Publications by authors named "Stefanie Märzheuser"

22 Publications

  • Page 1 of 1

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

Front Pediatr 2020 23;8:310. Epub 2020 Jun 23.

Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

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). Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL ( = 211), ARM ( = 204), and EA/TEF ( = 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. In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in , and , 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. 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.
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http://dx.doi.org/10.3389/fped.2020.00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324789PMC
June 2020

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

PLoS One 2020 5;15(6):e0234246. Epub 2020 Jun 5.

Institute of Human Genetics, Medical Faculty of Bonn, University of Bonn, Bonn, Germany.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234246PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274392PMC
August 2020

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

Orphanet J Rare Dis 2017 12 13;12(1):180. Epub 2017 Dec 13.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

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.
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http://dx.doi.org/10.1186/s13023-017-0729-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729416PMC
December 2017

Transition of care in patients with anorectal malformations: Consensus by the ARM-net consortium.

J Pediatr Surg 2017 Nov 23;52(11):1866-1872. Epub 2017 Jun 23.

Department of Surgery, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Fulham Palace Road, London W6 8RF, United Kingdom.

Objectives: To develop the first consensus to standardize the management of patients with Anorectal Malformations (ARMs) transitioning from childhood to adulthood.

Methods: A dedicated task force of experts performed an extensive literature review and multiple meetings to define the most important aspects of transition of care. The findings were discussed with all ARM-net consortium members and a set of practical recommendations agreed upon at the annual meeting in 2016.

Result: We defined seven domains that are essential to provide an effective and practical transition process. Within each domain we have developed a set of key recommendations that are important to be considered for ARM patients entering the age of transition.

Conclusions: It is crucial that transition begins at an early age with regular and well-structured follow-up. Cooperation with a selected multidisciplinary team of pediatric and adult practitioners is required to prepare patients and families for effective transition to adult care and to reduce long term morbidity.

Type Of Study: Review/Consensus paper.

Level Of Evidence: III.
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http://dx.doi.org/10.1016/j.jpedsurg.2017.06.008DOI Listing
November 2017

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

Birth Defects Res 2017 Jul 12;109(13):1063-1069. Epub 2017 Jun 12.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

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.
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http://dx.doi.org/10.1002/bdr2.1042DOI Listing
July 2017

Voiding Cystourethrography in the Diagnosis of Anorectal Malformations.

Eur J Pediatr Surg 2016 Dec 11;26(6):494-499. Epub 2016 Jan 11.

Department of Pediatric Surgery, Charité University Hospital, Berlin, Germany.

 In a newborn with an anorectal malformation (ARM), it is vital to determine the anatomy of the underlying defect. After a colostomy has been created, distal colostography (DCG) is currently the chosen modality for the detection of fistulas. The role of voiding cystourethrography (VCU) is unexplored.  The aim of this study was to analyze the reproducibility of DCG and VCU in assessing the underlying malformation in ARM, and to evaluate any degree of concordance among them.  A retrospective evaluation was undertaken comparing DCG and VCU findings with definitive surgical findings in children who received both investigations for the initial management of ARM.  In this study, 26 boys were included. Malformations were classified according to Krickenbeck classification. Four boys with perineal fistula were excluded from the analysis, as none of them needed a colostomy; therefore, comparison between both methods was not possible. VCU identified a rectourethral fistula in 12 cases, a rectovesical fistula in 4 cases, and excluded a fistula in 6 cases. VCU was false negative for a rectovesical fistula in one case. VCU showed a vesicoureteral reflux in 16 patients. Results obtained by VCU were compared with DCG. DCG showed a rectourethral fistula in 11 cases, a rectovesical in 3 cases, and excluded a fistula in 6 cases correctly. DCG was false negative in two cases, a rectoprostatic and a rectovesical fistula. The diagnostic accuracy, measuring the sensitivity was 95% in VCU (range: 76.18-99.88%) and 90% (range: 68.30-98.77%) in colostogram.  VCU can be as accurate as distal colostogram in the evaluation of male patients with ARM. VCU uses a natural orifice, without the need of a colostomy. VCU can be performed as an initial modality to determine the type of malformation and to decide on the type of early surgical management.
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http://dx.doi.org/10.1055/s-0035-1570102DOI Listing
December 2016

Improvements in Incontinence with Self-Management in Patients with Anorectal Malformations.

Eur J Pediatr Surg 2016 Apr 5;26(2):186-91. Epub 2015 Feb 5.

Department of Pediatric Surgery, Charité University Hospital, Berlin, Germany.

Unlabelled: There are limited data available in children with anorectal malformation (ARM) regarding the use of transanal colonic irrigation delivered with the Peristeen system (Coloplast Denmark A/S, Humlebaek, Denmark). To our knowledge no study has combined the element of controlled evacuation with self-management strategies. Our center began offering this management regimen 5 years ago to patients suffering from fecal incontinence. The aim of this study was to appraise the results of this approach in children from 4 to 18 years with incontinence and fecal soiling secondary to ARM.

Material And Methods: Bowel management was initiated with the help of hydrosonography to evaluate bowel motility and the volume of the enema. The Peristeen irrigation system was used. Anorectal irrigation was repeated every 24, 48, or 72 hours. A personal schedule was developed based on every patient's individual preferences. Irrigations were self-administered by the patient while sitting on the toilet. Patients were controlled for soiling, time needed for irrigation, time interval between irrigations 6 and 12 months after start of therapy, with further yearly follow-ups.

Results: A total of 40 patients aged between 4 and 18 years were evaluated. After 12 months of therapy, 32 patients were free of symptoms of soiling. Six patients were soiling occasionally. Two patients did not follow the therapeutic regime. The average time needed for irrigation was 35 minutes, with the lower limit of 12 minutes and the upper limit of 60 minutes, irrigations where done every 24 hours in 12 patients. Overall 25 patients irrigated twice every 48 and 72 hours to achieve a constant 7-day rhythm. One patient irrigated every 5 days. At follow-up after 2, 3, and 4 years success rates were stable.

Conclusion: We suggest that colonic irrigation should be combined with self-management strategies in children with ARM. Adherence to therapy can be enhanced with the use of an individualized irrigation schedule. The amount of time required for the irrigation can be significantly reduced. Therefore, when establishing colonic irrigation in children and adolescents a focus should be placed on time-saving measures and self-regulation.
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http://dx.doi.org/10.1055/s-0034-1544050DOI Listing
April 2016

Genome-wide mapping of copy number variations in patients with both anorectal malformations and central nervous system abnormalities.

Birth Defects Res A Clin Mol Teratol 2015 Apr 24;103(4):235-42. Epub 2014 Sep 24.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Background: Anorectal malformations (ARM) have a prevalence of around 1 in 2500 live births. In around 50% of patients, the malformation is isolated, while in the remainder it arises within the context of complex genetic abnormalities or a defined genetic syndrome. Recent studies have implicated rare copy number variations (CNVs) in both isolated and nonisolated ARM, and identified plausible candidate genes.

Methods: In the present study, array-based molecular karyotyping was performed to identify causative CNVs in 32 sporadic ARM patients with comorbid abnormalities of the central nervous system (CNS). This phenotype was selected to enrich for rare CNVs, since previous research has implicated rare CNVs in both CNS abnormalities and ARM.

Results: In five patients, a probable disease-causing CNV was identified (del6q14.3q16.3, del14q32.2, del17q12q21.2, and two patients with del22q11.21). In three of these patients, the CNVs were de novo. For the remaining two patients, no parental DNA was available. Deletions at 22q11.21 and 6q14.3 have been associated with both CNS abnormalities and ARM. In contrast, deletions at 14q32.2 have only been described in patients with CNS abnormalities, and the del17q12q21.2 is a novel CNV. Expression studies in mice suggest that NEUROD2 and RARA, which reside within the newly identified del17q12q21.2 region, are candidate genes for the formation of microcephaly and ARM.

Conclusion: The present data suggest that CNVs are a frequent cause of the ARM with CNS abnormalities phenotype, and that array-analysis is indicated in such patients.
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http://dx.doi.org/10.1002/bdra.23321DOI Listing
April 2015

Heterozygous FGF8 mutations in patients presenting cryptorchidism and multiple VATER/VACTERL features without limb anomalies.

Birth Defects Res A Clin Mol Teratol 2014 Oct 8;100(10):750-9. Epub 2014 Aug 8.

Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.

Background: The acronym VATER/VACTERL association describes the combination of at least three of the following cardinal features: vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. Although fibroblast growth factor-8 (FGF8) mutations have mainly found in patients with Kallmann syndrome, mice with a hypomorphic Fgf8 allele or complete gene invalidation display, aside from gonadotropin-releasing hormone deficiency, parts or even the entire spectrum of human VATER/VACTERL association.

Methods: We performed FGF8 gene analysis in 49 patients with VATER/VACTERL association and 27 patients presenting with a VATER/VACTERL-like phenotype (two cardinal features).

Results: We identified two heterozygous FGF8 mutations in patients displaying either VATER/VACTERL association (p.Gly29_Arg34dup) or a VATER/VACTERL-like phenotype (p.Pro26Leu) without limb anomalies. Whereas the duplication mutation has not been reported before, p.Pro26Leu was once observed in a Kallmann syndrome patient. Both our patients had additional bilateral cryptorchidism, a key phenotypic feature in males with FGF8 associated Kallmann syndrome. Each mutation was paternally inherited. Besides delayed puberty in both and additional unilateral cryptorchidism in one of the fathers, they were otherwise healthy. Serum hormone levels downstream the gonadotropin-releasing hormone in both patients and their fathers were within normal range.

Conclusion: Our results suggest FGF8 mutations to contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.
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http://dx.doi.org/10.1002/bdra.23278DOI Listing
October 2014

[Treatment for fecal incontinence in patients with anorectal malformations. Introduction of a therapeutic approach].

Pflege Z 2013 Oct;66(10):612-5

Klinik und Poliklinik für Kinderchirurgie, Charité Universitätsmedizin Berlin.

Unlabelled: Fecal incontinence is a serious problem that may lead to social segregation and psychological problems. Patients with anorectal malformations frequently suffer fecal incontinence even with an excellent anatomic repair. In these patients an effective management program with enemas can improve their quality of life. We want to present our experience with bowel management and anorectal irrigation as treatment for stool incontinence.

Material And Methods: Patients who presented with soiling regardless of the type of anomaly were included in the study. The diagnostic program comprised a careful clinical history, physical examination, exact classification of the malformation and stool protocol. All patients suffering from true fecal incontinence were included in a bowel management program. These patients received oral polyethylenglykol to evacuate stool impaction. Than anorectal irrigation was initiated and repeated every 24 or 48 hours. Patients were controlled for soiling, time needed for irrigation and time interval between irrigations 6 and 12 months after start oftherapy.

Results: 40 patients aged 4 to 54 with a mean age of 15,95 years were evaluated. 12 months after start of therapy 32 patients were free of symptoms of soiling. 6 patients were soiling occasionally once or twice per week. 2 patients did not follow the therapeutic regime and therefore did not show an improved condition concerning soiling in the long run. The average time needed for irrigation was 45 minutes, irrigations where done every 24 hours in 12 patients. 25 patients irrigated twice every 48 and 72 hours to achieve a constant seven day rhythm. One patient irrigated every five days.

Discussion: Patients born with anorectal malformation and suffering from stool incontinece can be kept clean of stool if they are subjected to an adequate treatment.
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October 2013

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

Kidney Int 2014 Jun 23;85(6):1310-7. Epub 2013 Oct 23.

1] Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

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 VACTERL association with CAKUT.
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http://dx.doi.org/10.1038/ki.2013.417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997628PMC
June 2014

De novo 13q deletions in two patients with mild anorectal malformations as part of VATER/VACTERL and VATER/VACTERL-like association and analysis of EFNB2 in patients with anorectal malformations.

Am J Med Genet A 2013 Dec 16;161A(12):3035-41. Epub 2013 Aug 16.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Anorectal malformations (ARMs) comprise a broad spectrum of conditions ranging from mild anal anomalies to complex cloacal malformations. In 40-50% of cases, ARM occurs within the context of defined genetic syndromes or complex multiple congenital anomalies, such as VATER/VACTERL (vertebral defects [V], ARMs [A], cardiac defects [C], tracheoesophageal fistula with or without esophageal atresia [TE], renal malformations [R], and limb defects [L]) association. Here, we report the identification of deletions at chromosome 13q using single nucleotide polymorphism-based array analysis in two patients with mild ARM as part of VATER/VACTERL and VATER/VACTERL-like associations. Both deletions overlap the previously defined critical region for ARM. Heterozygous Efnb2 murine knockout models presenting with mild ARM suggest EFNB2 as an excellent candidate gene in this region. Our patients showed a mild ARM phenotype, closely resembling that of the mouse. We performed a comprehensive mutation analysis of the EFNB2 gene in 331 patients with isolated ARM, or ARM as part of VATER/VACTERL or VATER/VACTERL-like associations. However, we did not identify any disease-causing mutations. Given the convincing argument for EFNB2 as a candidate gene for ARM, analyses of larger samples and screening of functionally relevant non-coding regions of EFNB2 are warranted. In conclusion, our report underlines the association of chromosome 13q deletions with ARM, suggesting that routine molecular diagnostic workup should include the search for these deletions. Despite the negative results of our mutation screening, we still consider EFNB2 an excellent candidate gene for contributing to the development of ARM in humans.
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http://dx.doi.org/10.1002/ajmg.a.36153DOI Listing
December 2013

De novo microduplications at 1q41, 2q37.3, and 8q24.3 in patients with VATER/VACTERL association.

Eur J Hum Genet 2013 Dec 3;21(12):1377-82. Epub 2013 Apr 3.

1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany [3] Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.

The acronym VATER/VACTERL association describes the combination of at least three of the following congenital anomalies: vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). We aimed to identify highly penetrant de novo copy number variations (CNVs) that contribute to VATER/VACTERL association. Array-based molecular karyotyping was performed in a cohort of 41 patients with VATER/VACTERL association and 6 patients with VATER/VACTERL-like phenotype including all of the patients' parents. Three de novo CNVs were identified involving chromosomal regions 1q41, 2q37.3, and 8q24.3 comprising one (SPATA17), two (CAPN10, GPR35), and three (EPPK1, PLEC, PARP10) genes, respectively. Pre-existing data from the literature prompted us to choose GPR35 and EPPK1 for mouse expression studies. Based on these studies, we prioritized GPR35 for sequencing analysis in an extended cohort of 192 patients with VATER/VACTERL association and VATER/VACTERL-like phenotype. Although no disease-causing mutation was identified, our mouse expression studies suggest GPR35 to be involved in the development of the VATER/VACTERL phenotype. Follow-up of GPR35 and the other genes comprising the identified duplications is warranted.
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http://dx.doi.org/10.1038/ejhg.2013.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831074PMC
December 2013

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

Orphanet J Rare Dis 2012 Sep 15;7:65. Epub 2012 Sep 15.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1186/1750-1172-7-65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519554PMC
September 2012

[Use of operationalized psychodynamic diagnostics in childhood and adolescence in patients with somatic diseases].

Psychother Psychosom Med Psychol 2012 Jul 9;62(7):259-65. Epub 2012 Jul 9.

Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Charité Universitätsmedizin Berlin.

Psychodynamic findings based on the Operationalized Psychodynamic Diagnostics in Childhood and Adolescence (OPD-CA) in patients with Anorectal Malformations (ARM) in comparison to psychiatric patients were presented focussing the psychic structure. Patients with ARM had significant better psychic structure especially with regard to coping with conflicts and communication of affects. Furthermore typical findings were generated: Patients with ARM had better treatment conditions and more positive relationships. Still they had fewer hypotheses about their disease and greater living burden. Structural strengthes facilitate acceptance and integration of the disease. Nonetheless more attention should be paid to child-oriented psychoeducation for development of age-appropriate hypotheses about the disease. Facing living burden, psychological-psychiatric support should be offered to patients with ARM.
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http://dx.doi.org/10.1055/s-0032-1314784DOI Listing
July 2012

Inheritance of the VATER/VACTERL association.

Pediatr Surg Int 2012 Jul 12;28(7):681-5. Epub 2012 May 12.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

VATER/VACTERL association refers to the non-random co-occurrence of the following component features: vertebral defects, anal atresia, cardiac malformations, tracheoesophageal atresia, renal abnormalities, and limb defects. Recently, Solomon et al. (Hum Genet 127:731-733, 2010) observed an increased prevalence of component features among first-degree relatives of VATER/VACTERL patients suggesting that in some patients, the disorder may be inherited. To replicate these findings, we investigated 87 VATER/VACTERL patients with the presence of a minimum of three component features and their first-degree relatives (n = 271). No increase in the overall prevalence of component features was observed in first-degree relatives compared to the general population (χ² = 2.68, p = 0.10). Separate analysis for the prevalence of single component features showed a higher prevalence of tracheoesophageal fistula/atresia among first-degree relatives compared to the general population (OR 17.65, 95% CI 2.47-126.05). However, this was based on occurrence in one family only. Our findings suggest that although familial occurrence renders a genetic contribution likely, the overall risk of recurrence among the first-degree relatives of patients with VATER/VACTERL association is probably very low. Since the patients in the present study were young and no offspring could be studied, estimation of the role of de novo mutations in the development of VATER/VACTERL was not possible.
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http://dx.doi.org/10.1007/s00383-012-3100-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126839PMC
July 2012

[In a 9-year-old boy: bicycle accident with sequelae. Perforation of the small bowel].

MMW Fortschr Med 2011 Jan;153(4)

Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Klinik für Strahlenheilkunde, Augustenburger Platz 1, D-13353 Berlin.

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http://dx.doi.org/10.1007/BF03367669DOI Listing
January 2011

Autosomal-dominant non-syndromic anal atresia: sequencing of candidate genes, array-based molecular karyotyping, and review of the literature.

Eur J Pediatr 2011 Jun 2;170(6):741-6. Epub 2010 Nov 2.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Introduction: Anorectal malformations (ARM) range from mild anal to severe anorectal anomalies. Approximately 50% are estimated to be non-syndromic with multiple familial cases reported that suggest underlying genetic factors. These, however, still await identification.

Materials And Methods: We report a familial case of non-syndromic ARM with a mother and her two children being affected. Mother and daughter had mild ARM that had only been diagnosed after the index patient was born with a more severe form and ultrashort Hirschsprung's disease. To reveal the genetic cause in our family genome-wide array analysis was carried out to ascertain microaberrations characterized by loss or gain of genomic material. In addition, sequence analysis of four major Hirschsprung's disease genes (RET, EDNRB, EDN3, and GDNF) and the HLXB9 gene was performed to identify a mutation common to all three family members; however, these analyses did not reveal any causal genetic alteration. To demonstrate the frequency of familial non-syndromic cases, we performed a literature search revealing 59 families with at least two affected members. Sufficient description of ARM phenotype and affection status of relatives to surely classify them as familial non-syndromic forms was given for 22 families.

Conclusion: The present family suggests that mild ARM may be overlooked in patients with non-specific clinical symptoms and that the incidence of ARM may thus be higher than previously estimated. With the new possibilities of whole exome sequencing, even small families hold the possibility to identify causal defects.
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http://dx.doi.org/10.1007/s00431-010-1332-2DOI Listing
June 2011

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.

Pediatr Surg Int 2010 Nov;26(11):1093-9

Department of Epidemiology, Biostatistics and HTA (133), Radboud University Nijmegen Medical Centre, P.O. box 9101, 6500 HB, Nijmegen, The Netherlands.

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.
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http://dx.doi.org/10.1007/s00383-010-2688-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962787PMC
November 2010

[Comorbidity and psychosocial need in children and adolescents with anorectal malformations].

Prax Kinderpsychol Kinderpsychiatr 2010 ;59(1):38-51

Charité Universitätsmedizin Berlin, Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes und Jugendalters, Berlin.

Anorectal malformations (ARM) are not externally visible and have an uncertain medical course. Only about half of the patients with ARM have satisfactory bowel functions. Studies of ARM have reported reduced quality of life and psychosocial problems in up to 73% of the patients. The aim of the current study was to document the psychiatric comorbidity and the psychosocial need of patients with ARM in a multidimensional diagnostic for the first time. The screening sample (N = 30) included 23 male and 7 female patients aged 4-17 years. The introduced Comprehensive Grading System with a sophisticated perspective of continence and associated problems showed 23 patients suffering severe burden. 70 % of the families confirmed increased psychosocial need. In the diagnostic one third of the patients had psychiatric diagnoses, one third had mild problems and one third had no difficulties. Therefore, a group program should be offered to all patients. To the patients with severe forms of ARM or with increased psychosocial need, the multidimensional diagnostic program including advices and recommendations should be offered. Psychosocial assistance is important to reinforce acceptance and integration of coping with the illness in one's life. Early intervention can prevent psychiatric disorders later in life.
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http://dx.doi.org/10.13109/prkk.2010.59.1.38DOI Listing
April 2010

[Traumatologic pediatric emergencies--part I: Injury, drowning and blunt abdominal trauma].

Anasthesiol Intensivmed Notfallmed Schmerzther 2009 Jun 12;44(6):440-4. Epub 2009 Jun 12.

Klinik für Kinderchirurgie der Charité - Universitätsmedizin Berlin.

Injuries are responsible for considerable morbidity and much long-term or permanent disability. They are also the leading cause of death for children aged 0 to 5. In high income countries around the world 20000 children die each year from injuries. A recent UNICEF report has compiled data for 2001 on the leading cause of death for Europe. The burden of disease measure has identified injury as causative in 40% of years lost from premature death in children. Drowning and near drowning is the number two killer for children aged 0 to 5. In 30% of all cases cardio-pulmonary resuscitation and intensive care are needed. 11.5% of all drowning accidents are fatal, 9.5% of nearly drowned children show extensive neurologic deficits. Though the absolute number of deaths from injury in children has decreased during the last 20 years (in 1980: 18.8 dead children per 100000; in 2004: 3.0 dead children in 100000), still approximately 400 children die from injuries in Germany every year. The public health approach to injury involves not only deaths but also the burden of disease and loss of health from disability. Severe traumatologic pediatric emergencies are thermal injury, drowning and blunt abdominal trauma.
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http://dx.doi.org/10.1055/s-0029-1225753DOI Listing
June 2009