Centralization as the key survival benefit in acute neonatal surgery.

Introduction: Centralization of neonatal surgical care for congenital malformations is already under discussion. Acute care of neonatal emergencies in perinatal centers with affiliated hospitals is not uniformly regulated in Germany. Materials and methods: Analyses are based on acute pediatric surgical care at four affiliated hospitals of a perinatal center. Epidemiologic data and outcome parameters "survival", "intracerebral hemorrhage", and "revision of surgical indication" are assessed. Comparison is made between patients receiving surgical treatment at affiliated hospitals (group A) and patients with transfer to the university center for therapy in case of surgical indication for gastrointestinal diseases (group B). Results: 17 group A-patients are compared to 40 group B-patients. Comparison of epidemiological data reveals no significant differences. There is a survival advantage with transfer to the university center (mortality of 29% in group A vs. 2% in group B, p = 0.007). Intracerebral hemorrhage occurred more frequently in externally treated patients (group A 24% vs. group B 2%, p = 0.024). Surgical indication was revised in 30% of group B at the university center (p = 0.011) with consecutive successful conservative treatment. Conclusion: Transfer of patients at the beginning of the acute phase of gastrointestinal diseases is key to optimize the quality of neonatal surgical care. However, larger population studies should confirm the presented results, discuss restricting factors of real care structures and should rule out bias in triage of patients.

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

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

Unraveling the Genetics of Congenital Diaphragmatic Hernia: An Ongoing Challenge.

Congenital diaphragmatic hernia (CDH) is a congenital structural anomaly in which the diaphragm has not developed properly. It may occur either as an isolated anomaly or with additional anomalies. It is thought to be a multifactorial disease in which genetic factors could either substantially contribute to or directly result in the developmental defect. Patients with aneuploidies, pathogenic variants or de novo Copy Number Variations (CNVs) impacting specific genes and loci develop CDH typically in the form of a monogenetic syndrome. These patients often have other associated anatomical malformations. In patients without a known monogenetic syndrome, an increased genetic burden of de novo coding variants contributes to disease development. In early years, genetic evaluation was based on karyotyping and SNP-array. Today, genomes are commonly analyzed with next generation sequencing (NGS) based approaches. While more potential pathogenic variants are being detected, analysis of the data presents a bottleneck-largely due to the lack of full appreciation of the functional consequence and/or relevance of the detected variant. The exact heritability of CDH is still unknown. Damaging de novo alterations are associated with the more severe and complex phenotypes and worse clinical outcome. Phenotypic, genetic-and likely mechanistic-variability hampers individual patient diagnosis, short and long-term morbidity prediction and subsequent care strategies. Detailed phenotyping, clinical follow-up at regular intervals and detailed registries are needed to find associations between long-term morbidity, genetic alterations, and clinical parameters. Since CDH is a relatively rare disorder with only a few recurrent changes large cohorts of patients are needed to identify genetic associations. Retrospective whole genome sequencing of historical patient cohorts using will yield valuable data from which today's patients and parents will profit Trio whole genome sequencing has an excellent potential for future re-analysis and data-sharing increasing the chance to provide a genetic diagnosis and predict clinical prognosis. In this review, we explore the pitfalls and challenges in the analysis and interpretation of genetic information, present what is currently known and what still needs further study, and propose strategies to reap the benefits of genetic screening.

Lessons Learned from CNV Analysis of Major Birth Defects.

The treatment of major birth defects are key concerns for child health. Hitherto, for the majority of birth defects, the underlying cause remains unknown, likely to be heterogeneous. The implicated mortality and/or reduced fecundity in major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. With the advent of systematic array-based molecular karyotyping, larger cohorts of affected individuals have been screened over the past decade. This review discusses the identification of disease-causing copy-number variations (CNVs) among individuals with different congenital malformations. It highlights the differences in findings depending on the respective congenital malformation. It looks at the differences in findings of CNV analysis in non-isolated complex congenital malformations, associated with central nervous system malformations or intellectual disabilities, compared to isolated single organ-system malformations. We propose that the more complex an organ system is, and the more genes involved during embryonic development, the more likely it is that mutational de novo events, comprising CNVs, will confer to the expression of birth defects of this organ system.

A classic twin study of isolated gastroschisis.

The etiology of gastroschisis remains elusive. A classic twin study was used to assess the relative contribution of environmental and genetic factors in its development. Screening of 4872 twin pregnancies identified three unreported twin pairs comprising two monozygous and one dizygous discordant pair of twins. Review of the literature identified an additional 21 twin pairs. We observed lower pair- and proband-wise concordance rates for monozygotic compared to dizygotic twin pairs, pair- and proband-wise concordance ratios below 1.0. Our results suggest environmental to play a greater role than genetic factors in the development of gastroschisis.