Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk ...factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (
-value of the lead SNV: 4.17 × 10
). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized
at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate
in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.
Abstract Background Congenital diaphragmatic hernia (CDH) is a lethal birth defect, which occurs in 1:2000–3000 live births. Bilateral CDH is a rare form (1%), with a high mortality. This study ...presents the outcomes of the largest cohort of bilateral CDH patients. Methods The records of patients with bilateral CDH from the Congenital Diaphragmatic Hernia Registry born between 1995 and 2015 were retrospectively analyzed to identify parameters associated with mortality. Results Eighty patients with a bilateral CDH were identified. Overall mortality was 74% (n = 59). Apgar scores at 1 and 5 min were statistically lower in the non-survivors compared to the survivors (median 3.0 and 5.0, versus 6.5 and 8.0, respectively, p < 0.001). All survivors were repaired (n = 21), compared to 22% of the non-survivors (n = 17). The type of repair was equally divided in the survivors (52% primary versus 48% patch), while non-survivors were mainly patch repaired (82% versus 12%). Nineteen were treated with extracorporeal membrane oxygenation (ECMO) (24%), only three of them survived. When calculating the risk on mortality for the patients who lived until repair, ECMO had an adjusted odds ratio for mortality of 10.8 (95%CI:2.0–57.7) and patch repair 5.2 (95%CI:0.8–34.9). Conclusions The treatment of bilateral CDH patients remains challenging with a high mortality rate. Lower Apgar-scores, ECMO (probably as a surrogate for the severity of disease), and patch repairwere negatively associated with outcome. Level of evidence : Level IV study
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.
Orofacial clefts (OFC) are among the most common birth defects worldwide. The etiology of non-syndromic OFC is still largely unknown. During embryonic development, the cell adhesion molecule ...E-cadherin, encoded by CDH1, is highly expressed in the median edge epithelium of the palate. Furthermore, in multiple families with CDH1 mutations, OFC cases are observed. To determine whether CDH1 is a causative gene for non-syndromic OFC and to assess whether CDH1 mutation screening in non-syndromic OFC patients enables identification of families at risk of cancer, direct sequencing of the full coding sequence of CDH1 was performed in a cohort of 81 children with non-syndromic OFC. Eleven children had heterozygous CDH1 sequence variants, 5 cases with 4 distinct missense mutations and 8 cases with 4 intronic variants. Using a combination of in silico predictions and in vitro functional assays, three missense mutations in four non-syndromic OFC patients were predicted to be damaging to E-cadherin protein function. The intronic variants including one tested in an in vitro assay appeared to be benign, showing no influence on splicing. Functionally relevant heterozygous CDH1 missense mutations were found in 4 out of 81 (5%) patients with non-syndromic OFC. This finding opens a new pathway to reveal the molecular basis of non-syndromic OFC. Cancer risk among carriers of these mutations needs to be defined.
Purpose Hypospadias is a common congenital malformation of the male external genitalia. Association studies for single nucleotide polymorphisms in genes encoding steroid 5alpha-reductase, estrogen ...receptors 1 and 2, and activating transcription factor 3 have been equivocal. We examined whether nonreplication of findings for 4 single nucleotide polymorphisms in these genes could be due to interaction with environmental exposures. Materials and Methods We genotyped 712 Dutch hypospadias case-parent triads for the 4 single nucleotide polymorphisms, used questionnaire information to determine exposures and performed association tests using the log-linear approach. We studied gene-environment interactions for the 4 single nucleotide polymorphisms with exposure to estrogens, cytokines or cigarette smoke, multiple birth, being born small for gestational age, maternal hypertension or preeclampsia, high body mass index or primiparity. In addition, the presence of maternal genetic and parent of origin effects was tested. Results Gene-environment interactions were identified for rs523349 in SRD5A2 with estrogen exposure and maternal hypertension or preeclampsia, as well as for rs11119982 in ATF3 with exposure to cytokines. Both single nucleotide polymorphisms seemed to influence hypospadias risk only in exposed cases. For rs6932902 in ESR1 only maternally derived alleles appeared to increase hypospadias risk in offspring. Conclusions Interactions between genetic and environmental factors may help to explain nonreplication in genetic studies of hypospadias.
Background
Chronic respiratory diseases and use of antiasthmatic medication during pregnancy may both play a role in the etiology of congenital anorectal malformations (ARM). However, it is unclear, ...whether the medication use or the underlying condition would be responsible. Therefore, our aim was to unravel the role of maternal chronic respiratory diseases from that of antiasthmatic medication in the etiology of ARM.
Methods
We obtained 412 ARM patients and 2,137 population‐based controls from the Dutch AGORA data‐ and biobank. We used maternal questionnaires and follow‐up telephone interviews to obtain information on chronic respiratory diseases, antiasthmatic medication use, and potential confounders. Multivariable logistic regression analyses were performed to estimate odds ratios (ORs) with 95% confidence intervals (95% CI).
RESULTS
We observed higher risk estimates among women with chronic respiratory diseases with and without medication use (1.4 0.8–2.7 and 2.0 0.8–5.0), both in comparison to women without a chronic respiratory disease and without medication use. Furthermore, increased ORs of ARM were found for women using rescue medication (2.4 0.8–7.3) or a combination of maintenance and rescue medication (2.5 0.9–6.7). In addition, increased risk estimates were observed for women having nonallergic triggers (2.5 1.0–6.3) or experiencing exacerbations during the periconceptional period (3.5 1.4–8.6).
CONCLUSIONS
Although the 95% CIs of most associations include the null value, the risk estimates all point towards an association between uncontrolled chronic respiratory disease, instead of antiasthmatic medication use, with ARM in offspring. Further in‐depth studies towards mechanisms of this newly identified risk factor are warranted.
Abstract Background Patients born with a Congenital Diaphragmatic Hernia (CDH) have a high mortality and morbidity. After discharge, complications and long term morbidity are still encountered. This ...study describes the factors related to the surgical long term outcomes in CDH survivors. Methods A cohort of CDH patients born between 2000–2014, with a minimum of two years follow up, were included in this retrospective study. Demographics, CDH specific characteristics, treatment, and long term surgical outcome were evaluated using multivariate logistic regression analyses. Results 112 patients were included, with a mean follow up of 7.3 years (SD 3.8). The majority had primary repair, but 31% received patch repair. Recurrence was reported in 7% of all patients. However, recurrence risk increased for patients with Extracorporeal Membrane Oxygenation (ECMO) treatment (ORadjusted:6.3, 95%CI:1.2–33.9). This risk was highest for patients needing both ECMO and patch repair (OR:11.2, 95%CI:2.3–54.1). Small bowel obstructions (SBO) were observed in 20% and was associated with patch repair (ORadjusted:3.5, 95%CI:1.2–10.0), but ECMO treatment seemed to reduce this risk (ORadjusted:0.2, 95%CI:0.0–1.0). Thoracic deformations (36%) was diagnosed most often after patch repair, especially when ECMO was needed (60%) as well. Conclusions This retrospective study shows that the incidence of surgical long term morbidity of CDH is relatively high, with different factors accounting for this. Diaphragmatic hernia recurrence was strongest associated with ECMO treatment in combination with patch repair, while SBO's were associated with patch repair, with an unexpected protective effect of ECMO treatment. Type of Study: Case Control Study-Level III.
To develop a prediction model for postoperative complications after primary one-stage hypospadias correction to improve preoperative parental counseling.
In this retrospective cohort study, data were ...collected from 356 patients with anterior or middle hypospadias who had a one-stage hypospadias correction from 2003 onwards. Potential treatment- and patient-related factors were selected and used to develop a prediction model for postoperative complications within one year (wound-related complications, urinary tract infections, fistulas, stenosis, and prepuce-related complications). Multivariable logistic regression analysis with stepwise backward selection and a p-value of 0.20 was used to select the final model, which was internally validated using the bootstrap procedure.
Complications within one year postoperatively occurred in 66 patients (19%), of which 13% and 37% were seen in anterior and middle type of hypospadias, respectively. Hypospadias phenotype, surgical technique, chordectomy, and surgeon's experience were included in the final prediction model, whereas none of the patient-related factors were. The final model had a good discriminative ability (bias corrected C statistic 0.70) and calibration.
Using easily obtainable information, this model showed good accuracy in predicting complications within one year after hypospadias surgery. It is a first step towards individualized risk prediction of postoperative complications for anterior and middle hypospadias and can assist in preoperative parental counseling.
Prognostic study.
Level II.
Congenital diaphragmatic hernia (CDH) is a rare birth defect with a high mortality and morbidity. Nonscrotal testes (NST) are the most reported genital anomaly in boys. Both defects have known ...associated anomalies, but little is known about the association between CDH and NST. This study evaluates this association and the location of the NST in a large cohort of male CDH survivors. Moreover, we analyzed possible associative factors for NST in CDH patients.
A cohort of CDH patients, born between January 2000 and March 2014 and treated in a high volume expertise center, was evaluated retrospectively. Boys with a minimum follow-up of 18months were included. The patients were evaluated for testes location, performed orchidopexy, and possible associative factors such as birth weight, gestational age, other congenital anomalies and CDH characteristics (surgical treatment, approach and ECMO).
Seventy-five CDH patients were included. Twenty-seven (36%) were diagnosed with NST, of which 22 (29%) received orchidopexy. In 54 patients (72%) there were reports on testes location at birth and location was known for all patients at the age of 18months, although side of NST was unknown in four. The location of the NST was mostly ipsilateral to the CDH (n=20, 87%), of which eight (35%) had a bilateral NST with a unilateral CDH. There were no significant differences in birth weight, gestational age, and CDH specific characteristics in patients with or without NST.
This study shows a strong association between CDH and NST, with a prevalence of 36%. However, no specific characteristics of the CDH were related to the NST. The testes of all male CDH patients should be thoroughly evaluated in the first year of their life, to ensure a proper and timely treatment.
Level IV; case series.
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