Genotype-phenotype correlation and management of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome: a descriptive cohort study

Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare genetic visceral myopathy, with a historically high mortality rate. Its genetic and phenotypic variability and management options remain poorly characterized. This study correlates genotype with phenotype and subsequently analyzes treatment and outcome of patients with pediatric-onset MMIHS. We retrospectively analyzed 26 MMIHS patients (median age 97 months, 62% female) with molecular diagnostics in 19 patients at a German quaternary intestinal rehabilitation center followed between 2012 and 2025. ACTG2 (15/19) was the most common causative gene variant, followed by MYH11 (2/19), MYLK (1/19), and LMOD1 (1/19). Megacystis was present in 96% (all detected prenatally), intestinal hypoperistalsis in 100%, and microcolon in 57%. High rates of proximal intestinal stenosis (35%), mal-/non-rotation (39%), IFALD (58%), and Cholelithiasis (65%) were observed. All patients experienced clinical (sub)ileus, with 85% requiring ostomy and parenteral nutrition, key determinants of unfavorable outcome. Notably, ACTG2 variants at P39 or R40 were significantly associated with more favorable outcome, evading these measures, in contrast to variants at R63, R178 or R257 (p ≤ 0.01). Overall long-term survival in our cohort was 88%. In this second-largest pediatric MMIHS cohort worldwide, genotype correlated with severity and outcomes, with ACTG2 P39/R40 variants linked to better prognosis. Frequent occurrences of proximal intestinal stenosis, mal/non-rotations, and cholelithiasis were identified, findings that have thus far been underestimated in clinical assessments. Prenatal megacystis enables presumptive diagnosis for MMIHS, which should prompt early molecular diagnostics and genotype-guided management. Individualized care at a multidisciplinary intestinal rehabilitation center resulted in 88% long-term survival.