Exome Survey and Candidate Gene Re-Sequencing Identifies Novel Exstrophy Candidate Genes and Implicates LZTR1 in Disease Formation.

BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) is a spectrum of congenital abnormalities that involves the abdominal wall, the bony pelvis, the urinary tract, the external genitalia, and, in severe cases, the gastrointestinal tract as well. METHODS: Herein, we performed an exome analysis of case-parent trios with cloacal exstrophy (CE), the most severe form of the BEEC. Furthermore, we surveyed the exome of a sib-pair presenting with classic bladder exstrophy (CBE) and epispadias (E) only. Moreover, we performed large-scale re-sequencing of CBE individuals for novel candidate genes that were derived from the current exome analysis, as well as for previously reported candidate genes within the CBE phenocritical region, 22q11.2. RESULTS: The exome survey in the CE case-parent trios identified two candidate genes harboring de novo variants (NR1H2, GKAP1), four candidate genes with autosomal-recessive biallelic variants (AKR1B10, CLSTN3, NDST4, PLEKHB1) and one candidate gene with suggestive uniparental disomy (SVEP1). However, re-sequencing did not identify any additional variant carriers in these candidate genes. Analysis of the affected sib-pair revealed no candidate gene. Re-sequencing of the genes within the 22q11.2 CBE phenocritical region identified two highly conserved frameshift variants that led to early termination in two independent CBE males, in LZTR1 (c.978_985del, p.Ser327fster6) and in SLC7A4 (c.1087delC, p.Arg363fster68). CONCLUSIONS: According to previous studies, our study further implicates LZTR1 in CBE formation. Exome analysis-derived candidate genes from CE individuals may not represent a frequent indicator for other BEEC phenotypes and warrant molecular analysis before their involvement in disease formation can be assumed.

Genome-wide identification of disease-causing copy number variations in 450 individuals with anorectal malformations.

Anorectal malformations (ARM) represent a spectrum of rare malformations originating from a perturbated development of the embryonic hindgut. Approximately 60% occur as a part of a defined genetic syndrome or within the spectrum of additional congenital anomalies. Rare copy number variations (CNVs) have been associated with both syndromic and non-syndromic forms. The present study represents the largest study to date to explore the contribution of CNVs to the expression of ARMs. SNP-array-based molecular karyotyping was applied in 450 individuals with ARM and 4392 healthy controls. CNVs were identified from raw intensity data using PennCNV. Overlapping CNVs between cases and controls were discarded. Remaining CNVs were filtered using a stringent filter algorithm of nine filter steps. Prioritized CNVs were confirmed using qPCR. Filtering prioritized and qPCR confirmed four microscopic chromosomal anomalies and nine submicroscopic CNVs comprising seven microdeletions (del2p13.2, del4p16.2, del7q31.33, del9p24.1, del16q12.1, del18q32, del22q11.21) and two microduplications (dup2p13.2, dup17q12) in 14 individuals (12 singletons and one affected sib-pair). Within these CNVs, based on their embryonic expression data and function, we suggest FOXK2, LPP, and SALL3 as putative candidate genes. Overall, our CNV analysis identified putative microscopic and submicroscopic chromosomal rearrangements in 3% of cases. Functional characterization and re-sequencing of suggested candidate genes is warranted.

First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B.

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10-8; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10-10; OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10-16; OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.

A Prevalence Estimation of Exstrophy and Epispadias in Germany From Public Health Insurance Data.

Introduction: The prevalence of rare diseases is very important for health care research. According to the European Surveillance of Congenital Anomalies (EUROCAT) registers, the live prevalence for exstrophy and/or epispadias (grades 1-3) is reported with 1:23,255 (95% CI: 1:26,316; 1:20,000). A Europe-wide prevalence evaluation based on reports from excellence centers estimates a prevalence for exstrophies of 1:32,200 and for isolated epispadias of 1:96,800 in 2010. However, the frequency of exstrophy [International Statistical Classification of Diseases and Related Health Problems revision 10 (ICD-10): Q64.1] and epispadias (ICD-10: Q64.0) treated in different age groups in Germany remains unclear. Material and Method: Public health insurance data from 71 million people (approximately 87% of the population) were provided by the German Institute for Medical Documentation and Information (DIMDI) in accordance to the German Social Insurance Code for this research purpose. DIMDI analyzed the data source for the ICD diagnoses exstrophy and epispadias between 2009 and 2011. As provided data were robust over the years, averaged data are mentioned. Detailed subgroup analysis of small numbers was forbidden due to privacy protection. Results: Annually, 126 persons of all ages with epispadias and 244 with exstrophy are treated as inpatients. In the observed population, 34 infants (<1 year of age) with epispadias and 19 with exstrophy (58% male) are treated as outpatients each year. This corresponds to an estimated live prevalence of 1:11,000 (95% CI: 1:14,700; 1:8,400) for EEC (exstrophy-epispadias complex), more specifically a prevalence of 1:17,142 for epispadias and of 1:30,675 for exstrophy. The male-to-female ratio for exstrophy is 1.4:1 for infants and 1.6:1 for all minors. In children and adolescents, 349 epispadias and 393 exstrophies (up to the age of 17) are treated annually, whereas adults with exstrophy and even more with epispadias make comparatively less use of medical care. Conclusion: With the help of DIMDI data, the live prevalence of bladder exstrophy and epispadias in Germany could be estimated. The prevalence of epispadias was higher than in previous reports, in which milder epispadias phenotypes (grade 1 or 2) may not have been included. These analyses might enlighten knowledge about nationwide incidence and treatment numbers of rare diseases such as the EEC.

Parental risk factors for congenital diaphragmatic hernia - a large German case-control study.

BACKGROUND: Evidence for periconceptional or prenatal environmental risk factors for the development of congenital diaphragmatic hernia (CDH) is still scarce. Here, in a case-control study we investigated potential environmental risk factors in 199 CDH patients compared to 597 healthy control newborns. METHODS: The following data was collected: time of conception and birth, maternal BMI, parental risk factors such as smoking, alcohol or drug intake, use of hairspray, contact to animals and parental chronic diseases. CDH patients were born between 2001 and 2019, all healthy control newborns were born in 2011. Patients and control newborns were matched in the ratio of three to one. RESULTS: Presence of CDH was significantly associated with maternal periconceptional alcohol intake (odds ratio = 1.639, 95% confidence interval 1.101-2.440, p = 0.015) and maternal periconceptional use of hairspray (odds ratio = 2.072, 95% confidence interval 1.330-3.229, p = 0.001). CONCLUSION: Our study suggests an association between CDH and periconceptional maternal alcohol intake and periconceptional maternal use of hairspray. Besides the identification of novel and confirmation of previously described parental risk factors, our study underlines the multifactorial background of isolated CDH.

SLC20A1 Is Involved in Urinary Tract and Urorectal Development.

Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.

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.

Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia.

INTRODUCTION: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. METHODS: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. RESULTS: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. CONCLUSION: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.

Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations.

INTRODUCTION: Anorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, assuming a multifactorial model. METHODS: We analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina HumanExome Beadchip array, which contains >240,000 rare and low-frequency coding variants. GenomeStudio clustering and calling was followed by re-calling of 'no-calls' using zCall for patients and controls simultaneously. Single variant and gene-based analyses were performed to identify statistically significant associations, applying Bonferroni correction. Following an extra quality control step, candidate variants were selected for validation using Sanger sequencing. RESULTS: When we applied a MAF of ≥1.0%, no variants or genes showed statistically significant associations with ARM. Using a MAF cut-off at 0.4%, 13 variants initially reached statistical significance, but had to be discarded upon further inspection: ten variants represented calling errors of the software, while the minor alleles of the remaining three variants were not confirmed by Sanger sequencing. CONCLUSION: Our results show that rare and low-frequency coding variants with large effect sizes, present on the exome chip do not contribute to ARM etiology.

Association Between Exstrophy-epispadias Complex And Congenital Anomalies: A German Multicenter Study.

OBJECTIVE: To further investigate associated anomalies in exstrophy-epispadias complex (EEC) patients congenital uro-rectal malformations network (CURE-Net) database was systematically screened. In literature the EEC comprises a spectrum of anomalies, mainly occurring "isolated" without additional congenital defects. Nevertheless, previous epidemiological studies indicated a higher association with renal, anorectal, and lower neurotubular anomalies, which may originate from the same developmental morphogenetic fields. MATERIALS AND METHODS: Seventy-three prospectively (born since 2009) and 162 cross-sectional recruited EEC patients (born 1948-2008) were analyzed. Associated anomalies were derived from patient's medical data as well as from a physical examination during a physician's interview, classified according to the international statistical classification of diseases and related health problems and grouped with the London Dysmorphology Database. Descriptive statistical analyses were performed. RESULTS: Majority of participants were male (68%) and expressed the classical bladder exstrophy phenotype (71%). Exstrophy variants occurred significantly more often in newborns (21%, P < .0001). Anomalies such as inguinal hernias, skeleton, and joint anomalies were equally present in both groups (P = .65 and P = .67). Heart defects were seen more often in newborns (6%) than in the cross-sectional group (1%; P = .033) and the general German population (1%). In total, 59% of the prospective and 48% of the cross-sectional patients had associated anomalies outside the spectrum (P = .16). CONCLUSION: Phenomenological multicenter data confirmed the dimension of associated anomalies inside and outside the EEC spectrum. The detected anomalies are either important in preparing for the primary reconstruction or later in long-term follow-up. Associated anomalies of EEC should be spotlighted during routine check-up in all EEC patients.

Utilization and determinants of follow-up colonoscopies within 6 years after screening colonoscopy: Prospective cohort study.

Previous studies have reported that repeat colonoscopies were often not conducted in the recommended time interval after screening colonoscopy. We prospectively followed participants of screening colonoscopy from Germany for 6 years to investigate utilization and determinants of repeat colonoscopies. In a longitudinal study on the effectiveness of screening colonoscopy in the state of Saarland (Germany), participants who had a screening colonoscopy between 2005 and 2007 were contacted by mail 6 years after screening and requested to fill in a standardized questionnaire on utilization of repeat colonoscopies. For all colonoscopies reported, colonoscopy and histology reports were requested from the physician(s). Of 6,407 screening participants, 2,212 (35%) have utilized another colonoscopy. Among participants with negative findings at screening (no adenomas), 962 (22%) had a subsequent colonoscopy within 6 years from screening, accounting for 43% of all patients with a repeat colonoscopy. Family history of CRC and detection of hyperplastic polyps were found to be determinants of higher repeat colonoscopy use. As many as 44% of the participants with low-risk adenomas (N = 509) and 39% with high-risk adenomas (N = 290) at screening did not utilize surveillance colonoscopy within 6 years. Utilization was better with higher school education, prior cancer screening participation and if high-risk adenomas were detected, lower among current smokers and lowest among participants ≥70 years. New strategies will be required considering determinants of adherence to avoid unnecessary colonoscopies and to improve utilization of surveillance according to recommended time intervals among patients at higher risk of CRC in the future.

Maternal drug use and the risk of anorectal malformations: systematic review and meta-analysis.

BACKGROUND: Origin of anorectal malformations (ARM) are considered multifactorial. Several genetic and non-genetic risk factors are discussed in literature. Maternal periconceptional medical drug use as possible risk factor, however, has not been reviewed systematically. METHODS: Studies published between 1977 and April 2017 were reviewed through systematic search in PubMed, ISI Web of Knowledge and Scopus databases. Furthermore, related and cross-referencing publications were reviewed. Pooled odds ratios (95% confidence intervals) were determined to quantify associations of maternal periconceptional use of folic acid, multivitamins, anti-asthma medication (separated in any anti-asthma medication, inhaled corticosteroids and salbutamol), thyroid hormone supplements, psychiatric drugs (separated in antidepressants, any selective serotonin reuptake inhibitors [SSRI], sertraline, citalopram, fluoxetine, paroxetine, hypnotics and benzodiazepine) and aspirin with ARM using meta-analyses. RESULTS: Thirty-seven studies that reported on the association between maternal periconceptional drug intake and infants born with ARM were included in this review. These were conducted in the United States of America (n = 14), Sweden (n = 6), Hungary (n = 5), Germany (n = 3), the Netherlands (n = 3), Denmark (n = 2), France (n = 2), Norway (n = 1) and the UK (n = 1). However, only few of these studies reported on the same risk factors. Studies were heterogeneous with respect to case numbers, period ingestion of medical drug use, control selection and adjustment for covariates. Consistently increased risks were observed for any anti-asthma medication, and hypnotics and benzodiazepine, but not for folic acid, multivitamins, inhaled corticosteroids, salbutamol, thyroid hormone supplements, antidepressants, any SSRI, sertraline, citalopram, fluoxetine, paroxetine and aspirin. In meta-analyses, pooled odds ratios (95% confidence intervals) for any anti-asthma medication, and hypnotics and benzodiazepine were 1.64 (1.22-2.21), and 2.43 (1.03-5.73), respectively. CONCLUSION: Evidence on maternal drug use before conception and during pregnancy as risk factor for ARM from epidemiological studies is still very limited. Nevertheless, the few available studies indicate any anti-asthma medication, and hypnotics and benzodiazepine to be associated with increased risks. Further, ideally large-scale multicenter and register-based studies are needed to clarify the role of maternal drug intake for the development of ARM.

Needs Assessment in Care of Adults With Anorectal Malformations and Exstrophy-Epispadias Complex in Germany.

Introduction: Medical needs of adults with anorectal malformations (ARM) and the exstrophy-epispadias complex (EEC) are not fully understood. Therefore, the aim of the study was to evaluate how affected individuals get along with the current national medical care and what their medical or social long-term requirements are. Patients and Methods: Between 11/2014-07/2016 all adult members (≥18 years, ARM n = 113, EEC n = 126) of the German self-help organizations SoMA e.V. and Blasenekstrophie/Epispadie e.V. were contacted via email or post and asked to fill out an anonymous online questionnaire regarding medical requirements, treatment satisfaction, daily life impairment and expectations regarding physicians soft skills. The results were compared between both groups and male and female participants. Results: 56 participants with ARM (median age 26 years, IQR 19-38) and 52 participants with EEC (median age 31 years, IQR 22-37) filled in the questionnaire completely. Forty-five percent of the ARM and 67% of the EEC participants contacted an urologist. A general surgeon was visited by 23% of the ARM individuals, a peadiatric surgeon by 20%. Although 60% of the females with ARM and 82% of the females with EEC assessed gynecological counseling as helpful or neutral, a small subgroup of ARM females (n = 6, 16%; 70% non-isolated ARM or ARM with Hirschsprung disease and additional associated anomalies) were not satisfied. The majority of both groups reported no or only minor daily life impairment (p = 0.38). Professional knowledge, paying attention to patients' concerns, having empathy and taking enough time was important for over 90% of all participants. Thirty-eight percent of the ARM and 27% of the EEC individuals needed psychological support. Most medical consultations were judged to be helpful. Conclusion: Although adults with ARM and EEC being a self-help organization member and thus well informed and generally cope well, participants expressed their wish for expert counseling regarding family planning, reconstructive procedures, continence management, urological care and social welfare issues. Furthermore, specific expert consultations for gynecological issues in a subgroup of ARM females, mainly non-isolated, might be required. Actual needs of adults with rare conditions must be better clarified to improve medical care beyond childhood and adolescence.

Sexual Function and Quality of Life in Adult Male Individuals with Exstrophy-Epispadias Complex-a Survey of the German CURE-Network.

OBJECTIVE: To investigate sexual function and quality of life (QoL) in adult male individuals with exstrophy-epispadias complex (EEC). Data from the German Network for Congenital Urorectal Malformations (CURE-Net) were used. PATIENTS AND METHODS: Fifty-one male participants (≥18 years) recruited by CURE-Net between 2009 and 2012 were re-contacted per mail and asked to fill out 4 questionnaires including International Index of Erectile Function (IIEF-5), Cologne Assessment of Erectile Dysfunction (KEED), the Short-Form 36 (SF-36), and one self-designed questionnaire about their medical history, current health status, and sexual experience. The SF-36 results were compared with general German population. RESULTS: Nineteen male participants (37%) completed all questionnaires (median age 26 years, 84% classical bladder exstrophy). The majority (68%) was reconstructed in a staged or single-staged approach; further 32% had a primary urinary diversion. Seventy-four percent of the participants reported a certain degree of urinary incontinence. Mean IIEF-15 results showed mild to moderate or moderate impairment in all domains. The SF-36 results revealed no difference in the German population. Subgroup analysis showed statistically significant lower results in certain SF-36 domains with regard to incontinence, dissatisfaction with genital appearance, and antihypertensive drug intake. CONCLUSION: Although there is no difference in overall QoL comparing male individuals with EEC to the general German population, incontinence, dissatisfaction with genital appearance, and taking antihypertensive medication seem to have a considerable impact on QoL. Furthermore, mild to moderate erectile dysfunction and moderate intercourse satisfaction were confirmed, suggesting the need for further improvement in care for adult male individuals with EEC.

Esophageal Atresia with or without Tracheoesophageal Fistula (EA/TEF): Association of Different EA/TEF Subtypes with Specific Co-occurring Congenital Anomalies and Implications for Diagnostic Workup.

BACKGROUND: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) represents the most common developmental malformation of the upper digestive tract. It is classified into six subtypes according to the classification of Vogt, depending on anatomical variation of this malformation. Around 50% of the patients with EA/TEF present additional anomalies, which often influence, next to the EA/TEF subtype, the overall prognosis of EA/TEF newborns. Here, we investigated the association of the different EA/TEF subtypes with co-occurring congenital anomalies in EA/TEF patients and demonstrate their implications for postnatal diagnostic workup. MATERIALS AND METHODS: We investigated 333 patients of a large German multicenter study born between 1980 and 2012. After evaluation of all available clinical records, 235 patients were included in our analysis. We compared our results with existing data. RESULTS: The highest risk for co-occurring anomalies was seen in patients with most common Vogt 3b (p = 0.024), especially for additional gastrointestinal anomalies (p = 0.04). Co-occurring anomalies of the skin were significantly more common in patients with subtype Vogt 2 (p = 0.024). A significant correlation was observed for an impaired neurodevelopmental outcome and EA/TEF Vogt 3a (p = 0.041). Patients with EA/TEF showed a higher risk to present with any additional congenital anomaly compared with the general population (p < 0.001). CONCLUSION: Our results warrant thorough clinical workup for gastrointestinal anomalies especially in patients with Vogt 3b. Moreover, it might be necessary to focus on a thorough aftercare for neurocognitive development in patients with Vogt 3a. The here presented observations need to be confirmed by future studies.

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.

Complication Rates in Colonoscopy Screening for Cancer.

BACKGROUND: Screening colonoscopy has been offered in Germany since 2002. Complications during colonoscopy were reported to be rare, but data on potential complications after colonoscopy are sparse. We aimed to comprehensively assess the frequency of complications arising during or within four weeks of screening colonoscopy. METHODS: Residents of the German federal state of Saarland without a history of colorectal cancer and without previous polypectomy who underwent a screening colonoscopy between 2010 and 2013 were included. A follow-up was conducted three months after the screening colonoscopy, including participant questionnaires and subsequent validation of self-reported complications arising during or within four weeks of screening colonoscopy, by reviewing colonoscopy records and contacting the treating physicians. A comprehensive mortality follow-up was conducted for non-responders. RESULTS: We recruited a total of 5527 participants from 26 practices (median age 61 years, 52% women). 5252 (95%) fully completed the questionnaire on complications and met the inclusion criteria for analysis. Among these participants, 16 cases of physician-confirmed bleeding (0.30%) and four cases of physician-confirmed perforation (0.08%) occurred during or within four weeks of colonoscopy. According to consistent reports from patients and physicians, bleeding and perforation led to hospitalization in 5 (0.095%) and 2 (0.04%) cases, respectively. Three participants died within three months of colo - noscopy. In none of these cases was the cause of death related to colonoscopy. CONCLUSION: We found the risk of complications of screening colonoscopy to be low, even when taking into account a potential delay of up to four weeks.

Array-based molecular karyotyping in 115 VATER/VACTERL and VATER/VACTERL-like patients identifies disease-causing copy number variations.

BACKGROUND: The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CF): vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia, renal malformations (R), and limb defects (L). Patients presenting with at least three CFs are diagnosed as having VATER/VACTERL association while patients presenting with only two CFs are diagnosed as having VATER/VACTERL-like phenotypes. Recently, rare causative copy number variations (CNVs) have been identified in patients with VATER/VACTERL association and VATER/VACTERL-like phenotypes. METHODS: To detect further causative CNVs we performed array based molecular karyotyping in 75 VATER/VACTERL and 40 VATER/VACTERL-like patients. RESULTS: Following the application of stringent filter criteria, we identified 13 microdeletions and seven microduplications in 20 unrelated patients all of which were absent in 1,307 healthy inhouse controls (n < 0.0008). Among these, microdeletion at 17q12 was confirmed to be de novo. Three microdeletions at 5q23.1, 16q23.3, 22q11.21, and one microduplication at 10q11.21 were all absent in the available parent. Microdeletion of chromosomal region 22q11.21 was previously found in VATER/VACTERL patients rendering it to be causative in our patient. The remaining 15 CNVs were inherited from a healthy parent. CONCLUSION: In two of 115 patients' causative CNVs were found (2%). The remaining identified rare CNVs represent candidates for further evaluation. Rare inherited CNVs may constitute modifiers of, or contributors to, multifactorial VATER/VACTERL or VATER/VACTERL-like phenotypes. Birth Defects Research 109:1063-1069, 2017. © 2017 Wiley Periodicals, Inc.

Should Screening Colonoscopy Be Offered From Age 50?

BACKGROUND: The introduction of colonoscopic screening in 2002 for persons aged 55 and older was followed by a marked decline in the incidence of colon cancer in the corresponding age groups in Germany. The prevalence of colorectal neoplasia among persons aged 50 to 54 has remained unknown until now. Expert committees currently recommend colonoscopic screening for persons aged 50 and older. This option has been offered since 2014 by the AOK Baden-Württemberg and by Bosch BKK in the framework of their specialized medical care program. METHODS: In April 2014 and 2015, 84 726 insurees aged 50-54 were invited by mail to participate in colonoscopic screening. The utilization and results of colonoscopic screening were studied. A questionnaire about risks was additionally sent to half of the participants, who were selected at random (study registration: DRKS00006268). RESULTS: Within one year, 1.9% of persons to whom invitations had been sent took up the offer of colonoscopic screening; these persons included 3.3% of those already enrolled in the specialized medical care program. The 1396 colonoscopies that were performed revealed advanced neoplasia (colon cancer or advanced adenoma) in 6.8% of cases. The prevalence of advanced neoplasia among men aged 50 to 54 was nearly twice as high as that among women in the same age group (8.6% vs. 4.5%, p = 0.0027). It was also higher than the prevalences documented in the German nationwide cancer registry for women aged 55 to 79. The additional sending of a risk questionnaire along with the invitation had no effect on the rate of detection of relevant findings or on the rate of participation in colonoscopic screening. CONCLUSION: These findings lend support to the demand that the offer of colonoscopic screening should be extended at least to men aged 50 and above.