Exome survey of individuals affected by VATER/VACTERL with renal phenotypes identifies phenocopies and novel candidate genes.

The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac anomalies (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb anomalies (L). For the clinical diagnosis, the presence of at least three CFs is required, individuals presenting with only two CFs have been categorized as VATER/VACTERL-like. The majority of VATER/VACTERL individuals displays a renal phenotype. Hitherto, variants in FGF8, FOXF1, HOXD13, LPP, TRAP1, PTEN, and ZIC3 have been associated with the VATER/VACTERL association; however, large-scale re-sequencing could only confirm TRAP1 and ZIC3 as VATER/VACTERL disease genes, both associated with a renal phenotype. In this study, we performed exome sequencing in 21 individuals and their families with a renal VATER/VACTERL or VATER/VACTERL-like phenotype to identify potentially novel genetic causes. Exome analysis identified biallelic and X-chromosomal hemizygous potentially pathogenic variants in six individuals (29%) in B9D1, FREM1, ZNF157, SP8, ACOT9, and TTLL11, respectively. The online tool GeneMatcher revealed another individual with a variant in ZNF157. Our study suggests six biallelic and X-chromosomal hemizygous VATER/VACTERL disease genes implicating all six genes in the expression of human renal malformations.

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

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.

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

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

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

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.

Bowel Management in Hirschsprung Disease-Pre-, Peri- and Postoperative Care for Primary Pull-Through.

(1) Background: Bowel management contributes throughout the pathway of care for children with Hirschsprung. Preoperative bowel management prepares the child and family for the pull-through surgery. Perioperative bowel management supports early recovery and tailored bowel management in the follow-up supports the achievement of social continence. (2) Methods: We conducted a cross-sectional assessment of our institutional bowel management program to illustrate the pre-, peri- and postoperative bowel management strategies. (3) Results: A total of 31 children underwent primary pull-through, 23 without a stoma and 8 with a stoma, at a median age of 9 months. All children without a stoma were prepared for surgery by using rectal irrigations. Children with a stoma were prepared for surgery with a transfer of stoma effluent. Transanal irrigation supported early recovery. (4) Conclusions: Bowel management is a key pillar of the management of children with Hirschsprung disease. Incorporating bowel management in the pathway of care facilitates primary pull-through and supports perioperative recovery.

Treatment of Anorectal Malformations in German Hospitals: Analysis of National Hospital Discharge Data from 2016 to 2021.

BACKGROUND: Anorectal malformations (ARMs) are complex congenital anomalies. The corrective operation is demanding and schedulable. Based on complete national data, patterns of care have not been analyzed in Germany yet. METHODS: All cases with ARM were analyzed (1) at the time of birth and (2) during the hospital stay for the corrective operation, based on the national hospital discharge data (DRG statistics). Patient's comorbidities, treatment characteristics, hospital structures, and the outcome of corrective operations were analyzed with respect to the hospitals' caseload. RESULTS: From 2016 to 2021, 1,726 newborns with ARM were treated at the time of birth in 388 hospitals. Of these hospitals, 19% had neither a pediatric nor a pediatric surgical department. At least one additional congenital anomaly was present in 49% of cases and 7% of the newborns had a birthweight below 1,500 g.In all, 2,060 corrective operations for ARM were performed in 113 hospitals in the same time period. In 24.5% of cases, at least one major complication was documented. One-third of the operations were performed in 56 hospitals, one-third in 20 hospitals, and one-third in 10 hospitals with median annual case numbers of 2, 5, and 10, respectively.Hospitals with the highest caseload operated cloacal defects more often than hospitals with the lowest caseload (7 vs. 2%) and had more early complications than hospitals with the lowest caseload (30 vs. 21%). This difference was not statistically significant after risk adjustment. CONCLUSIONS: Children with ARM are multimorbid. Early complications after corrective surgery are common. Considering the large number of hospitals with a very low caseload, centralization of care for the complex and elective corrective surgery for ARM remains a key issue for quality of care.

Treatment of Hirschsprung's Disease in Germany: Analysis of National Hospital Discharge Data From 2016 to 2022.

BACKGROUND: Hirschsprung's disease (HD) is a rare and complex malformation. The corrective operation is challenging and schedulable. The complete care situation for the corrective surgery for HD in Germany is uninvestigated. METHODS: For the years 2016-2022, the microdata of the diagnosis-related groups (DRG) -statistics provided by the Research Data Center of the German Federal Statistical Office were accessed. All hospital stays for corrective surgery of HD in patients aged 0-17 were analyzed for patient's comorbidities, treatment characteristics and hospital structures. The occurrence of severe early postoperative complications during the hospital stay were documented. RESULTS: The care structure for HD in Germany is decentralized with 109 hospitals performing 1199 corrective surgeries in 7 years. 75% of the participating hospitals performed three or less cases per year and 55 participating hospitals did not perform corrective surgery for HD each year. Early postoperative complications were common with at least one severe early complication in 18.6% of the cases. With an overall low case load per hospital, a volume outcome relationship cannot be established within Germany. Compared to international high volume centers the quality of outcomes for some of the investigated parameters was reduced. Despite the establishing of centers of expertise by the European reference network ERNICA for the treatment of HD no trend towards centralization occurred in Germany. CONCLUSIONS: The corrective surgery for HD in Germany is decentralized and results in an overall high rate of early complications. The comparison with international studies from high-volume centers indicates potential for improvement for the corrective surgery of HD. Centralization remains essential for the improvement of care for patients with HD.

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.

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.

[Treatment for fecal incontinence in patients with anorectal malformations. Introduction of a therapeutic approach]. / Therapie der Inkontinenz am Beispiel anorektaler Fehlbildungen Vorstellung eines Behandlungskonzepts.

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.

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.

Inheritance of the VATER/VACTERL association.

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.

[Use of operationalized psychodynamic diagnostics in childhood and adolescence in patients with somatic diseases]. / Anwendung der Operationalisierten Psychodynamischen Diagnostik im Kindes- und Jugendalter bei somatischer Krankheit Eine Pilotstudie bei Patienten mit Anorektaler Malformation.

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.

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

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.

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.

[Comorbidity and psychosocial need in children and adolescents with anorectal malformations]. / Psychiatrische Komorbidität und psychosozialer Betreuungsbedarf bei Kindern und Jugendlichen mit anorektalen Malformationen.

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.

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

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.

[Traumatologic pediatric emergencies--part I: Injury, drowning and blunt abdominal trauma]. / Traumatologische Kindernotfälle (Teil I): Verbrennungen, Ertrinken und stumpfes Bauchtrauma.

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.

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.

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

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.