Megacystis-microcolon-intestinal Hypoperistalsis Syndrome Research Articles

A lmod1a mutation causes megacystis microcolon intestinal hypoperistalsis in a CRISPR/Cas9-modified zebrafish model.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is defined as a congenital visceral myopathy with genetic mutations. However, the etiology and pathophysiology are not fully understood. We aimed to generate a gene leiomodin-1a (lmod1a) modification technique to establish a zebrafish model of MMIHS. We targeted lmod1a in zebrafish using CRISPR/Cas9. After confirming the genotype, we measured the expression levels of the target gene and protein associated with MMIHS. A gut transit assay and spatiotemporal mapping were conducted to analyze the intestinal function. Genetic confirmation showed a 5-base-pair deletion in exon 1 of lmod1a, which caused a premature stop codon. We observed significant mRNA downregulation of lmod1a, myh11, myod1, and acta2 and the protein expression of Lmod1 and Acta2 in the mutant group. A functional analysis of the lmod1a mutant zebrafish showed that its intestinal peristalsis was fewer, slower, and shorter in comparison to the wild type. This study showed that targeted deletion of lmod1a in zebrafish resulted in depletion of MMIHS-related genes and proteins, resulting in intestinal hypoperistalsis. This model may have the potential to be utilized in future therapeutic approaches, such as drug discovery screening and gene repair therapy for MMIHS.

Fetal Magnetic Resonance Imaging of Megacystis microcolon intestinal hypoperistalsis syndrome

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHs) is a rare congenital anomaly, involve urinary tract and gastrointestinal tract. The prognosis is dismal, the death is caused by infection. In general the diagnosis is made based on ultrasonography (US) examination during the antenatal period due to the presence megacystis in the female fetus. Fetal Magnetic Resonance Imaging (MRI) has excellent tissue contrast can depict colon caliber and meconium distribution, hence definitive diagnosis can be established and useful for counseling and post natal management.

Exploring the complexities of megacystis-microcolon-intestinal hypoperistalsis syndrome: insights from genetic studies.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is an uncommon genetic disorder inherited in an autosomal recessive pattern that affects the muscles that line the bladder and intestines. The most common genes associated with MMIHS mutations are ACTG2, LMOD1, MYH11, MYL9, MYLK, and PDCL3. However, the complete genetic landscape of MMIHS still needs to be fully understood. The diagnosis of MMIHS can be challenging. However, advances in prenatal and diagnostic techniques, such as ultrasound and fetal urine analysis, have improved the ability to detect the syndrome early. Targeted next-generation sequencing (NGS) and other diagnostic tests can also diagnose MMIHS. The management of MMIHS involves addressing severe intestinal dysmotility, which often necessitates total parenteral nutrition (TPN), which can lead to complications such as hepatotoxicity and nutritional deficiencies. Multivisceral and intestinal transplantation has emerged as therapeutic options, offering the potential for improved outcomes and enteral autonomy.Understanding the genetic underpinnings of MMIHS is crucial for personalized care. While the prognosis varies, timely interventions and careful monitoring enhance patient outcomes. Genetic studies have given us valuable insights into the molecular mechanisms of MMIHS. These studies have identified mutations in genes involved in the development and function of smooth muscle cells. They have also shown that MMIHS is associated with defects in the signaling pathways that control muscle contraction. Continued research in the genetics of MMIHS holds promise for unraveling the complexities of MMIHS and improving the lives of affected individuals.

Troubleshooting Tips for Diagnosing Complex Fetal Genitourinary Malformations.

Fetal genitourinary anomalies can present a diagnostic challenge for the radiologist. The absence of a normally located kidney may represent agenesis or be secondary to a fusion or migration abnormality. A dilated renal pelvis should prompt evaluation for a specific cause, including ureteropelvic junction obstruction, reflux, or an obstructed duplicated system. Cystic parenchymal changes are characteristic of a multicystic dysplastic kidney but may also be seen in obstructive cystic dysplasia. There are numerous causes of megacystis including chromosomal (trisomy 18 syndrome), obstruction (posterior urethral valves, urethral atresia), or muscular dysfunction (prune belly syndrome, megacystis microcolon intestinal hypoperistalsis syndrome). Important mimics of a large bladder include hydrocolpos and urogenital sinus or cloacal malformation. Complications of genitourinary malformations are common and include oligohydramnios, urinary ascites, and urinoma. Making an accurate diagnosis often requires additional US views beyond those obtained in the standard fetal survey and occasionally performing fetal MRI. The appropriate use of orthogonal T2-weighted sequences, in conjunction with diffusion-weighted images for evaluation of the kidneys and gradient-recalled-echo sequences for evaluation of T1-hyperintense meconium in the colon, can play an integral role in diagnosis. Accurate diagnosis of fetal genitourinary malformations is vital to direct patient counseling and pregnancy management as outcomes are highly variable. Some conditions can be surgically corrected quite simply, some require multiple complex procedures, and some are lethal. The authors offer troubleshooting tips to narrow the differential diagnosis for four observations: unilateral absent kidney, dilated renal pelvis, cystic renal parenchyma, and megacystis and its mimics. ©RSNA, 2023 Test Your Knowledge questions are available in the Online Learning Center.

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome Berdon’s syndrome - First Report in Romania

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare motility disorder with high mortality rate described by Berdon in 1976. We present the first case of Berdon’s syndrome (heterozygous pathogenic variant in the ACTG2 gene) reported

Single-center outcome analysis of 46 fetuses with megacystis after intrauterine vesico-amniotic shunting with the Somatex®intrauterine shunt

ObjectivesTo assess the spectrum of underlying pathologies, the intrauterine course and postnatal outcome of 46 fetuses with megacystis that underwent intrauterine vesico-amniotic shunting (VAS) with the Somatex® shunt in a single center.MethodsRetrospective analysis of 46 fetuses with megacystis that underwent VAS either up to 14 + 0 weeks (early VAS), between 14 + 1 and 17 + 0 weeks (intermediate VAS) or after 17 + 0 weeks of gestation (late VAS) in a single tertiary referral center. Intrauterine course, underlying pathology and postnatal outcome were assessed and correlated with the underlying pathology and gestational age at first VAS.Results46 fetuses underwent VAS, 41 (89%) were male and 5 (11%) were female. 28 (61%) fetuses had isolated and 18 (39%) had complex megacystis with either aneuploidy (n = 1), anorectal malformations (n = 6), cloacal malformations (n = 3), congenital anomalies overlapping with VACTER association (n = 6) or Megacystis–Microcolon Intestinal–Hypoperistalsis Syndrome (MMIHS) (n = 2). The sonographic ‘keyhole sign’ significantly predicted isolated megacystis (p < 0.001). 7 pregnancies were terminated, 4 babies died in the neonatal period, 1 baby died at the age of 2.5 months and 34 (74%) infants survived until last follow-up. After exclusion of the terminated pregnancies, intention-to-treat survival rate was 87%. Mean follow-up period was 24 months (range 1–72). The underlying pathology was highly variable and included posterior urethral valve (46%), hypoplastic or atretic urethra (35%), MMIHS or prune belly syndrome (10%) and primary vesico-ureteral reflux (2%). In 7% no pathology could be detected postnatally. No sonographic marker was identified to predict the underlying pathology prenatally. 14 fetuses underwent early, 24 intermediate and 8 late VAS. In the early VAS subgroup, amnion infusion prior to VAS was significantly less often necessary (7%), shunt complications were significantly less common (29%) and immediate kidney replacement therapy postnatally became less often necessary (0%). In contrast, preterm delivery ≤ 32 + 0 weeks was more common (30%) and survival rate was lower (70%) after early VAS compared to intermediate or late VAS. Overall, 90% of liveborn babies had sufficient kidney function without need for kidney replacement therapy until last follow-up, and 95% had sufficient pulmonary function without need for mechanical respiratory support. 18% of babies with complex megacystis suffered from additional health restrictions due to their major concomitant malformations.ConclusionsOur data suggest that VAS is feasible from the first trimester onward. Early intervention has the potential to preserve neonatal kidney function in the majority of cases and enables neonatal survival in up to 87% of cases. Despite successful fetal intervention, parents should be aware of the potential of mid- or long-term kidney failure and of additional health impairments due to concomitant extra-renal anomalies that cannot be excluded at time of intervention.

Heterozygous Actg2R257C mice mimic the phenotype of megacystis microcolon intestinal hypoperistalsis syndrome.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare and serious congenital disorder with poor outcomes, where a heterozygous missense mutation is present in the ACTG2 gene. Here, we aimed to investigate the pathogenesis of ACTG2 in MMIHS. A cohort with 20 patients with MMIHS was screened. Actg2R257C heterozygous mutant mice were generated using the CRISPR/Cas9 system. Gastrointestinal (GI) motility, voluntary urination, collagen gel contraction, and G-actin/F-actin analysis were performed. The R257C variant of ACTG2 most frequently occurred in patients with MMIHS and demonstrated the typical symptoms of MMIHS. Actg2R257C heterozygous mutant mice had dilated intestines and bladders. The functional assay showed a prolonged total time of GI transit and decreased urine spot area. Collagen gel contraction assay and G-actin/F-actin analysis indicated that mutant mice showed reduced area of contraction of smooth muscle cells (SMCs) and impaired actin polymerization. A mouse model demonstrating MMIHS-like symptoms was generated. The Actg2R257C heterozygous variant impairs SMCs contraction by interfering with actin polymerization, leading to GI motility disorders.

EP26.18: Megabladder: five cases reported in the last five years in our tertiary centre

The aim of this study was to present a series of cases of megabladders diagnosed prenatally in the last 5 years in our centre. This was a descriptive retrospective study of fetus with megabladder diagnosed in our hospital in last 5 years and their follow-up. Mean age women patients was 27 years old (SD +− 10). Mostly of the patients were not any medical conditions (only an interventricular communication without follow-up). 4 was primiparous and one gestation was with reproduction techniques. Ultrasound diagnoses were at first trimester ultrasound in three cases, remaining two were in early morphological ultrasound (17wk and 18wk). Mean bladder volume of fetuses with diagnosed in first trimester was 14.5 mm3 and in fetuses with diagnosed in second trimester was 27.83 mm3. Two fetus had not any associated malformations and one of them has a spontaneous resolution (already pregnancy is in course). The other one had a Berdon Syndrome, diagnosed with amniocentesis (parents decided termination). In the remaining fetus, one of them was diagnosed of hydrops and late miscarriage was happened. Other one also had other urinary anomalies and the last one severe oligohydramnios (both of them were interrupted legally). In 4 of the 5 cases, pregnancies ended in late miscarriage or in legal termination, similar statistic has been described in bibliography. Prevalence of megabladder diagnosed ranges between 0.06% and 0.3%. Differential diagnosis should be made with other abdominal masses such as ovarian cysts or peritoneal cysts. Once confirmed associated abnormalities or syndrome should be taken into account such as posterior urethral valves, urethral stricture, Prune-Belly syndrome or other rarer syndromes such as Beuren syndrome. Termination or miscarriage is the major described end.

Megacystis-Microcolon–Intestinal Hypoperistalsis Syndrome: A Case Report

A 1-day-old girl, late preterm (36 weeks 3 days) infant, was admitted to the neonatal intensive care unit for respiratory distress and megacystis seen on a prenatal ultrasound at 24 weeks of gestation. A babygram (anteroposterior view of the entire body) showed absence of bowel gas, and abdominal ultrasound revealed grade 4 bilateral hydronephrosis. The patient was subsequently diagnosed with megacystis-microcolon–intestinal hypoperistalsis syndrome and was taken to the operating room for appropriate treatment.

Hirschsprung Disease.

Hirschsprung Disease.

Phenotypic diversity in clinical and manometric characteristics of pediatric patients with ACTG2 mutations

Abstract Heterogenous missense variants in ACTG2 have been identified in individuals with visceral myopathy and megacystis, microcolon, intestinal hypoperistalsis syndrome (MMIHS). Though varying degrees of severity of chronic intestinal pseudo obstruction have been correlated to the disease phenotype when ACTG2 is mutated, little is known about the details of motility disorder affecting different regions of the gastrointestinal tract. This is a case series of 5 patients, age 9 months to 9 years, with ACTG2 mutations who underwent gastrointestinal manometry testing at an academic pediatric hospital. Esophageal manometry was performed in two patients with p.R257C mutations. Each was abnormal. Antral fed response with low amplitude response to azithromycin was found in one patient with a p.R257H mutation. Antral activity differed in the patients with p.R257C mutations, two having normal gastric motility (contractions in response to feeding and normal response to erythromycin), and the other having gastric dysmotility (absent fed response and no response to erythromycin). Small bowel and colonic motility did not differ significantly among patients. All patients required gastrostomy tubes and diverting ileostomies, with differing reliance on supplemental parenteral nutrition. These findings suggest that ACTG2 mutations can have varied manometric presentations within different segments of the gastrointestinal tract, which may translate to differing patient outcomes.

出生前診断できなかった巨大膀胱短小結腸腸管蠕動不全症（MMIHS）の1例

出生前診断できなかった巨大膀胱短小結腸腸管蠕動不全症（MMIHS）の1例

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome: A Case Series With Long-term Follow-up and Prolonged Survival.

Describe clinical characteristics, management, and outcome in a cohort of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) patients. We conducted a retrospective chart review of MMIHS patients followed at a large transplant and intestinal rehabilitation center over a period of 17 years. We identified 25 patients with MMIHS (68% girls, 13 transplanted). One transplanted and 1 nontransplanted patient were lost to follow-up. We estimated 100, 100, and 86% for 5-, 10-, and 20-year survival, respectively, with only 1 death. Of the 22 patients alive at the time of study (11 transplanted, 11 nontransplanted), median age was 9.2 years (range 2.7-22.9 years). Longest posttransplant follow-up was 16 years. Seventeen patients had available prenatal imaging reports; all showed distended bladder. Eight had genetic testing (5, ACTG2; 2, MYH11; 1, MYL9). Almost all patients had normal growth with median weight z-score -0.77 (interquartile range -1.39 to 0.26), height z score -1.2 (-2.04 to -0.48) and body mass index z-score 0.23 (-0.37 to 0.93) with no statistical difference between transplanted and nontransplanted patients. All nontransplanted patients were on parenteral nutrition with minimal/no feeds, and all except 1 of the transplanted patients were on full enteral feeds. Recent average bilirubin, INR, albumin, and creatinine fell within the reference ranges. This is the largest single-center case series with the longest duration of follow-up for MMIHS patients. In the current era of improved intestinal rehabilitation and transplantation, MMIHS patients have excellent outcomes in survival, growth, and liver function. This observation contradicts previous reports and should alter counselling and management decisions in these patients at diagnosis.

Prenatal diagnostic and management of megacystis microcolon intestinal hypoperistalsis syndrome: A report on a rare case in Cipto Mangunkusumo Hospital, Jakarta, Indonesia

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare and the most severe form of functional intestinal obstruction in the newborn. The characteristic features of this congenital and fatal disease are abdominal distension, absent or decreased bowel peristalsis. Abdominal distension is a consequence of the distended, unobstructed urinary bladder with or without hydro nephrosis. Some previous reports have revealed that the typical antenatal sonographic findings are as follows: a greatly distended bladder, bilateral hydro nephrosis, and a normal amount of amniotic fluid; however, the antenatal diagnosis of this syndrome is occasionally difficult.

Síndrome de Berdon: reporte de caso clínico en Ecuador

Introducción: El síndrome de megavejiga – microcolon - hipoperistaltismo intestinal (MMIHS) o síndrome de Berdon es una grave enfermedad congénita autosómica recesiva que se caracteriza por obstrucción intestinal funcional, distensión vesical o retención urinaria e hipoperistaltismo intestinal desde el nacimiento además de otras alteraciones. Presenta una incidencia muy baja y la esperanza de vida apenas supera el año de vida con una pésima calidad y fallecen generalmente por procesos sépticos. Para su diagnóstico el Radiólogo juega un papel fundamental, ya que las pruebas radiológicas son en su mayor parte patognomónicas. En el manejo de estos pacientes es fundamental el soporte nutricional que en muchas ocasiones se basa en nutrición parenteral durante largos periodos de tiempo. A pesar de la mejoría en la asistencia a estos pacientes, este síndrome sigue presentando una elevada morbilidad y mortalidad siendo el trasplante intestinal una alternativa terapéutica.&#x0D; Objetivo: Describir un caso clínico de Síndrome de Berdon o síndrome de megavejiga microcolon hipoperistaltismo intestinal presentado en Ecuador.&#x0D; Material y métodos: Estudio descriptivo retrospectivo, presentación de caso clínico.&#x0D; Resultados: Se presenta a continuación el caso de un paciente femenino que desde el nacimiento presentó mala tolerancia oral, distensión abdominal y bajo gasto urinario; radiológica y clínicamente fue diagnosticada de Síndrome de Berdon, recibió nutrición parenteral intrahospitalaria sin buena ganancia ponderal, con mala calidad de vida y que fallece a los 2 meses por sepsis.&#x0D; Conclusiones: El síndrome de Berdon es una enfermedad rara de baja incidencia que presenta alta morbilidad y mortalidad a pesar de los avances en su manejo.

Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy.

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome: An Overview

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital anomaly that is considered the most severe form of functional obstruction of the gastrointestinal tract. This devastating condition is composed of non-obstructed urinary bladder, microcolon with decreased or absent intestinal peristalsis. This study was designed to describe the incidence and outcome of MMIHS.

Use of pediatric donor en bloc kidneys along with bladder segment in pediatric liver‐kidney and multivisceral‐kidney transplantation

The combination of pediatric multivisceral and kidney transplantation leads to additional recipient risks due to the number of anastomoses and to the small sizes of donor structures. The inclusion of donor kidneys, ureters, and a bladder patch en bloc with multivisceral organs decreases the number and complexity of anastomoses and has not yet been reported. Four patients were transplanted in this fashion; three underwent multivisceral-kidney and one underwent liver-kidney transplantation. The first patient was a 3-year-old male with polycystic kidney disease and congenital hepatic fibrosis. The second was a 7-year-old female with complications from necrotizing enterocolitis. The third was a 12-month-old male with megacystis microcolon intestinal hypoperistalsis syndrome and secondary hydronephrosis, and the fourth was a 3-year-old male with multiple intestinal resections secondary to incarcerated hernia. The third patient developed a right ureteral stenosis with an intact bladder patch. The fourth child expired from maintained abdominal sepsis. The first 3 patients maintained normal graft function. There were no cases of thrombosis, arterial stenosis, or urinary leakages. These reported cases demonstrate that small pediatric en bloc transplantation of the multivisceral organs and dual kidneys with a bladder patch anastomosis is a feasible and less complex alternative to the standard procedure.

1604 Multidisciplinary Approach for Prolonged Survival of Patients With MMIHS

INTRODUCTION: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS)/Berdon syndrome is a rare disorder characterized by a distended non-obstructed bladder, microcolon, and decreased intestinal peristalsis with average life expectancy less than 6 months. We present case of a patient with MMIHS. CASE DESCRIPTION/METHODS: A 23-year-old female with MMIHS presented to the emergency department for abdominal pain and inability to tolerate oral or feeds through gastrostomy tube for 3 weeks. She had extensive surgical history since birth with LADD’s procedure due to intestine malrotation, exploratory laparotomy and subtotal colectomy for volvulous, colectomy with end ileostomy, Bilroth I, gastrostomy tube, and multiple nephrostomy tube for recurrent urinary infection. Patient had similar recurrent symptoms thought to be due to small intestinal bacterial overgrown and recurrent urinary tract infection. It appeared with each hospitalization her ability to tolerate oral intake declined to a lower baseline. At home patient was on Cisapride 14ml four times daily. During hospitalization lab work and imaging was non-contributory other than urine culture positive for Klebsiella. A small bowel follow through showed delayed gastric empting. Due to inability to tolerate oral intake or feeds patient was started on total parenteral nutrition (TPN). Esophagogastroduodenoscopy showed esophagitis, moderate chronic active gastritis with widely patent gastrojejunostomy anastomosis and jejunal limb. Her symptoms were likely due to progression of hypomotility syndrome. Cisapride was increased by 14%, under direction of outpatient pediatric gastroenterologist, with good response. However, due to prolonged QTc on electrocardiogram, upon discharge she was changed to Lubipristone. DISCUSSION: Our case demonstrates a complex presentation of a rare but fatal intestinal myopathy with most patients not surviving past infancy with even fewer cases surviving long term. Complications such as perforation, sepsis, malnutrition, multi-organ failure and pseudo-obstruction is not well understood in these patients and needs to be ruled out at each hospitalization. A multidisciplinary approach is needed for long term survival of patients with MMIHS. Main goals of treatment include providing a bladder-emptying strategy and adequate nutrition. In our case study, we demonstrate off label use of Cisapride and Lubiprostone for dysmotility. Close long term follow-up is necessary with multidisciplinary approach for long term survival.

Megacystis-Microcolon-intestinal hypoperistalsis syndrome

Abstract Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital anomaly that presents with severe form of functional obstruction of the gastrointestinal tract which is usually fatal. Here, we report a full term female infant with MMIHS presented with feeding intolerance, huge abdominal distension, bile-stained vomiting, absent bowel sounds and a large abdominal cystic mass. Exploration revealed hugely distended urinary bladder, micro colon, short bowel and malrotation of the small intestine. Ladd's procedure, ileostomy and vesicostomy were performed.