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

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

From the other side: therapy, aftercare and qualitiy of life in children and adolescents with anorectal malformations

Unter dem Oberbegriff der anorektalen Fehlbildungen wird ein breites Spektrum unterschiedlich komplexer Fehlbildungsvarianten zusammengefasst. Begleitfehlbildungen an anderen Organsystemen wie Herz, Nieren und ableitenden Harnwegen, Geschlechtsorganen oder Extremitäten treten bei mehr als 60% aller betroffenen Kinder auf. Stuhlentleerungsstörungen wie Inkontinenz und Obstipation können trotz adäquater chirurgischer Therapie ein Leben lang bei 30 – 80 % der Betroffenen bestehen. Je nach Art der Malformation stehen Inkontinenz, oder Obstipation im Vordergrund des klinischen Beschwerdebildes. Viele Betroffene tragen zeitlebens Windeln oder Einlagen. Eine gravierende Einschränkung der Lebensqualität ist daher nicht selten. Mit einem differenzierten Therapiekonzept, das den Unterschied zwischen Überlaufenkopresis bei intaktem Kontinenzorgan und Inkontinenz bei mangelhafter Verschlussfunktion respektiert, können Patienten eine soziale Kontinenz erwerben. Patienten, bei denen die Obstipation die Ursache der Symptomatik ist, erhalten eine individualisierte Therapie, die sich aus unterschiedlichen supportiven Behandlungsmodulen zusammensetzt. Bei einer absoluten Inkontinenz für Stuhl wird durch eine kontrollierte Darmspülung idealerweise das gesamte Kolon entleert, so dass der Patient für einen Zeitraum von 24 – 72 Stunden frei von unwillkürlichem Stuhlverlust ist. Mit der Methode der Hydrosonographie, die in dieser Arbeit erstmals von uns beschrieben wird, kann das erforderliche Flüssigkeitsvolumen für die Darmspülung unkompliziert und schnell individuell bemessen werden. Ein Bowel Management Programm, das die Eigenständigkeit des Patienten frühzeitig fördert und individuell auf die Bedürfnisse des Einzelnen zugeschnitten ist, verkürzt die Zeit, die für eine Behandlungsmaßnahme erforderlich ist und erhöht die Compliance. Die Wahrscheinlichkeit zusätzlich zu einer anorektalen Fehlbildung eine urologische Fehlbildung zu haben, nimmt mit zunehmender Komplexität der Fehlbildungsvariante zu. Urologische Symptome können jedoch auch eine Konsequenz der Operation sein. Eine sichere Unterscheidung war anhand unserer Daten nicht zu leisten, da eine detaillierte Angabe zur präoperativen urologischen Situation in den meisten Fällen fehlte. Es fand sich allerdings eine gehäufte Anzahl urologischer Komplikationen bei männlichen Patienten mit komplexeren Fehlbildungsformen, die mit einer abdominosakroperinealen Operationstechnik korrigiert worden waren. Bei weiblichen Patienten war die Anzahl von Harnwegsinfektionen erhöht, unabhängig davon, welche Fehlbildungsvariante zugrunde lag. Die Ergebnisse unserer Untersuchungen waren schlechter als die vergleichbarer Studien, eine mögliche Erklärung dieser Diskrepanz könnte in der speziellen Konzeption der multizentrischen CURE-Net Studie und der Datenerhebung durch unabhängige Untersucher begründet sein. Eine Untersuchung zur Sexualität von erwachsenen Menschen mit anorektalen Fehlbildungen gab es bisher nicht. In unserer Studie zeigte sich, dass betroffene Jugendliche im Alter von 22 Jahren weniger sexuelle Erfahrungen als altersgleiche Jugendliche hatten, sowohl in Bezug auf sexuelle Phantasien als auch auf Masturbation. Neben psychosozialen Einschränkungen der Sexualentwicklung bestanden funktionelle Störungen wie Erektions- und Ejakulationsstörungen bei Männern und Dyspareunien bei Frauen. Bei der initialen chirurgischen Korrektur der Fehlbildung und bei der Institution von Nachsorgemaßnahmen sollte an die Bewahrung der Fertilität gedacht und der Respekt vor der Intimsphäre gewahrt werden. Wir beobachteten bei Jugendlichen und jungen Erwachsenen eine medizinische Versorgungslücke, die mit dem 18. Lebensjahr beginnt. Eine konsequente Transition aus der Betreuung in der Kindermedizin in das Erwachsenen Gesundheitssystem findet derzeit nicht statt. Aus dieser Versorgungslücke können Schäden verschiedener Organsysteme resultieren. Eine Betreuung in interdisziplinären Spezialambulanzen in einem Zentrum und die Entwicklung eines standardisierten krankheitsspezifischen Nachsorgeprotokolls könnten dieses Defizit beheben.The term Anorectal Malformations (ARM) comprises a wide spectrum of complex morphologic variants. The main concerns for the surgeon in correcting these anomalies are bowel control, urinary control and sexual function. With correct diagnosis, management of associated anomalies and adequate surgical repair, patients have the chance for a good funcitonal outcome. But still defecating disorders can occur. Patients born with anorectal malformation can be kept clean of stool if they are subjected to an adequate treatment. Hydrocolonic sonography is a helpful diagnostic tool to assess colonic volume und motility to predict the type and volume of enema needed for an effective bowel management. Colonic irrigation should be combined with self-management strategies. Adherence to therapy can bei enhanced with the use of an individualized irrigation schedule. Besides reconstructing the ARM, another main goal is the preservation of lower urinary tract function and sexual function. According to our data, there seems to be a close relationship between operative strategies and postoperative urologic complications. Adults with ARM, regardless of severity of handicap are interested in sexual activity. The prevalence of infertility in this population is unknown, but paternity is possible. Furthermore, we found a close relationship between psychosocial development and sexual activity. Medical follow-up for patients with ARM in the transition phase is still inadequate. Patients should be transferred smoothly from pediatric to adult care. ARM should be regionally anchored in special facilities willing to make a commitment to their care. Ideally pediatric and adult surgeons should collaborate. ARM care should be multidisciplinary, wherever possible, and in supraregional centers

Assisted reproductive techniques and the risk of anorectal malformations: a German case-control study

Abstract Background The use of assisted reproductive techniques (ART) for treatment of infertility is increasing rapidly worldwide. However, various health effects have been reported including a higher risk of congenital malformations. Therefore, we assessed the risk of anorectal malformations (ARM) after in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Methods Data of the German Network for Congenital Uro-REctal malformations (CURE-Net) were compared to nationwide data of the German IVF register and the Federal Statistical Office (DESTATIS). Odds ratios (95% confidence intervals) were determined to quantify associations using multivariable logistic regression accounting for potential confounding or interaction by plurality of births. Results In total, 295 ARM patients born between 1997 and 2011 in Germany, who were recruited through participating pediatric surgeries from all over Germany and the German self-help organisation SoMA, were included. Controls were all German live-births (n = 10,069,986) born between 1997 and 2010. Overall, 30 cases (10%) and 129,982 controls (1%) were born after IVF or ICSI, which translates to an odds ratio (95% confidence interval) of 8.7 (5.9–12.6) between ART and ARM in bivariate analyses. Separate analyses showed a significantly increased risk for ARM after IVF (OR, 10.9; 95% CI, 6.2–19.0; P  Conclusions There is a strongly increased risk for ARM among children born after ART. Elevations of risk were seen after both IVF and ICSI. Further, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed increased risks in each group. An increased risk of ARM was also seen among both singletons and multiple births.</p

Assisted reproductive techniques and the risk of anorectal malformations: a German case-control study

Background: The use of assisted reproductive techniques (ART) for treatment of infertility is increasing rapidly worldwide. However, various health effects have been reported including a higher risk of congenital malformations. Therefore, we assessed the risk of anorectal malformations (ARM) after in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Methods: Data of the German Network for Congenital Uro-REctal malformations (CURE-Net) were compared to nationwide data of the German IVF register and the Federal Statistical Office (DESTATIS). Odds ratios (95% confidence intervals) were determined to quantify associations using multivariable logistic regression accounting for potential confounding or interaction by plurality of births. Results: In total, 295 ARM patients born between 1997 and 2011 in Germany, who were recruited through participating pediatric surgeries from all over Germany and the German self-help organisation SoMA, were included. Controls were all German live-births (n = 10,069,986) born between 1997 and 2010. Overall, 30 cases (10%) and 129,982 controls (1%) were born after IVF or ICSI, which translates to an odds ratio (95% confidence interval) of 8.7 (5.9-12.6) between ART and ARM in bivariate analyses. Separate analyses showed a significantly increased risk for ARM after IVF (OR, 10.9; 95% CI, 6.2-19.0; P < 0.0001) as well as after ICSI (OR, 7.5; 95% CI, 4.6-12.2; P < 0.0001). Furthermore, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed strong associations with ART (ORs 4.9, 11.9 and 7.9, respectively). After stratification for plurality of birth, the corresponding odds ratios (95% confidence intervals) were 7.7 (4.6-12.7) for singletons and 4.9 (2.4-10.1) for multiple births. Conclusions: There is a strongly increased risk for ARM among children born after ART. Elevations of risk were seen after both IVF and ICSI. Further, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed increased risks in each group. An increased risk of ARM was also seen among both singletons and multiple births

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

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. © 2010 The Author(s)

A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies

© Copyright © 2020 van de Putte, Dworschak, Brosens, Reutter, Marcelis, Acuna-Hidalgo, Kurtas, Steehouwer, Dunwoodie, Schmiedeke, Märzheuser, Schwarzer, Brooks, de Klein, Sloots, Tibboel, Brisighelli, Morandi, Bedeschi, Bates, Levitt, Peña, de Blaauw, Roeleveld, Brunner, van Rooij and Hoischen. Background: The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Methods: Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL (n = 211), ARM (n = 204), and EA/TEF (n = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. Results: In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in SALL1, SALL4, and MID1, genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. Conclusions: None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families

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