Epidemiologic analysis of families with isolated anorectal malformations suggests high prevalence of autosomal dominant inheritance

Background: Anorectal malformations (ARM) are rare abnormalities that occur in approximately 1 in 3000 live births with around 40% of patients presenting with isolated forms. Multiple familial cases reported, suggest underlying genetic factors that remain largely unknown. The recurrence in relatives is considered rare, however transmission rates of ARM by affected parents have never been determined before. The inheritance pattern of ARM was investigated in our database of patients with isolated ARM. Results: Within our cohort of 327 patients with isolated ARM we identified eight adult patients from eight families who had in total 16 children with their healthy spouse. Of these ten had ARM, resulting in a recurrence risk of approximately one in two live births (10 of 16; 62%). From 226 families with 459 siblings we found two affected siblings in five families. Hence, the recurrence risk of ARM among siblings is approximately one in 92 live births (5 of 459; 1.0%). Conclusions: Comparing the observed recurrence risk in our cohort with the prevalence in the general population, we see a 1500-fold increase in recurrence risk for offspring and a 32-fold increase if a sibling is affected. The recurrence risk of approximately 62% indicates an autosomal dominant mode of inheritance. Reliable figures on recurrence of ARM are becoming increasingly important since improved surgical techniques are able to maintain sexual function resulting in more offspring of patients with ARM. These data allow more precise counseling of families with ARM and support the need for genetic studies

Treatment Strategies and Outcome of the Exstrophy–Epispadias Complex in Germany: Data From the German CURE-Net

Introduction: To evaluate the impact of reconstructive strategies and post-operative management on short- and long-term surgical outcome and complications of classical bladder exstrophy (CBE) patients' comprehensive data of the multicenter German-wide Network for Congenital Uro-Rectal malformations (CURE-Net) were analyzed. Methods: Descriptive analyses were performed between 34 prospectively collected CBE patients born since 2009, median 3 months old [interquartile range (IQR), 2–4 months], and 113 cross-sectional patients, median 12 years old (IQR, 6–21 years). Results: The majority of included individuals were males (67%). Sixty-eight percent of the prospectively observed and 53% of the cross-sectional patients were reconstructed using a staged approach (p = 0.17). Although prospectively observed patients were operated on at a younger age, the post-operative management did not significantly change in the years before and after 2009. Solely, in prospectively observed patients, peridural catheters were used significantly more often (p = 0.017). Blood transfusions were significantly more frequent in males (p = 0.002). Only half of all CBE individuals underwent inguinal hernia repair. Cross-sectional patients after single-stage reconstructions showed more direct post-operative complications such as upper urinary tract dilatations (p = 0.0021) or urinary tract infections (p = 0.023), but not more frequent renal function impairment compared to patients after the staged approach (p = 0.42). Continence outcomes were not significantly different between the concepts (p = 0.51). Self-reported continence data showed that the majority of the included CBE patients was intermittent or continuous incontinent. Furthermore, subsequent consecutive augmentations and catheterizable stomata did not significantly differ between the two operative approaches. Urinary diversions were only reported after the staged concept. Conclusions: In this German multicenter study, a trend toward the staged concept was observed. While single-stage approaches tended to have initially more complications such as renal dilatation or urinary tract infections, additional surgery such as augmentations and stomata appeared to be similar after staged and single-stage reconstructions in the long term

Bowel function and associated risk factors at preschool and early childhood age in children with anorectal malformation type rectovestibular fistula:An ARM-Net consortium study

Background: Outcome of patients operated for anorectal malformation (ARM) type rectovestibular fistula (RVF) is generally considered to be good. However, large multi-center studies are scarce, mostly describing pooled outcome of different ARM-types, in adult patients. Therefore, counseling parents concerning the bowel function at early age is challenging. Aim of this study was to evaluate bowel function of RVF-patients at preschool/early childhood age and determine risk factors for poor functional outcome. Methods: A multi-center cohort study was performed. Patient characteristics, associated anomalies, sacral ratio, surgical procedures, post-reconstructive complications, one-year constipation, and Bowel Function Score (BFS) at 4–7 years of follow-up were registered. Groups with below normal (BFS < 17; subgroups ‘poor’ ≤ 11, and ‘fair’ 11 < BFS < 17) and good outcome (BFS ≥ 17) were formed. Univariable analyses were performed to detect risk factors for outcome. Results: The study included 111 RVF-patients. Median BFS was 16 (range 6–20). The ‘below normal’ group consisted of 61 patients (55.0%). Overall, we reported soiling, fecal accidents, and constipation in 64.9%, 35.1% and 70.3%, respectively. Bowel management was performed in 23.4% of patients. Risk factors for poor outcome were tethered cord and low sacral ratio, while sacral anomalies, low sacral ratio, prior enterostomy, post-reconstructive complications, and one-year constipation were for being on bowel management. Conclusions: Although median BFS at 4–7 year follow-up is nearly normal, the majority of patients suffers from some degree of soiling and constipation, and almost 25% needs bowel management. Several factors were associated with poor bowel function outcome and bowel management. Level of Evidence: Level III

Research perspectives in the etiology of congenital anorectal malformations using data of the International Consortium on Anorectal Malformations: evidence for risk factors across different populations

Contains fulltext : 89406.pdf (publisher's version ) (Closed access)PURPOSE: The recently established International Consortium on Anorectal Malformations aims to identify genetic and environmental risk factors in the etiology of syndromic and nonsyndromic anorectal malformations (ARM) by promoting collaboration through data sharing and combined research activities. METHODS: The consortium attempts to recruit at least 1,000 ARM cases. DNA samples are collected from case-parent triads to identify genetic factors involved in ARM. Several genetic techniques will be applied, including SNP arrays, gene and whole exome sequencing, and a genome-wide association study. Questionnaires inquiring about circumstances before and during pregnancy will be used to obtain environmental risk factor data. RESULTS: Currently, 701 ARM cases have been recruited throughout Europe. Clinical data are available from all cases, and DNA samples and questionnaire data mainly from the Dutch and German cases. Preliminary analyses on environmental risk factors in the Dutch and German cohort found associations between ARM and family history of ARM, fever during first trimester of pregnancy and maternal job exposure to cleaning agents and solvents. CONCLUSION: First results show that both genetic and environmental factors may contribute to the multifactorial etiology of ARM. The International Consortium on Anorectal Malformations will provide possibilities to study and detect important genes and environmental risk factors for ARM, ultimately resulting in better genetic counseling, improved therapies, and primary prevention.1 november 201

Whole exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum-stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle’s loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or CAKUT in VACTERL association

Clinical Differentiation between a Normal Anus, Anterior Anus, Congenital Anal Stenosis, and Perineal Fistula: Definitions and Consequences—The ARM-Net Consortium Consensus

In the past, an anteriorly located anus was often misdiagnosed and treated as an anorectal malformation (ARM) with a perineal fistula (PF). The paper aims to define the criteria for a normal anus, an anterior anus (AA) as an anatomic variant, and milder types of ARM such as congenital anal stenosis (CAS) and PF. An extensive literature search was performed by a working group of the ARM-Net Consortium concerning the subject “Normal Anus, AA, and mild ARM”. A consensus on definitions, clinical characteristics, diagnostic management, and treatment modalities was estab-lished, and a diagnostic algorithm was proposed. The algorithm enables pediatricians, midwives, gynecologists, and surgeons to make a timely correct diagnosis of any abnormally looking anus and initiate further management if needed. Thus, the routine physical inspection of a newborn should include the inspection of the anus and define its position, relation to the external sphincter, and caliber. A correct diagnosis and use of the presented terminology will avoid misclassifications and allow the initiation of correct management. This will provide a reliable comparison of different therapeutic management and outcomes of these patient cohorts in the future

Perineal Groove : An Anorectal Malformation Network, Consortium Study

Objective: To review the Anorectal Malformation Network experience with perineal groove (PG) focusing on its clinical characteristics and management. Study design: Data on patients with PG managed at 10 participating Anorectal Malformation Network centers in 1999-2019 were collected retrospectively by questionnaire. Results: The cohort included 66 patients (65 females) of median age 1.4 months at diagnosis. The leading referral diagnosis was anal fissure (n = 20 [30.3%]): 23 patients (34.8%) had anorectal malformations. Expectant management was practiced in 47 patients (71.2%). Eight (17%) were eventually operated for local complications. The median time to surgery was 14 months (range, 3.0-48.6 months), and the median age at surgery was 18.3 months (range, 4.8-58.0 months). In the 35 patients available for follow-up of the remaining 39 managed expectantly, 23 (65.7%) showed complete or near-complete self-epithelization by a mean age 15.3 months (range, 1-72 months) and 4 (11.4%) showed partial self-epithelization by a mean age 21 months (range, 3-48 months). Eight patients showed no resolution (5 were followed for ≤3 months). Nineteen patients (28.7%) were primarily treated with surgery. In total, 27 patients were operated. Dehiscence occurred in 3 of 27 operated patients (11.1%). Conclusions: PG seems to be an underestimated anomaly, frequently associated with anorectal malformations. Most cases heal spontaneously; therefore, expectant management is recommended. When associated with anorectal malformations requiring reconstruction, PG should be excised in conjunction with the anorectoplasty

HSPA6: A new autosomal recessive candidate gene for the VATER/VACTERL malformation spectrum

Background The VATER/VACTERL association refers to the nonrandom co-occurrence of at least three of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Patients presenting with two CFs have been termed VATER/VACTERL-like phenotypes. Methods We surveyed the exome for recessive disease variants in three affected sib-pairs. Sib-pair 971 consisted of two brothers with ARM and additional hydronephrosis in one brother. Sib-pair 1098 consisted of two sisters with ARM. In family 1346, the daughter presented with ARM and additional hypoplasia of both small fingers and ankyloses. Her brother presented with unilateral isolated radial hypoplasia. Sib-pairs 971 and 1346 resembled a VATER/VACTERL-like phenotype. Results We detected a novel maternally inherited missense variant (c.1340G > T) and a rare paternally inherited deletion of the trans-allele in HSPA6 in both siblings of family 1346. HSPA6 belongs to the heat shock protein (HSP) 70 family. Re-sequencing of HSPA6 in 167 patients with VATER/VACTERL and VATER/VACTERL-like phenotypes did not reveal any additional bi-allelic variants. Conclusions Until now, only TNF-receptor associated protein 1 (TRAP1) had been reported as an autosomal recessive disease-gene for the VATER/VACTERL association. TRAP1 belongs to the heat shock protein 90 family (HSP90). Both Hsp70 and Hsp90 genes have been shown to be important embryonic drivers in the formation of mouse embryonic forelimb tissue. Our results suggest HSPA6 as a new candidate gene in VATER/VACTERL-like phenotypes