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Genetics of Bladder-Exstrophy-Epispadias Complex (BEEC): Systematic Elucidation of Mendelian and Multifactorial Phenotypes.

ABSTRACT: The Bladder-Exstrophy-Epispadias Complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and has a profound impact on continence, and on sexual and renal function. While previous reports of familial occurrence, in-creased recurrence among first-degree relatives, high concordance rates among monozygotic twins, and chromosomal aberra-tions were suggestive of causative genetic factors, the recent identification of copy number variations (CNVs), susceptibility regions and genes through the systematic application of array based analysis, candidate gene and genome-wide association studies (GWAS) provide strong evidence. These findings in human BEEC cohorts are underscored by the recent description of BEEC(-like) murine knock-out models. Here, we discuss the current knowledge of the potential molecular mechanisms, mediating abnormal uro-rectal development leading to the BEEC, demonstrating the importance of ISL1-pathway in human and mouse and propose SLC20A1 and CELSR3 as the first BEEC candidate genes, identified through systematic whole-exome sequencing (WES) in BEEC patients.

SUBMITTER: Reutter H

PROVIDER: S-EPMC4780475 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Genetics of Bladder-Exstrophy-Epispadias Complex (BEEC): Systematic Elucidation of Mendelian and Multifactorial Phenotypes.

Reutter Heiko H Keppler-Noreuil Kim K E Keegan Catherine C Thiele Holger H Yamada Gen G Ludwig Michael M

Current genomics 20160201 1

The Bladder-Exstrophy-Epispadias Complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and has a profound impact on continence, and on sexual and renal function. While previous reports of familial occurrence, in-creased recurrence among first-degree relatives, high concordance rates among monozygotic twins, and chromosomal aberra-tions were suggestive of causative genetic factors, the recent identification of copy number variations (CNVs), susceptibility regions and g ...[more]

PMID: 27013921

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Project description: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.

Project description:Introduction/backgroundBladder exstrophy patients have a high prevalence of inguinal hernia that often become clinically evident following bladder closure. Understanding when the bladder exstrophy patient is under greatest risk of developing an inguinal hernia following bladder closure is important, since incarceration resulting in strangulation of intra-abdominal contents can lead to significant morbidity if not addressed in a timely fashion. Although the incidence and risk factors of inguinal hernia have been reported, the timing of occurrence is not well understood.ObjectiveThe primary objective of this study was to assess the timing of inguinal hernia following complete primary repair of bladder exstrophy (CPRE). In addition, we aimed to evaluate possible risk factors associated with inguinal hernia, including sex, age at bladder closure and iliac osteotomy status.Study designA multi-institutional retrospective review identified patients with bladder exstrophy repaired by CPRE under 6 months of age while excluding those who underwent inguinal hernia repair before or during bladder closure. Timing of inguinal hernia following bladder closure was evaluated using Kaplan-Meier methods. Cox proportional hazards model was used to investigate association of sex, age at bladder closure, and osteotomy on the risk of developing of inguinal hernia while clustering for institution.Results91 subjects were included in our analysis with median follow-up time of 6.5 years. 34 of 53 males (64.2%) and 2 of 38 females (5.3%) underwent inguinal hernia repair. The median time to inguinal hernia was 4.7 months following closure. The greatest hazard of inguinal hernia was within the first six months following closure. In multivariate analysis, male sex was strongly associated with inguinal hernia (HR = 19.00, p = 0.0038). Osteotomy and delay in closure were not significantly associated with inguinal hernia. 7 of 36 patients (19.4%) who underwent inguinal hernia repair presented with recurrence on the ipsilateral side.DiscussionOur results suggest that the greatest risk of inguinal hernia is within the first six months following bladder closure. The decreased risk of inguinal hernia after one year of follow-up may reflect anatomic stability that is reached following major reconstruction of the pelvis. While male bladder exstrophy patients are significantly more susceptible to inguinal hernias following CPRE, osteotomy and delayed bladder closure do not appear to be protective factors for inguinal hernia development following initial bladder closure.ConclusionsThere is a heightened risk of inguinal hernia in the first six months following closure. The rate of recurrence following inguinal hernia repair is significantly elevated compared to the general pediatric population.

Project description:Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special issue on Parkinson disease.

Dataset Information

Genetics of Bladder-Exstrophy-Epispadias Complex (BEEC): Systematic Elucidation of Mendelian and Multifactorial Phenotypes.

Publications

Genetics of Bladder-Exstrophy-Epispadias Complex (BEEC): Systematic Elucidation of Mendelian and Multifactorial Phenotypes.

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