth muscle cell of the bladder / visceral smooth muscle cell (CL:0000514). - CHEBI: calcium(2+) (CHEBI:29108); ATP (CHEBI:15422).

Section 7. Anatomical Structures Affected

Organ level. - Primary: Urinary bladder (UBERON:0001255) → megacystis; large intestine/colon (UBERON:0001155) → microcolon; small intestine (UBERON:0002108) → hypoperistalsis. - Secondary: Ureter (UBERON:0000056) → hydroureter; kidney (UBERON:0002113) → hydronephrosis, chronic kidney disease; liver (UBERON:0002107) → TPN-associated cholestasis. - Body systems: Digestive/gastrointestinal and urinary (renal) systems are primary.

Tissue and cell level. - Tissue: visceral (smooth) muscle — muscularis propria of gut and detrusor of bladder (UBERON:0001135 smooth muscle tissue). - Cell population: visceral smooth muscle cells (CL:0000192 smooth muscle cell; CL:0000514 smooth muscle cell of the bladder/visceral). Enteric neurons/ganglia and interstitial cells of Cajal are spared (normal).

Subcellular level. - Contractile apparatus / myosin filament (GO:0032982), contractile fiber (GO:0043292), actomyosin cytoskeleton (GO:0042641). The primary compartment is the contractile cytoskeleton, not mitochondria/nucleus/ER/lysosome.

Localization / laterality. Bilateral and diffuse — both the entire lower urinary tract and the intestinal tract are affected symmetrically (a systemic visceral myopathy, not a focal lesion).

Section 8. Temporal Development

Onset. Congenital. Megacystis and polyhydramnios are detectable prenatally (megacystis on antenatal ultrasound; bowel findings may appear late in gestation — PMID: 15543490). ~63–65% of cases are identified by prenatal imaging (PMID: 27421821). Symptoms manifest as neonatal functional bowel obstruction with distended bladder and microcolon in essentially all patients (PMID: 26413901).

Onset pattern. Chronic/congenital from birth (not acute or relapsing).

Progression. The primary smooth-muscle defect is stable (fixed genetic lesion), but the disease course is progressive because of accumulating secondary organ injury — TPN-associated liver disease, chronic kidney disease from chronic uropathy, and recurrent sepsis. Disease duration is lifelong; there is no self-limited course and no spontaneous remission.

Critical periods / intervention windows. The neonatal period is critical for diagnosis and establishment of bladder drainage, enteral/parenteral nutrition, and enteric diversion. Preventing TPN-associated liver failure defines the window for considering isolated intestinal transplant before multivisceral/liver transplant becomes necessary (PMID: 41591435).

Section 9. Inheritance and Population

Epidemiology. MMIHS is ultra-rare (no precise prevalence/incidence per 100,000 is established; Orphanet ORPHA:2241). Systematic reviews aggregate ~227 total cases across the literature since 1976 (PMID: 21792650); MMIHS2 (MYH11) is a small minority of these, most published as individual families.

Inheritance (MMIHS2). Autosomal recessive, biallelic null (Finding F001). Consanguinity is a recurring feature. Penetrance appears complete for biallelic null genotypes; expressivity varies (sex-associated severity differences). No genetic anticipation (not a repeat-expansion disorder). No established germline mosaicism or founder effect specific to MYH11 MMIHS2. Carrier frequency is very low, consistent with strong gnomAD LoF constraint (Finding F008); heterozygous carriers of MYH11 null alleles are generally unaffected for MMIHS (though other heterozygous MYH11 variant classes cause dominant aortic/dysmotility disease).

Population demographics. - Sex ratio: Strong female preponderance (Findings F003, F005). Across 227 cases, "A clear preponderance for female infants was found (female 70.6 vs. male 29.4%)" (PMID: 21792650); a 121–135-patient review found "73% (88/121) of the patients were female" (PMID: 27421821). In an ACTG2 cohort (n=103), girls had higher rates of microcolon (p=0.009), PN dependency (p=0.003), and death/transplant (p=0.029) (PMID: 35149643). - Geographic/ethnic distribution: No specific endemic distribution; cases reported worldwide (e.g., consanguineous kindreds, a Chinese family, a Japanese nationwide cohort). Consanguineous populations are over-represented for recessive forms. - Age distribution: Present at birth; historically few survived beyond infancy, though survivors now reach the second–third decade (oldest historical survivor 24 years).

Section 10. Diagnostics

Clinical/imaging. Diagnosis rests on the clinico-radiological triad: distended non-obstructed bladder (megacystis) + microcolon + intestinal hypoperistalsis, often with hydronephrosis/hydroureter and malrotation. Imaging (prenatal ultrasound, then neonatal radiographs, contrast studies, ultrasound, MRI) is central; the radiologist frequently first suggests the diagnosis and later monitors for mechanical obstruction vs dysmotility, CKD, and TPN-cholestasis (PMID: 41591435).

Biopsy / histopathology. Full-thickness intestinal biopsy shows present, normal ganglion cells (excluding Hirschsprung) and often near-normal muscle on routine histology/EM, with only non-specific changes (hypertrophy, distension necrosis) and preserved MYH11 immunostaining (PMID: 36571289, PMID: 26413901). Histology alone is therefore insufficient — genetic testing is required for subtype assignment.

Genetic testing (definitive for MMIHS2). - Recommended approach: NGS gene panel or exome sequencing covering ACTG2, MYH11, LMOD1, MYLK, MYL9 (± PDCL3), plus chromosomal microarray (CMA) to detect CNVs such as 16p13.11 deletions unmasking a MYH11 allele (PMID: 38461165, PMID: 31044419). - WES/WGS successfully identified the founding MYH11 variants (PMID: 25407000); trio/targeted exome identified compound-het variants (PMID: 31427716). - Karyotyping/FISH have limited utility except for detecting large structural changes; mitochondrial DNA and repeat-expansion testing are not applicable.

Biomarkers / omics. No specific circulating biomarker exists. Western blot for MYH11 protein and cDNA analysis are research/confirmatory tools. No validated metabolomic/proteomic diagnostic signature.

Clinical criteria / differential diagnosis. Differential includes Hirschsprung disease (distinguished by aganglionosis — HP:0002251, absent in MMIHS2), other visceral myopathies/CIPO, ACTG2/LMOD1/MYLK/MYL9 MMIHS subtypes, prune-belly syndrome, and mechanical obstruction. MMIHS is formally classified among "variants of Hirschsprung's disease" (congenital smooth-muscle-cell disorders with present ganglia) (PMID: 23943250).

Screening. Prenatal ultrasound (megacystis/polyhydramnios) is the de facto screen. Carrier and cascade screening for at-risk families and prenatal/preimplantation genetic testing are available once the family's biallelic MYH11 variants are known.

Section 11. Outcome / Prognosis

Survival/mortality.

Cohort N Female % Survival Notes PMID
Systematic review 1976–2011 227 70.6% 19.7% (43/218); oldest survivor 24 y Deaths: sepsis, malnutrition, MOF 21792650
Urologic-focus review ~121–135 73% 57% (68/121) 15% transplant; 63% prenatal detection 27421821
Japan nationwide survey 19 84% (16/19) 5-y 63%, 10-y 57% 16/19 needed PN; 9 died (sepsis/liver failure) 26413901
ACTG2 cohort (related) 103 52% 25.7% died, 5.8% transplant Girls worse outcomes 35149643

Modern management (TPN, intestinal rehabilitation, multivisceral transplant) now allows survival into the second decade of life (PMID: 41591435). Overall modern survival is roughly 55–65%. Main causes of death are "sepsis, malnutrition and multiple organ failure" (PMID: 21792650).

Morbidity/function. Very high: lifelong PN dependence, bladder drainage, enteric stomas; chronic complications include TPN-cholestatic liver disease, CKD, and recurrent sepsis. Disability is substantial.

Complications. Sepsis, malnutrition/multiple-organ failure (leading causes of death); TPN-associated liver failure; chronic kidney disease.

Prognostic factors. Female sex predicts worse outcomes (higher microcolon, PN dependence, death/transplant — PMID: 35149643); early onset (<2 y) associates with full MMIHS features. Development of TPN-liver failure is a key adverse prognostic event driving transplant need. Successful transplantation can restore enteral autonomy (PMID: 23167913).

Section 12. Treatment

No disease-specific pharmacotherapy exists (Finding F006). In the Japanese cohort, "although various medications were given, the patients did not show significant improvement" (PMID: 26413901). Prokinetics and related drugs are ineffective because the defect is the absence of the myosin motor itself. Management is supportive and surgical:

Nutritional / supportive. - Total parenteral nutrition (TPN) and intestinal rehabilitation — mainstay for enteral failure (NCIT: Total Parenteral Nutrition). 16/19 patients required PN in the Japanese cohort (PMID: 26413901). - Prophylactic antibiotics for urinary/enteric infection.

Urologic. - Clean intermittent catheterization or vesicostomy for bladder drainage (30% [22/73] had vesicostomy) (PMID: 27421821) (NCIT: Vesicostomy; Intermittent Catheterization).

Enteric/surgical diversion. - Gastrostomy, ileostomy, jejunostomy for decompression/venting (PMID: 27421821) (NCIT: Gastrostomy; Ileostomy).

Transplantation (definitive). - Isolated intestinal transplantation restored enteral autonomy: "We report an eight-yr-old patient with MMIHS who was treated with isolated intestinal transplantation. She had completely oral intake during the four yr of follow-up" (PMID: 23167913) (NCIT: Intestinal Transplantation). - Combined living-related liver + bowel transplantation restored enteral autonomy when TPN-liver failure developed (PMID: 18280270) (NCIT: Liver Transplantation; Multivisceral Transplantation). - Multivisceral transplantation used when TPN-associated liver failure supervenes; ~15% (18/116) of patients received intestinal/multivisceral transplant (PMID: 27421821).

Advanced / experimental therapeutics. No approved gene therapy, cell therapy, RNA-based, targeted, or immunotherapy exists for MMIHS2. Given the biallelic-null LOF mechanism, gene-replacement strategies are conceptually attractive but remain experimental/preclinical. No pharmacogenomic guidance applies.

Treatment strategy. Neonatal stabilization → bladder drainage + enteric diversion + PN → intestinal rehabilitation → transplantation if PN fails or TPN-liver disease develops. Personalized care depends on genetic confirmation for counseling and family planning.

Section 13. Prevention

Because MMIHS2 is a fully penetrant recessive Mendelian disorder, prevention is genetic/reproductive, not lifestyle-based.

  • Primary prevention: Not achievable by risk-factor modification. Genetic counseling for consanguineous/at-risk couples; carrier testing once family variants are known; prenatal diagnosis and preimplantation genetic testing (PGT) to prevent recurrence.
  • Secondary prevention: Prenatal ultrasound detection of megacystis/polyhydramnios enables early diagnosis and planning (PMID: 15543490, PMID: 27421821).
  • Tertiary prevention (complication avoidance): Meticulous line/TPN management to prevent sepsis and cholestatic liver disease; timely transplant referral; upper-urinary-tract protection to limit CKD (PMID: 41591435).
  • Immunization / public-health / environmental interventions / prophylactic drugs: Not applicable to disease causation; standard infection prophylaxis applies to catheter/TPN care.
  • Counseling: Genetic counseling is central — recurrence risk is 25% for future pregnancies of carrier couples; cascade testing offered to relatives.

Section 14. Other Species / Natural Disease

Orthologous genes (Finding F007; HomoloGene 128512):

Species Gene NCBI Gene ID Database
Mouse (Mus musculus, NCBI Taxon 10090) Myh11 17880 MGI
Rat (Rattus norvegicus, 10116) Myh11 24582 RGD
Zebrafish (Danio rerio, 7955) myh11a 554168 ZFIN
Chicken (Gallus gallus, 9031) MYH11 396211 —
Dog (Canis lupus familiaris, 9615) MYH11 479836 —
Cow (Bos taurus, 9913) MYH11 530050 —

Natural disease in animals. No well-characterized naturally occurring MYH11-MMIHS analog is documented in companion animals or wildlife (no established OMIA entry identified in this investigation). Comparative biology shows the smooth-muscle contractile pathway is deeply conserved across vertebrates, supporting mechanistic translation from model organisms. No zoonotic potential (genetic disease).

Section 15. Model Organisms

Mouse (Mus musculus) — the principal model (Finding F002). - A Myh11 knockout / haploinsufficiency mouse recapitulates core MMIHS features: "Myh11 deficiency leads to significant bladder enlargement, smooth muscle thickening, collagen accumulation, and voiding dysfunction, establishing a good disease model for MMIHS" (PMID: 41797110). - Earlier work cited by the founding human study noted that loss of Myh11 function in mice produces a bladder and intestinal phenotype "highly reminiscent of MMIHS" (PMID: 25407000).

Model types available. Constitutive knockout, haploinsufficient (heterozygous), and conditional/lineage models exist; Myh11-CreER driver lines are widely used for smooth-muscle-specific gene manipulation (e.g., Myh11CreER;Yy1fl/fl, Myh11CreER;Mettl3fl/fl — PMID: 40795179), and a CRISPR knock-in EGFP-SMII mouse enables live imaging of myosin filament dynamics (PMID: 42094517).

Phenotype recapitulation. Good for the bladder phenotype (megacystis, voiding dysfunction, muscle thickening, collagen accumulation). Recapitulation of the full microcolon / intestinal-aperistalsis triad and neonatal lethality is less completely characterized in the reviewed literature.

Limitations. Constitutive Myh11 null mice may have confounding vascular/aortic phenotypes (heterozygous MYH11 causes aortic disease), and mouse gut anatomy/physiology differs from human; the human microcolon feature and TPN-dependence course are not fully modeled.

Applications. Study of smooth-muscle contractile mechanics, bladder/voiding physiology, myosin-filament assembly dynamics, and preclinical testing of interventions.

In vitro / other systems. Rat aortic SMC lines (A7R5) and patient-derived approaches inform SMII biology; iPSC-derived smooth muscle and organoid models are plausible but not established for MMIHS2 in the reviewed literature. Resources: MGI, RGD, ZFIN, IMPC/IMSR.

Mechanistic Model / Interpretation

   Biallelic LOF variants in MYH11 (16p13.11)
   (nonsense / frameshift / missense-over-deletion; germline, recessive)
     │  [Western blot: reduced MYH11 protein]
     ▼
   Absent / reduced SM myosin II (the dominant SMC motor protein)
     │  (no functional thick filaments to engage actin)
     ▼
   Failure of smooth-muscle-cell CONTRACTION (functional, not structural)
│                                            │
▼ (bladder branch)                           ▼ (gut branch)
   Detrusor fails --> MEGACYSTIS               Muscularis fails --> hypo/aperistalsis
│                                            │
▼                                            ▼
   Hydroureter --> Hydronephrosis          MICROCOLON (unused bowel) +
│                                   abdominal distention
▼                                            │
   Chronic kidney disease                            ▼
                          Enteral failure --> TPN dependence
                                       │
                                       ▼
                    TPN-cholestatic liver disease, SEPSIS,
                    multi-organ failure --> leading cause of death
                                       │
                                       ▼
                    Rescue: isolated intestinal / multivisceral
                    (+/- liver) transplantation --> enteral autonomy

   NB: Enteric ganglia + interstitial cells of Cajal are NORMAL
       (distinguishes MMIHS from Hirschsprung disease).

Upstream vs downstream. The mutation → protein loss → contractile failure steps are upstream and demonstrated at the molecular level. The organ-level distension, microcolon, uropathy, and TPN-related complications are downstream, demonstrated clinically/radiologically. The gut and bladder branches are parallel consequences of the same single lesion.

Genotype–phenotype logic. MYH11 is a "double-hit-dependent" locus: heterozygous null carriers are unaffected for MMIHS (strong gnomAD LoF constraint reflects selection against other heterozygous variant classes that cause dominant aortic/dysmotility disease), while only biallelic null genotypes cause the recessive MMIHS2 visceral myopathy. This clean loss-of-function logic makes gene replacement a rational (though unproven) therapeutic direction.

Evidence Base

PMID Contribution Supports finding
25407000 First homozygous LOF MYH11 (p.Lys1200Ter) in MMIHS; mouse phenotype note F001, F002
31427716 Compound-het MYH11; Western blot reduced protein F001
31044419 16p13.11 deletion unmasks missense; states biallelic-null mechanism F001, F004
41797110 Myh11 KO/haploinsufficient mouse recapitulates megacystis F002
31848803 Contractile-apparatus genes → abnormal smooth-muscle contraction F004
36571289 Near-normal histology/EM → functional (not structural) defect F004
42094517 SMII = dominant motor of SMC contraction; EGFP-SMII model F004
27421821 73% female; 63% prenatal detection; 15% transplant; 57% survival F003
35149643 Girls worse outcomes (p=0.009/0.003/0.029); ACTG2 cohort F003
21792650 227 cases: 70.6% female; 19.7% survival; sepsis/MOF deaths F005
23943250 Classifies MMIHS as a "variant of Hirschsprung's" (ganglia present) F005
26413901 Japan survey: no drug benefit; 5/10-y survival 63/57% F006
23167913 Isolated intestinal transplant → 4 y oral intake F006
18280270 Combined living-related liver+bowel transplant F006
41591435 Modern survival into 2nd decade; imaging/complication surveillance F003
31944481 Dominant MYH11 mechanism distinct from recessive MMIHS F001/F008 context
28602422, 29453416, 32621347, 38461165 Genetic heterogeneity (MYLK, MYL9, PDCL3; landscape review) Section 4 context

Limitations and Knowledge Gaps

  1. Small case numbers. MMIHS2 (MYH11-specific) is described in a handful of families; most epidemiologic/survival statistics are drawn from mixed-genotype MMIHS cohorts (including the far more common ACTG2 form), so MYH11-specific prognosis and frequencies are extrapolated, not directly measured.
  2. No precise prevalence/incidence for MMIHS2 exists; the disease is ultra-rare.
  3. Female predominance is unexplained. The strong female skew (~70%) is well documented but mechanistically unresolved for a nominally autosomal-recessive condition; it may reflect ascertainment, X-linked/hormonal modifiers, or sex-specific smooth-muscle biology — none proven.
  4. Mechanism step 2 (filament-assembly failure) is inferred, not directly demonstrated in patient tissue; histology is near-normal, so the functional deficit is deduced from protein loss and physiology.
  5. Intestinal-branch modeling is incomplete. Mouse models robustly show the bladder phenotype; full microcolon/aperistalsis recapitulation is less characterized.
  6. No biomarkers, no disease-specific drug, no gene/cell therapy — the therapeutic pipeline is empty beyond supportive care and transplantation.
  7. Modifier genes and epigenetics for MMIHS2 severity are essentially unstudied.

Proposed Follow-up Experiments / Actions

  1. Genotype-stratified natural-history study. Assemble a MYH11-specific MMIHS2 registry to derive subtype-specific survival, transplant rates, and complication timelines (vs ACTG2 and other genes).
  2. Investigate the female-predominance mechanism. Test for X-linked or sex-hormone modifiers of visceral smooth-muscle contractility in Myh11-deficient mice of both sexes; re-examine ascertainment bias.
  3. Complete the intestinal phenotype in models. Generate/characterize smooth-muscle-conditional Myh11 knockouts assessing colonic caliber, peristalsis (spatiotemporal mapping), and neonatal survival to fully model the triad.
  4. Preclinical gene-replacement proof-of-concept. Given the clean biallelic-LOF mechanism, test AAV- or nanoparticle-delivered MYH11 restoration (or read-through agents for nonsense alleles such as p.Lys1200Ter) in patient-derived iPSC smooth-muscle/organoid systems and mouse models.
  5. Biomarker discovery. Explore whether circulating SM-myosin fragments, urodynamic parameters, or bowel-motility signatures can serve as diagnostic/prognostic markers and transplant-timing tools.
  6. Refine transplant timing. Compare outcomes of pre-emptive isolated intestinal transplant versus multivisceral (± liver) transplant after TPN-liver failure develops, to optimize the intervention window.
  7. Prenatal-diagnosis optimization. Correlate prenatal megacystis/polyhydramnios findings with genetically confirmed MMIHS2 to improve early counseling and PGT uptake in at-risk families.

Report compiled from 9 confirmed findings and 26 reviewed papers. Evidence types span human clinical case reports and systematic reviews (majority), mouse model-organism studies (Myh11 KO/haploinsufficiency), in vitro smooth-muscle biology, and computational/population-genetics constraint data (gnomAD).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 22
Resolved 22
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 22
On topic 17
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 36
Resolved 34
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 16
Terms named correctly 0
Terms named as a different term 9
Terms whose name is worth a second look 7

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0025708 (2 mentions) - the report calls it "MONDO"; MONDO calls it megacystis-microcolon-intestinal hypoperistalsis syndrome 2
  • HP:0004388 (1 mention) - the report calls it "Physical/imaging sign"; HP calls it Microcolon
  • HP:0004389 (1 mention) - the report calls it "Clinical sign"; HP calls it Intestinal pseudo-obstruction
  • HP:0002579 (1 mention) - the report calls it "Clinical sign"; HP calls it Gastrointestinal dysmotility
  • HP:0000126 (1 mention) - the report calls it "Imaging sign"; HP calls it Hydronephrosis
  • HP:0000072 (1 mention) - the report calls it "Imaging sign"; HP calls it Hydroureter
  • HP:0002566 (1 mention) - the report calls it "Structural"; HP calls it Intestinal malrotation
  • HP:0001561 (1 mention) - the report calls it "Prenatal sign"; HP calls it Polyhydramnios
  • HP:0011968 (1 mention) - the report calls it "Symptom"; HP calls it Feeding difficulties

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0003270 (1 mention) - the report calls it "Clinical sign"; HP calls it Abdominal distention, and lists "Abdominal swelling" among its other names
  • GO:0006939 (1 mention) - the report calls it "GO biological process: smooth muscle contraction"; GO calls it smooth muscle contraction
  • GO:0000146 (1 mention) - the report calls it "GO molecular function: microfilament motor activity"; GO calls it microfilament motor activity, and lists "actin filament motor activity" among its other names
  • GO:0032982 (2 mentions) - the report calls it "GO cellular component: myosin filament", "Contractile apparatus / myosin filament"; GO calls it myosin filament
  • CL:0000192 (2 mentions) - the report calls it "CL cell types: smooth muscle cell"; CL calls it smooth muscle cell
  • UBERON:0001255 (1 mention) - the report calls it "Primary: Urinary bladder"; UBERON calls it urinary bladder**
  • UBERON:0000056 (1 mention) - the report calls it "Secondary: Ureter"; UBERON calls it ureter**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HGNC:7569 - called "MYH11", "HGNC"
  • GO:0032982 - called "GO cellular component: myosin filament", "Contractile apparatus / myosin filament"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.