Kidney function and transplants in prune belly syndrome: a scoping review.

BACKGROUND: Children with prune belly syndrome (PBS) are at higher risk of developing kidney dysfunction and requiring kidney replacement therapy (KRT). While studies have described surgical and survival outcomes in these populations, there has yet to be a focused synthesis of evidence regarding kidney outcomes in this population. Here, the focus of this scoping review was to highlight knowledge gaps and report standards on kidney outcomes in PBS of all ages. METHODS: Following scoping review methodology, EMBASE, MEDLINE, and Scopus were searched for peer-reviewed literature that describe kidney outcomes in PBS. All studies with a broad set of kidney outcomes (such as kidney function measures, chronic kidney disease (CKD), KRT and associated outcomes) were included. Findings were summarized and qualitatively synthesized. RESULTS: Of the 436 unique records identified, 25 were included for synthesis. A total of 17 studies (441 patients) reported on kidney insufficiency outcomes, with an estimated prevalence of CKD ranging from 8 to 66%. A total of 15 studies (314 patients) described KRT, primary kidney transplant, and outcomes. Of these, the age for KRT ranged from 4 to 21 years, and graft survival ranged from 22 to 87% by last follow-up (range 1.3-27 years). CONCLUSIONS: There is significant variability in studies reporting kidney outcomes in PBS which limits meaningful synthesis. There is a need for future studies with comprehensive reporting of confounders and drivers for kidney insufficiency in PBS.

Respiratory support in the absence of abdominal muscles: A case study of ventilatory management in prune belly syndrome.

Prune belly syndrome (PBS) results in a total lack of abdominal musculature. Abdominal muscles have an important function during inspiration and expiration. This puts the patient at risk for respiratory complications since they have a very limited ability to cough up secretions. Patients in an intensive care unit (ICU) with PBS who receive mechanical ventilation are at even greater risk for respiratory complications. We review the function of the abdominal muscles in breathing and delineate why they are important in the ICU. We include an illustrative case of a long-term ventilated patient with PBS and offer respiratory management options.

The role of intra-abdominal pressure in human testicular migration.

OBJECTIVES: This review aims to study the role of the abdominal wall in testicular migration process during the human fetal period. MATERIALS AND METHODS: We performed a descriptive review of the literature about the role of the abdominal wall in testicular migration during the human fetal period. RESULTS: The rise in intra-abdominal pressure is a supporting factor for testicular migration. This process has two phases: the abdominal and the inguinal-scrotal stages. The passage of the testis through the inguinal canal occurs very quickly between 21 and 25 WPC. Bilateral cryptorchidism in Prune Belly syndrome is explained by the impaired contraction of the muscles of the abdominal wall; mechanical obstruction due to bladder distention and structural alteration of the inguinal canal, which hampers the passage of the testis during the inguinoscrotal stage of testicular migration. Abdominal wall defects as gastroschisis and omphaloceles are associated with undescended testes in around 30 to 40% of the cases. CONCLUSIONS: Abdominal pressure wound is an auxiliary force in testicular migration. Patients with abdominal wall defects are associated with undescendend testis in more than 30% of the cases probably due to mechanical factors; the Prune Belly Syndrome has anatomical changes in the anterior abdominal wall that hinder the increase of intra-abdominal pressure which could be the cause of cryptorchidism in this syndrome.

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene.

BACKGROUND: Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. METHODS: We performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations. RESULTS: We identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin A (FLNA) (c.4952 C > T (p.A1448V), c.6727C > T (p.C2160R), c.5966 G > A (p.G2236E)) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19-21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor ß-integrin 1 (ITGß1). CONCLUSIONS: FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.

A potential serious complication in infants with congenital obstructive uropathy: Secondary pseudohypoaldosteronism.

Patients who have secondary pseudohypoaldosteronism (PHA) in addition to hyponatraemia, hyperpotassaemia and high serum aldosterone levels for the age were included in this retrospective study.Among eight patients, seven patients were diagnosed with PHA secondary to obstructive uropathy (OUP), whereas one patient had PHA secondary to ileostomy. Six patients with OUP had simultaneous urinary tract infection (UTI) and in all except one patient, secondary PHA recovered with only UTI treatment before applying surgical correction. All the patients were younger than 3 months age. In three patients with PUV diagnosis, salt wasting recurred in an UTI episode under 3 months of age.

Copy number variations in a population with prune belly syndrome.

Prune Belly Syndrome (PBS) is a congenital multisystem myopathy with mild to lethal severity. While of uncertain etiology, 95% male predominance and familial occurrence suggest a genetic basis. As copy number variations (CNVs) can cause unexplained genetic disorders, we tested for novel CNVs in a large PBS population. We genotyped 21 unrelated PBS patients by high-resolution array comparative genomic hybridization (aCGH) and phenotyped using a novel PBS severity scoring system. Available parents were screened for detected CNV via quantitative PCR (qPCR). We additionally screened for recurrence of identified novel candidate CNVs on 106 PBS probands by qPCR. We identified 10 CNVs in 8 of 21 PBS patients tested (38%). Testing confirmed inheritance from an unaffected biological parent in six patients; parental samples were unavailable in two probands. One candidate CNV includes duplication of the X-chromosome AGTR2 gene, known to function in urinary tract development. Subsequent screening of the larger PBS cohort did not identify any recurrent CNVs. Presence of CNV did not correlate with PBS severity scoring. CNVs were uncommon in this large PBS population, but analysis of identified variants may inform disease pathogenesis and reveal targets for therapeutic intervention for this rare, severe disorder.

Structural study of the bladder in fetuses with prune belly syndrome.

AIMS: To study the bladder structure of fetuses with prune belly syndrome (PBS). METHODS: We studied three bladders obtained from three male fetuses with PBS and seven bladders from seven male fetuses without anomalies. Each bladder was dissected and embedded in paraffin, from which 5 µm thick sections were obtained and stained with Masson's trichrome (to quantify connective tissue and smooth muscle) and picrosirius red with polarization (to observe collagen). Immunohistochemistry with tubulin (Tubulin, beta III, Mouse Monoclonal Antibody) was applied to observe the bladder nerves. The images were captured with an Olympus BX51 microscope and Olympus DP70 camera. The stereological analysis was done with the Image Pro and Image J programs, using a grid to determine volumetric densities (Vv). Means were statistically compared using the Mann-Whitney test (P < 0.05). RESULTS: Quantitative analysis documented that smooth muscle fibers were significantly smaller (P = 0.04) in PBS fetuses (9.67% to 17.75%, mean = 13.2%) compared to control group (13.33% to 26.56%, mean = 17.43%). The analysis of collagen fibers showed predominance of green in the control group, suggesting collagen type III presence, and predominance of red in the in PBS fetal bladders, suggesting collagen type I presence in this group. The qualitative analysis of the nerves with immunohistochemistry with tubulin showed predominance of nerves in the control group. CONCLUSION: The bladder in PBS had lower concentrations of smooth muscle fibers, collagen type III, and nerves. These structural alterations can be one of the factors involved in urinary tract abnormality such as distended bladder in patients with PBS.

Outcomes of renal replacement therapy in boys with prune belly syndrome: findings from the ESPN/ERA-EDTA Registry.

BACKGROUND: As outcome data for prune belly syndrome (PBS) complicated by end-stage renal disease are scarce, we analyzed characteristics and outcomes of children with PBS using the European Society for Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry data. METHODS: Data were available for 88 male PBS patients aged <20 years who started renal replacement therapy (RRT) between 1990 and 2013 in 35 European countries. Patient characteristics, survival, and transplantation outcomes were compared with those of male patients requiring RRT due to congenital obstructive uropathy (COU) and renal hypoplasia or dysplasia (RHD). RESULTS: Median age at onset of RRT in PBS was lower [7.0; interquartile range (IQR) 0.9-12.2 years] than in COU (9.6; IQR: 3.0-14.1 years) and RHD (9.4; IQR: 2.7-14.2 years). Unadjusted 10-year patient survival was 85% for PBS, 94% for COU, and 91% for RHD. After adjustment for country, period, and age, PBS mortality was similar to that of RHD but higher compared with COU [hazard ratio (HR) 1.96, 95% confidence interval (CI) 1.03-3.74]. Seventy-four PBS patients (84%) received a first kidney transplant after a median time on dialysis of 8.4 (IQR 0.0-21.1) months. Outcomes with respect to time on dialysis before transplantation, chance of receiving a first transplant within 2 years after commencing RRT, and death-censored, adjusted risk of graft loss were similar for all groups. CONCLUSIONS: This study in the largest cohort of male patients with PBS receiving RRT to date demonstrates that outcomes are comparable with other congenital anomalies of the kidney and urinary tract, except for a slightly higher mortality risk compared with patients with COU.

Pseudo Prune Belly Syndrome: Diagnosis Revealed by Imaging - A Case Report and Brief Review.

BACKGROUND: Prune Belly Syndrome (PBS) is a rare entity, usually found in male neonates. It comprises complex urinary tract anomalies, bilateral undescended testis and absence of anterior abdominal wall muscles. Patients with unilateral abdominal wall deficiency, unilateral undescended testis and female neonates with abdominal wall laxity are classified as Pseudo Prune Belly syndrome (PPBS). Reports on PPBS do not highlight the radiological and imaging characteristics of this syndrome and the current literature on the role of newer imaging modalities, such as Magnetic Resonance Imaging (MRI), remains relatively sparse. We describe a new case of PPBS and emphasize the role of imaging, especially ultrasound and MRI in the process of diagnosis and briefly review the subject. CASE REPORT: A male infant of four months of age was referred for evaluation of left-sided cryptorchidism. Clinical examination revealed laxity of the left abdominal wall. Ultrasound examination of the abdomen, pelvis and scrotum was performed together with routine laboratory tests. Ultrasound examination was followed by intravenous urography, voiding cysto-urethrography and MRI of the abdomen. On ultrasound, the left testis was located in the inguinal canal, the right kidney was slightly enlarged and the left kidney could not be localized. Ultrasound appearances suggested chronic obstruction in the urinary bladder. Intravenous urography, voiding cysto-urethrography and MRI confirmed the ultrasound diagnosis and also revealed a left dysplastic kidney with a dilated, tortuous ureter. Clinical and imaging features were consistent with pseudo prune belly syndrome (PPBS). CONCLUSIONS: We report a new occurrence of PPBS, a rare entity. The imaging approach for a comprehensive evaluation of the renal system in PPBS, especially with MRI, is emphasized.

Genetics of Vesicoureteral Reflux.

Vesicoureteral reflux (VUR) is the retrograde passage of urine from the bladder to the upper urinary tract. It is the most common congenital urological anomaly affecting 1-2% of children and 30-40% of patients with urinary tract infections. VUR is a major risk factor for pyelonephritic scarring and chronic renal failure in children. It is the result of a shortened intravesical ureter with an enlarged or malpositioned ureteric orifice. An ectopic embryonal ureteric budding development is implicated in the pathogenesis of VUR, which is a complex genetic developmental disorder. Many genes are involved in the ureteric budding formation and subsequently in the urinary tract and kidney development. Previous studies demonstrate an heterogeneous genetic pattern of VUR. In fact no single major locus or gene for primary VUR has been identified. It is likely that different forms of VUR with different genetic determinantes are present. Moreover genetic studies of syndromes with associated VUR have revealed several possible candidate genes involved in the pathogenesis of VUR and related urinary tract malformations. Mutations in genes essential for urinary tract morphogenesis are linked to numerous congenital syndromes, and in most of those VUR is a feature. The Authors provide an overview of the developmental processes leading to the VUR. The different genes and signaling pathways controlling the embryonal urinary tract development are analyzed. A better understanding of VUR genetic bases could improve the management of this condition in children.

Structural study of gubernaculum testis in fetuses with prune belly syndrome.

PURPOSE: We compared and contrasted the structure of the gubernaculum testis in fetuses with prune belly syndrome and normal controls. MATERIALS AND METHODS: We studied a total of 6 gubernacula from 3 male fetuses with prune belly syndrome and a total of 14 from 7 male fetuses without an anomaly. Gubernacular specimens were cut into 5 µm sections and stained with Masson trichrome to quantify connective tissue and smooth muscle cells, with Weigert stain to observe elastic fibers and with picrosirius red with polarization to observe collagen. Immunohistochemical analysis was done with tubulin to observe the nerves. Images were captured with a BX51 microscope and DP70 camera (Olympus®). Stereological analysis was done with Image-Pro and ImageJ (MediaCybernetics®) using a grid to determine volumetric density. Means were statistically compared with the Mann-Whitney test. All tests were 2-sided with p <0.05 considered statistically significant. RESULTS: Prune belly syndrome fetuses were at 17 to 31 weeks of gestation and control fetuses were at 12 to 35 weeks of gestation. Quantitative analysis showed no difference in the volumetric density of smooth muscle cells in prune belly syndrome vs control gubernacula (mean 15.70% vs 19%, p = 0.2321). Collagen fiber analysis revealed a predominance of green areas in prune belly syndrome gubernacula, suggesting collagen type III, and a predominance of red areas in control gubernacula, suggesting collagen type I. Elastic fibers were significantly smaller in prune belly syndrome gubernacula than in control gubernacula (mean 14.06% vs 24.6%, p = 0.0190). Quantitative analysis demonstrated no difference in the volumetric density of nerves in prune belly syndrome or control gubernacula (mean 5.200% vs 3.158%, p = 0.2302). CONCLUSIONS: The gubernaculum in fetuses with prune belly syndrome had altered concentrations of collagen and elastic fibers. These structural alterations could be one of the factors involved in cryptorchidism in prune belly syndrome.

Pulmonary complications of abdominal wall defects.

The abdominal wall is an integral component of the chest wall. Defects in the ventral abdominal wall alter respiratory mechanics and can impair diaphragm function. Congenital abdominal wall defects also are associated with abnormalities in lung growth and development that lead to pulmonary hypoplasia, pulmonary hypertension, and alterations in thoracic cage formation. Although infants with ventral abdominal wall defects can experience life-threatening pulmonary complications, older children typically experience a more benign respiratory course. Studies of lung and chest wall function in older children and adolescents with congenital abdominal wall defects are few; such investigations could provide strategies for improved respiratory performance, avoidance of respiratory morbidity, and enhanced exercise ability for these children.

Fertility prospects for the prune-belly patient: A scoping review.

INTRODUCTION: With advances in medical care and assisted reproductive technologies (ART), fertility prospects for prune-belly syndrome (PBS) men may be changing. This review aims to identify the factors influencing fertility and optimization of reproductive health for PBS patients. MATERIAL AND METHODS: A scoping review was performed on all records published over 70 years (1952-2022) analyzing fertility in PBS males. Records were summarized in a table and narrative describing cryptorchidism, orchiopexy, testicle histology; prostate characteristics; sex hormone function; semen analyses, ART, and conception ability. This review was registered on Open Science Framework (OSF) and conducted using PRISMA methodology. RESULTS: 827 articles were identified and 83 were selected for data extraction. Before 2000, there were 0.85 publications/year whereas after 2000 there were 1.95 publications/year. Orchiopexy successfully relocated 86 % of PBS testicles into the scrotum. Testicular histology demonstrated 50 % of patients had no spermatogonia, while 47.2 % and 2.7 % had reduced or normal numbers respectively. Leydig hyperplasia and Sertoli only histology were found in 19.4 % of patients. Prostatic hypoplasia and prostatic urethral dilation were found in 93.6 % and 91.4 % of patients respectively. Testosterone, Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH) were normal in 93.9 %, 87.7 % and 77.9 % of patients respectively. Azoospermia and oligospermia was found in 75.7 % and 21.6 % of patients respectively while 60.7 % had antegrade ejaculation. ART successfully extracted sperm in 6 instances and resulted in 4 conceptions, while natural conception was reported twice. CONCLUSIONS: Data analysis indicates increased attention to fertility prospects for PBS males with evaluation of PBS patient's hormonal function, semen analyses, ART, and conception ability. The reviewed data suggest that PBS males may father biological offspring with contemporary management and also demonstrate the need for consistent reproductive management approaches to maximize their fertility prospects.

Prune belly syndrome: A rare case report.

Key Clinical Message: In babies presenting with an omphalocele, other components of the prune belly syndrome should be scrutinized for early diagnosis and timely intervention. Abstract: A male baby on his 13th day of life presented with an omphalocele. On evaluation, he had congenital absence of left kidney and bilateral cryptorchidism. Therefore, he was diagnosed with prune belly syndrome. He responded well to abdminoplasty, and wait and watch policy was applied for his cryptorchidism.

Novel minimally invasive abdominoplasty for selected cases of prune belly syndrome: Step-by-step technique description and clinical indications.

BACKGROUND: Prune belly syndrome (PBS) is characterized by the triad of abdominal flaccidity, bilateral undescended testicles and genitourinary tract anomalies. A variable spectrum of abdominal wall laxity is observed in PBS. We present the first case of a novel technique using a minimally invasive abdominoplasty to specifically address patients with localized abdominal wall weakness in PBS. CASE PRESENTATION: A two-years-old child with PBS presented with recurrent febrile urinary tract infections. Ultrasonography demonstrated a dysplastic right kidney associated with significant ipsilateral ureterohydronephrosis. Voiding urethrocystogram did not show vesicoureteral reflux and DMSA scan depicted a non-functioning right kidney. During laparoscopic right nephroureterectomy and first stage Fowler-Stephens bilateral orchiopexies, a significant right-sided lateral abdominal wall bulging was observed. A minimally invasive laparoscopic abdominoplasty was performed with a one-way running suture using an unabsorbable 2.0 prolene approximating the edges of the musculofascial defect. While undergoing the second-stage Fowler-Stephens orchiopexy, no bulging was observed. CONCLUSION: A minimally invasive abdominoplasty to improve abdominal wall lateral bulging in PBS was feasible and presented good cosmetic result. We anticipate that this technique can be applied for children with PBS with primary lateral abdominal wall bulging, employing one or more suture lines depending on the fascial defect size.

Prune-Belly Syndrome: An Update.

The Prune-Belly (Eagle-Barrett) syndrome (PBS) is a congenital and genetically heterogeneous disease, more prevalent in males, defined by the clinical triad (1) deficiency of abdominal muscles, (2) bilateral cryptorchidism, and (3) urinary tract abnormalities. The abdomen of an infant with PBS has a typical appearance, similar to the aspect of a prune, which gives it its name. Although the etiology of this disorder is still unknown, numerous theories, mutations, and genetic disturbances have been proposed to explain the origin of PBS. Prognosis can differ a lot from one patient to another, since this condition has a wide spectrum of clinical presentation. Despite being a rare condition, the importance of PBS should not be underestimated, in the light of the potential of the disorder to lead to chronic kidney disease and other severe complications. In that regard, this review gathers the most up-to-date knowledge about the etiopathogenesis, clinical features, diagnosis, management and prognosis of PBS.

Contemporary epidemiological trends in complex congenital genitourinary anomalies.

PURPOSE: Anecdotal evidence suggests that complex congenital genitourinary anomalies are occurring less frequently. However, few epidemiological studies are available to confirm or refute this suggestion. MATERIALS AND METHODS: The Kids' Inpatient Database (KID) is a national, all payer database of several million inpatient pediatric hospitalizations per year, including complicated and uncomplicated in-hospital births. We reviewed the 1997 to 2009 KID to determine the birth prevalence of spina bifida, posterior urethral valves, bladder exstrophy, epispadias, prune belly syndrome, ambiguous genitalia and imperforate anus. For posterior urethral valves and prune belly syndrome we limited our search to newborn males only. RESULTS: During the study period, there was a diagnosis of spina bifida in 3,413 neonates, bladder exstrophy in 214, epispadias in 1,127, ambiguous genitalia in 726, prune belly syndrome in 180, posterior urethral valves in 578 and imperforate anus in 4,040. We identified no significant change in the birth prevalence of spina bifida (from 33.9 new spina bifida births of 100,000 uncomplicated births to 29.0/100,000, p = 0.08), posterior urethral valves (from 10.4/100,000 to 11.0/100,000, p = 0.51), prune belly syndrome (from 4.8/100,000 to 3.3/100,000, p = 0.44) or ambiguous genitalia (from 5.82/100,000 to 5.87/100,000, p = 0.38). There was a significant decrease in the birth prevalence of bladder exstrophy (from 2.4/100,000 to 1.6/100,000 uncomplicated births, p = 0.01) and a significant increase in epispadias (from 8.0/100,000 to 11.6/100,000) and imperforate anus (from 33.6/100,000 to 35.0/100,000, each p = 0.04) during the study period. CONCLUSIONS: The birth prevalence of spina bifida, posterior urethral valves and prune belly syndrome appears to have been stable in the last 12 years. Epispadias, ambiguous genitalia and imperforate anus diagnoses in newborns became more common in the same period, while bladder exstrophy diagnoses became less common.

Prune belly syndrome with congenital pouch colon.

We report a rare case of prune belly syndrome associated with congenital pouch colon, which was managed successfully.

Simultaneous second-stage Fowler-Stephens Orchiopexy and microvascular testicular autotransplantation in a patient with prune belly syndrome with cryptorchidism.

We present a case of simultaneous second-stage Fowler-Stephens Orchiopexy (FSO) with microvascular testicular autotransplantation for cryptorchidism and in a patient with prune belly syndrome. At 5 months old, the patient underwent laparoscopic bilateral first-stage FSO with the right testicle located 1 cm from the liver and the left slightly more caudal. An ultrasound on postoperative Day 72 following second-stage FSO and microvascular autotransplantation showed patent testicular vasculature. Our experience shows that this combination technique is safe and effective to supercharge the testicle and augment collateral vessels if clinical suspicion for monotherapy failure is high.

Use of whole genome sequencing to determine the genetic basis of visceral myopathies including Prune Belly syndrome.

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 ACTG2, ACTA2, MYH11, MYLK, LMOD1, CHRM3, MYL9, FLNA and KNCMA1 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 ACTG2 variants, 7 had likely pathogenic variants including 1 novel likely pathogenic allele. There were 4 patients in whom we identified a heterozygous MYH11 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 KCNMA1 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, ACTG2 is the largest monogenic cause of VM-related disease accounting for 9% of the cohort, supported by a variant burden test approach, which identified ACTG2 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 ACTG2 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 ACTG2 and associated VM phenotypes. Supplementary Information: The online version contains supplementary material available at 10.1007/s44162-023-00012-z.