Iris A.L.M. van Rooij

Teratogenic mechanisms of medical drugs

BACKGROUND Although prescription drug use is common during pregnancy, the human teratogenic risks are undetermined for more than 90% of drug treatments approved in the USA during the past decades. A particular birth defect may have its origins through multiple mechanisms and possible exposures, including medications. A specific pathogenic process may result in different outcomes depending upon factors such as embryonic age at which a drug is administered, duration and dose of exposure and genetic susceptibility. This review focuses on the teratogenic mechanisms associated with a number of medications. METHODS We used three methods to identify the teratogenic mechanisms of medications: the MEDLINE and EMBASE databases, two recent books on teratogenic agents and a list of drugs classified as U.S. Food and Drug Administration class D or X. Mechanisms were included only if they are associated with major structural birth defects and medications that are used relatively frequently by women of reproductive age. RESULTS We identified six teratogenic mechanisms associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption and specific receptor- or enzyme-mediated teratogenesis. Many medications classified as class X are associated with at least one of these mechanisms. CONCLUSIONS Identifying teratogenic mechanisms may not only be relevant for etiologic and post-marketing research, but may also have implications for drug development and prescribing behavior for women of reproductive age, especially since combinations of seemingly unrelated prescription and over the counter medications may utilize similar teratogenic mechanisms with a resultant increased risk of birth defects.

Neuromuscular involvement in various types of Ehlers-Danlos syndrome.

Ehlers–Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Muscle involvement is plausible based on recently discovered interactions between muscle cells and extracellular matrix molecules; however, muscle symptoms are only sporadically reported. We designed a cross‐sectional study to find out whether neuromuscular features are part of EDS.

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

PurposeThe 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.MethodsThe 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.ResultsCurrently, 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.ConclusionFirst 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.

Risk factors for different phenotypes of hypospadias: results from a Dutch case-control study

The various phenotypes of hypospadias may result from disturbances of dissimilar embryonic processes in different time windows, suggesting aetiological heterogeneity; however, only a few studies have investigated the risk factors for the different hypospadias phenotypes. The study confirmed that genetic predisposition possibly plays a role in anterior and middle hypospadias, as shown by the large effect estimates for familial occurrence of these forms of hypospadias. By contrast, the posterior phenotype was more often associated with pregnancy‐related factors, such as primiparity, preterm delivery, and being small for gestational age. New findings were that hormone‐containing contraceptive use after conception increased the risk of middle and posterior hypospadias, while multiple pregnancies were associated with the posterior form in particular.

Long-term follow-up of functional outcome in patients with a cloacal malformation: A systematic review

BACKGROUND Reconstructive surgery is performed in patients with cloacal malformations to achieve anorectal, urological, and gynecological function. The aim of this study was to evaluate the functional outcome of cloacal malformation repair as reported in literature. METHODS A systematic literature search was conducted according to PRISMA guidelines using PubMed, EMbase, and Web-of-Science. Records were assessed for the reporting of functional outcomes, which was divided into anorectal, urological, or gynecological function. Studies were used in qualitative (Rangel score) and quantitative syntheses. RESULTS Twelve publications were eligible for inclusion. Voluntary bowel movements were reported in 108 of 188 (57%), soiling in 146 of 205 (71%), and constipation in 31 of 61 patients (51%). Spontaneous voiding was reported for 138 of 299 patients (46%). 141 of 332 patients (42%) used intermittent catheterization, and 53 of 237 patients (22%) had a urinary diversion. Normal menstruations were reported for 25 of 71 patients (35%). Centers with limited experience reported similar outcome compared to centers with more experience (≥1 patients/year). CONCLUSION In this review we present functional outcome of the largest pooled cohort of patients with cloacal malformations as reported from 1993 to 2012. Functional disturbances are frequently encountered in anorectal, urological, as well as gynecological systems. Reporting of functional outcome in these patients should improve to increase knowledge about long-term results in patients with this rare malformation and to reach higher study quality. Especially, sacral and spinal anomalies should always be reported given their impact on functional outcome. Specialized care centers may be of great importance for patients with rare and complex conditions.

Transanal endorectal pull-through for classic segment Hirschsprung's disease: With or without laparoscopic mobilization of the rectosigmoid?

BACKGROUND It has been suggested that the outcome of transanal endorectal pull-through for classic Hirschprungs disease can be improved by laparoscopically mobilizing the colon before the pullthrough. METHODS Charts of 43 patients (2005-2009) with proven recto-sigmoid aganglionosis were retrospectively analyzed with respect to postoperative outcomes. Twenty-one had been treated with the transanal endorectal pull through (TERPT) and 22 with the laparoscopically assisted TERPT (LTERPT). RESULTS Gender ratio, congenital anomalies, preoperative enterostomy, and follow up did not differ between the groups. More colon was resected in the TERPT group: median 25 cm vs. 15 cm in the L-TERPT group (p<0.001). The TERPT-procedure took less time: median 153 min. vs. L-TERPT 263 min (p<0.001). Postoperatively, three patients showed colonic torsions after TERPT (p=0.07). The long-term clinical outcomes did not differ significantly between both groups. There was a significant association between length of resection and obstructive symptoms (OR=0.92, p=0.01). CONCLUSION Postoperative and clinical outcomes are similar using the TERPT or L-TERPT to correct classic segment Hirschsprungs disease. Prevention of colonic torsion should be the prime concern during the TERPT procedure. L-TERPT requires laparoscopic equipment and takes more operation time, whereas TERPT leaves no visible scars. The positive relation between the larger length of resection and obstructive symptoms requires additional research.

Genetics of hypospadias: are single nucleotide polymorphisms in srd5a2, esr1, esr2 and atf3 really associated with the malformation?

Purpose Hypospadias is a common congenital malformation of the male external genitalia with a multifactorial etiology. Little is known about the genes involved in Hypospadias. A few genetic associations have been reported, but mainly in studies of small sample size. Most of these associations have not been replicated. The aim of this study was to investigate whether previously reported associations for four single nucleotide polymorphisms (SNPs) in genes involved in hormonal pathways could be replicated in a large Dutch Hypospadias sample. The SNPs investigated are rs523349 in steroid-5-alpha-reductase (SRD5A2), rs6932902 in estrogen receptor 1 (ESR1), rs2987983 in ESR2 and rs11119982 in activating transcription factor 3 (ATF3). Material and Methods We genotyped 620 Caucasian Hypospadias cases and 596 controls for the four SNPs using TaqMan-based genotyping. Results We did not replicate the associations of the SNPs in SRD5A2 and ESR1 with Hypospadias. The SNPs in ESR2 and ATF3 were borderline associated with Hypospadias (odds ratios 0.9 (95% confidence interval (CI) 0.7-1.0) and 1.2 (95% CI 1.0-1.4), respectively), but in the opposite direction compared to earlier publications. Stratification according to the localization of the urethral opening produced comparable results in the subgroups. Conclusions The lack of consistency between our and previously performed studies might represent spurious results or chance findings found in our or the earlier studies, differences in criteria used to select the study populations, or a real difference between the populations. These results once again confirm the importance of replication in genetic association approaches.