巨大膀胱短小結腸腸管蠕動不全症

INTRODUCTION: The diagnostic odyssey in rare diseases often involves the misinterpretation of genetic data, particularly when multidisciplinary approaches are lacking. This study illustrates the critical process of interpreting variants from next-generation sequencing (NGS) through a real-life case of a child misdiagnosed with Marfan Syndrome (MFS). The misdiagnosis was maintained for over seven years despite repeated clinical evaluations by different specialists. An initial clinical suspicion of MFS due to joint hypermobility at 3 years of age became a definitive diagnosis after an external laboratory reported a heterozygous variant in the MYH11 gene at age 5, despite the patient never fulfilling the established clinical diagnostic criteria for the disease. METHODS: To provide an accurate diagnosis and end the family's diagnostic odyssey, a complete clinical and genetic reinterpretation was performed when the patient was 7 years old. The proband and 9 asymptomatic relatives were recruited for a functional study of the MYH11 c.5544_5548del, p.(D1848Efs*60) variant. RESULTS: The functional analysis demonstrated that the variant operates through a loss-of-function mechanism, leading to nonsense-mediated mRNA decay. While gain-of-function variants in MYH11 are associated with thoracic aortic aneurysms and dissections, loss-of-function variants are linked to autosomal recessive Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS). As a heterozygous carrier of a loss-of-function variant, the patient is asymptomatic for MMIHS and definitively does not have MFS. Currently, the 11-year-old child is progressing favorably without any notable pathology. CONCLUSIONS: This case exposes the entire diagnostic odyssey suffered by the patient's family and highlights three fundamental systemic errors: the critical delay in genetic counseling, the over-interpretation of NGS data by external laboratories lacking phenotypic context, and the health system's inefficiency in integrating clinical geneticists. Overcoming these barriers is essential for the true implementation of personalized precision medicine.

BACKGROUND: Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a fatal rare disorder characterized by bladder and colonic smooth muscle dysfunction. Mutations in the MYH11 gene have been identified as one of the causative factors of MMIHS. OBJECTIVE: This study aimed to generate a Myh11 knockout mouse model, evaluate the phenotypes and function of the bladder and intestines, and investigate the association between Myh11 deficiency and the core clinical features of MMIHS. STUDY DESIGN: Gene expression was assessed by qRT-PCR and Western blot. Protein localization and expression were determined using immunohistochemistry. Histomorphological changes were evaluated through hematoxylin-eosin (H&E) and Masson staining. Bladder function was analyzed via void spot assay and post-void residual volume measurements, while smooth muscle contractility was measured using muscle tension assays. Intestinal motility was assessed using established gastrointestinal transit tests, and cell proliferation was examined by BrdU incorporation assay. RESULTS: Compared with wildtype mice, Myh11+/- heterozygote mice showed significantly reduced Myh11 expression at both mRNA and protein levels in bladder tissues (P < 0.001). 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). Phenotypically, 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). Functionally, 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). At the molecular level, the up-regulation of PCNA protein expression and the increased incorporation of BrdU suggests active cell proliferation (P < 0.05). DISCUSSION: Myh11+/- mice successfully recapitulate the core bladder phenotypes of MMIHS, including megacystis and voiding dysfunction. This confirms the critical role of Myh11 in both the development and contractile function of the bladder, thereby providing a reliable in vivo model for in-depth investigation into the pathological mechanisms underlying bladder dysfunction in MMIHS. CONCLUSION: Myh11 deficiency leads to significant bladder enlargement, smooth muscle thickening, collagen accumulation, and voiding dysfunction, establishing a good disease model for MMIHS.

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), also known as Berdon syndrome, is a rare genetic congenital disorder of impaired smooth muscle contractility, resulting in functional obstruction of the bladder and bowel. 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. The radiologist plays a key role in the initial workup of these patients and is often the first to suggest the diagnosis. Furthermore, with patients living longer, the radiologist's role now includes the following: (1) identifying complications on follow-up imaging, such as distinguishing mechanical obstruction from dysmotility; (2) following findings of chronic kidney disease; and (3) recognizing cholestatic TPN-related liver disease. With expedient diagnosis and management, survival can be extended, and quality of life can be improved. This pictorial essay aims to demonstrate the spectrum of imaging findings in the prenatal stage, the neonatal period, and later childhood in confirmed cases. Clinical findings, management, and outcomes of MMIHS, as well as imaging features that differentiate MMIHS from similar conditions, will be discussed.

BACKGROUND: Megacystitis-megacolon-intestinal hypoperistalsis syndrome is a phenotypic variant of visceral neuromuscular dysfunction. Megacystitis-microcolon-intestinal hypoperistalsis syndrome is a recognized entity. However, presentation with megacolon is rarely reported, with only one case documented in association with intestinal neuronal dysplasia (IND) and malrotation. CASE REPORT: We report such a case of Megacystitis-megacolon-intestinal hypoperistalsis coexisting with IND type B and atypical malrotation in a 2-year-old male, presented with intestinal obstruction. Despite multiple surgical interventions, the patient remained TPN-dependent and eventually succumbed to sepsis. Histopathology evaluation revealed hyperganglionosis, including the presence of immature and giant ganglion cells, which supported the diagnosis of IND type B, alongside the features of visceral myopathy. CONCLUSION: This case highlights the diagnostic and therapeutic complexity posed by overlapping features of megacolon and MMIHS, especially when hyperganglionosis was present. Our case highlights the need for clinico-pathological correlation and genetic analysis in diagnosing complex pediatric motility disorders.

BACKGROUND: 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. RESULTS: 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%. CONCLUSIONS: 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.