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Surgery Today Sep 2023Hirschsprung disease (HSCR) and its associated disorders (AD-HSCR) often result in severe hypoperistalsis caused by enteric neuropathy, mesenchymopathy, and myopathy.... (Review)
Review
Hirschsprung disease (HSCR) and its associated disorders (AD-HSCR) often result in severe hypoperistalsis caused by enteric neuropathy, mesenchymopathy, and myopathy. Notably, HSCR involving the small intestine, isolated hypoganglionosis, chronic idiopathic intestinal pseudo-obstruction, and megacystis-microcolon-intestinal hypoperistalsis syndrome carry a poor prognosis. Ultimately, small-bowel transplantation (SBTx) is necessary for refractory cases, but it is highly invasive and outcomes are less than optimal, despite advances in surgical techniques and management. Thus, regenerative therapy has come to light as a potential form of treatment involving regeneration of the enteric nervous system, mesenchyme, and smooth muscle in affected areas. We review the cutting-edge regenerative therapeutic approaches for managing HSCR and AD-HSCR, including the use of enteric nervous system progenitor cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells as cell sources, the recipient intestine's microenvironment, and transplantation methods. Perspectives on the future of these treatments are also discussed.
PubMed: 37668735
DOI: 10.1007/s00595-023-02741-6 -
Journal of Rare Diseases (Berlin,... 2023The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle. They manifest in both the GI and GU tracts,...
OBJECTIVES/AIMS
The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle. They manifest in both the GI and GU tracts, ranging from megacystis to Prune Belly syndrome. We aimed to apply a bespoke virtual genetic panel and describe novel variants associated with this condition using whole genome sequencing data within the Genomics England 100,000 Genomes Project.
METHODS
We screened the Genomics England 100,000 Genomes Project rare diseases database for patients with VM-related phenotypes. These patients were screened for sequence variants and copy number variants (CNV) in , , , , , , , and by analysing whole genome sequencing data. The identified variants were analysed using variant effect predictor online tool, and any possible segregation in other family members and novel missense mutations was modelled using in silico tools. The VM cohort was also used to perform a genome-wide variant burden test in order to identify confirm gene associations in this cohort.
RESULTS
We identified 76 patients with phenotypes consistent with a diagnosis of VM. The range of presentations included megacystis/microcolon hypoperistalsis syndrome, Prune Belly syndrome and chronic intestinal pseudo-obstruction. Of the patients in whom we identified heterozygous variants, 7 had likely pathogenic variants including 1 novel likely pathogenic allele. There were 4 patients in whom we identified a heterozygous variant of uncertain significance which leads to a frameshift and a predicted protein elongation. We identified one family in whom we found a heterozygous variant of uncertain significance in which in silico models predicted to be disease causing and may explain the VM phenotype seen. We did not find any CNV changes in known genes leading to VM-related disease phenotypes. In this phenotype selected cohort, is the largest monogenic cause of VM-related disease accounting for 9% of the cohort, supported by a variant burden test approach, which identified variants as the largest contributor to VM-related phenotypes.
CONCLUSIONS
VM are a group of disorders that are not easily classified and may be given different diagnostic labels depending on their phenotype. Molecular genetic analysis of these patients is valuable as it allows precise diagnosis and aids understanding of the underlying disease manifestations. We identified as the most frequent genetic cause of VM. We recommend a nomenclature change to 'autosomal dominant ACTG2 visceral myopathy' for patients with pathogenic variants in and associated VM phenotype.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s44162-023-00012-z.
PubMed: 37288276
DOI: 10.1007/s44162-023-00012-z -
JPGN Reports Nov 2022Pediatric intestinal pseudo-obstruction (PIPO) is a heterogeneous condition characterized by impaired gastrointestinal propulsion, a broad clinical spectrum, and...
UNLABELLED
Pediatric intestinal pseudo-obstruction (PIPO) is a heterogeneous condition characterized by impaired gastrointestinal propulsion, a broad clinical spectrum, and variable severity. Several molecular bases underlying primary PIPO have been identified, of which autosomal dominant ACTG2-related visceral myopathy is the most common in both familial or sporadic primary PIPO cases. We present a family with autosomal recessive ACTG2-related disease in which both parents have mild gastrointestinal symptoms and sons have severe PIPO and bladder dysfunction.
METHODS
Clinical genome sequencing was performed on the patients and the mother. Immunohistochemistry was performed on intestinal tissue from the patients to show expression levels of the .
RESULTS
Genome sequencing identified a 6.8 kb 2p13.1 loss that includes the gene and a maternally inherited missense variant p.Val10Met in the gene.
DISCUSSION
This case demonstrates that monoallelic hypomorphic variants may underly mild primary gastrointestinal symptoms, while biallelic mild variants can cause severe diseases. The Deletions of the noncoding exon can be an under-recognized cause of mild gastrointestinal symptoms unidentifiable by exome sequencing, explaining some instances of interfamilial variability with an apparent autosomal dominant inheritance. Genome sequencing is recommended as a genetic work-up for primary or idiopathic PIPO because of genetic heterogeneity.
PubMed: 37168481
DOI: 10.1097/PG9.0000000000000258 -
Pediatric Surgery International Apr 2023Interstitial cells of Cajal (ICCs) are pacemaker cells of gastrointestinal motility that generate and transmit electrical slow waves to smooth muscle cells in the gut... (Review)
Review
Interstitial cells of Cajal (ICCs) are pacemaker cells of gastrointestinal motility that generate and transmit electrical slow waves to smooth muscle cells in the gut wall, thus inducing phasic contractions and coordinated peristalsis. Traditionally, tyrosine-protein kinase Kit (c-kit), also known as CD117 or mast/stem cell growth factor receptor, has been used as the primary marker of ICCs in pathology specimens. More recently, the Ca-activated chloride channel, anoctamin-1, has been introduced as a more specific marker of ICCs. Over the years, various gastrointestinal motility disorders have been described in infants and young children in which symptoms of functional bowel obstruction arise from ICC-related neuromuscular dysfunction of the colon and rectum. The current article provides a comprehensive overview of the embryonic origin, distribution, and functions of ICCs, while also illustrating the absence or deficiency of ICCs in pediatric patients with Hirschsprung disease intestinal neuronal dysplasia, isolated hypoganglionosis, internal anal sphincter achalasia, and congenital smooth muscle cell disorders such as megacystis microcolon intestinal hypoperistalsis syndrome.
Topics: Infant; Child; Humans; Child, Preschool; Interstitial Cells of Cajal; Clinical Relevance; Hirschsprung Disease; Gastrointestinal Motility; Anal Canal; Proto-Oncogene Proteins c-kit
PubMed: 37101012
DOI: 10.1007/s00383-023-05467-1 -
Urology Jun 2023Uretero-inguinal hernia (UIH) is a rare condition in children. We present our experience with an unexpected UIH in a male infant with associated anomalies and a... (Review)
Review
Uretero-inguinal hernia (UIH) is a rare condition in children. We present our experience with an unexpected UIH in a male infant with associated anomalies and a literature review of pediatric cases. A full-term male newborn was referred to our hospital for microcolon and right hydroureteronephrosis. Voiding cystourethrography showed grade-IV right vesicoureteral reflux and a dilated, convoluted, ureter protruding in the right inguinal canal, suggesting a right UIH, which was uneventfully repaired at 2 months of life. UIH is a rare type of inguinal hernia in children that pediatric urologists and surgeons should be aware of. In experienced hands, and when preoperatively suspected, surgical management is safe and effective.
Topics: Infant; Infant, Newborn; Child; Humans; Male; Hernia, Inguinal; Ureter; Inguinal Canal; Vesico-Ureteral Reflux; Hydronephrosis
PubMed: 36841359
DOI: 10.1016/j.urology.2023.02.015 -
Annals of Clinical Biochemistry Mar 2023Purple Urine Bag Syndrome (PUBS) is a rare disorder seen in elderly persons, wherein the urinary bag and the tubing turn in to purple colour. It is usually seen in...
INTRODUCTION
Purple Urine Bag Syndrome (PUBS) is a rare disorder seen in elderly persons, wherein the urinary bag and the tubing turn in to purple colour. It is usually seen in patients who are on urinary catheters for a long time. It consists of a change in the colour of the urine that turns purple in a very specific context.
CASE REPORT
We report the case of a paediatric female patient with Berdon Syndrome with symptoms consistent with urinary tract infection and purple urine discolouration. Urine test revealed leukocyturia and bacteriuria.
DISCUSSION
Several risk factors have been proposed regarding this syndrome. Among them the commonest are female gender, advanced age, kind of diet (increased dietary tryptophan), alkaline urine and diverse situations that leads to urinary retentions which allows bacteria to work on their substrate for a longer time. Although it is a process that is not associated with gravity, recognizing it is important as treatment is simple and can minimize patient and family distress.
Topics: Humans; Female; Child; Aged; Male; Urinary Tract Infections; Intestinal Pseudo-Obstruction; Tryptophan
PubMed: 36645843
DOI: 10.1177/00045632231152565 -
Archives of Gynecology and Obstetrics Jan 2024To assess the spectrum of underlying pathologies, the intrauterine course and postnatal outcome of 46 fetuses with megacystis that underwent intrauterine vesico-amniotic...
OBJECTIVES
To 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.
METHODS
Retrospective 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.
RESULTS
46 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.
CONCLUSIONS
Our 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.
Topics: Pregnancy; Infant, Newborn; Infant; Humans; Male; Female; Retrospective Studies; Amnion; Ultrasonography, Prenatal; Fetus; Urethra
PubMed: 36604332
DOI: 10.1007/s00404-022-06905-6 -
Fetal and Pediatric Pathology Jun 2023We evaluated the obstetrical outcomes, ultrasonographic characteristics, and final diagnosis in pregnancies with fetal megacystis (FM). We evaluated the obstetrical...
We evaluated the obstetrical outcomes, ultrasonographic characteristics, and final diagnosis in pregnancies with fetal megacystis (FM). We evaluated the obstetrical outcomes and associated structural abnormalities of fetuses with FM detected between FM between 2000 and 2021. 17 FM were diagnosed, 16 had follow up. 16 were early megacystis. 14/16 (87.5%) of pregnancies were terminated, 1/16 (6.25%) resulted in intrauterine death, and 1/16 (6.25%) survived. FM was associated with 13 other abnormal sonographic findings in 12/16 (75%) pregnancies. The most common associated ultrasound abnormality was umbilical cord cyst in 3/16 (18.75%). Recognized etiologies included posterior urethral valves (2), trisomy 18 (2), trisomy 13 (1), Prune Belly syndrome (1), and Megacystis-Microcolon-Hypoperistalsis syndrome (1). Most FM are detected in the 2nd trimester, most are electively terminated, are associated with other ultrasonic abnormalities in 75%, most commonly umbilical cord cyst, and have an identifiable cause in 44%.
Topics: Pregnancy; Female; Humans; Ultrasonography, Prenatal; Fetal Diseases; Urinary Bladder; Cysts
PubMed: 36582017
DOI: 10.1080/15513815.2022.2158052 -
Pediatric and Developmental Pathology :... 2023Pathogenic mutations in the smooth muscle myosin heavy chain gene, , cause megacystis megacolon intestinal hypoperistalsis syndrome and other forms of chronic intestinal...
BACKGROUND
Pathogenic mutations in the smooth muscle myosin heavy chain gene, , cause megacystis megacolon intestinal hypoperistalsis syndrome and other forms of chronic intestinal pseudo-obstruction. Evaluation of intestinal tissues from affected patients is often performed before mutational analysis, but the pathological findings of -variant visceral myopathy have not been well defined.
METHODS
Light microscopic, immunohistochemical, and ultrastructural findings from multiple intestinal samples from 2 patients with MYH11-variant visceral myopathy were reviewed, including MYH11-specific immunohistochemistry. The findings were compared with intestinal samples from patients with gamma-smooth muscle actin ()-variant visceral myopathy and non-pseudo-obstruction controls.
RESULTS
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. 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.
CONCLUSIONS
Myopathic morphological or immunohistochemical changes may not be present in intestinal specimens from patients with -variant visceral myopathy. Molecular genetic studies should be considered for patients with chronic intestinal pseudo-obstruction and normal or non-specific pathology findings.
Topics: Female; Humans; Colon; Abnormalities, Multiple; Intestinal Pseudo-Obstruction; Mutation; Fetal Diseases; Actins; Myosin Heavy Chains
PubMed: 36571289
DOI: 10.1177/10935266221128133 -
Fetal Diagnosis and Therapy 2022Megacystis microcolon hypoperistalsis syndrome (MMIHS) is a rare condition with high morbidity and mortality. It is characterized by megacystis, microcolon, and...
INTRODUCTION
Megacystis microcolon hypoperistalsis syndrome (MMIHS) is a rare condition with high morbidity and mortality. It is characterized by megacystis, microcolon, and intestinal hypoperistalsis leading to various grades of bladder and bowel obstruction.
CASE PRESENTATION
This report describes a pregnant woman with a history of bowel obstruction, urine retention, and heavy postpartum bleeding where ultrasound findings of fetal megacystis during pregnancy led to genetic testing in the family. The fetus, the pregnant woman, and four female family members were heterozygous for a pathogenic variant detected in the ACTG2 gene. The fetus was treated successfully for hydronephrosis using vesicoamniotic shunting.
DISCUSSION
Early diagnosis of a fetus with MMIHS is important to secure multidisciplinary prenatal and neonatal treatment. Furthermore, gene testing must be considered when a woman presents a history of pseudo-obstruction and urine retention to prevent complications during pregnancy and labor. Finally, recurrent familial postpartum bleeding should lead to referral to genetic evaluation.
Topics: Infant, Newborn; Pregnancy; Humans; Female; Urinary Bladder; Abnormalities, Multiple; Intestinal Pseudo-Obstruction; Colon; Postpartum Period; Actins
PubMed: 36509086
DOI: 10.1159/000528625