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PURPOSE: To assess the number, characteristics, and functional short-, and midterm outcomes of patients with rectal atresia (RA) and stenosis (RS) in the ARM-Net registry. METHODS: Patients with RA/RS were retrieved from the ARM-Net registry. Patient characteristics, associated anomalies, surgical approach, and functional bowel outcomes at 1 and 5-year follow-up were assessed. RESULTS: The ARM-Net registry included 2619 patients, of whom 36 (1.3%) had RA/RS. Median age at follow-up was 7.0 years (IQR 2.3-9.0). Twenty-three patients (63.9%, RA n = 13, RS n = 10) had additional anomalies. PSARP was the most performed reconstructive surgery for both RA (n = 9) and RS (n = 6) patients. At 1-year follow-up, 11/24 patients with known data (45.8%, RA n = 5, RS n = 6) were constipated, of whom 9 required stool softeners and/or laxatives. At 5-year follow-up, 8/9 patients with known data (88.9%, RA n = 4, RS n = 4) were constipated, all requiring laxatives and/or enema. CONCLUSION: RA and RS are rare types of ARM, representing 1.3% of patients in the ARM-Net registry. Additional anomalies were present in majority of patients. Different surgical approaches were performed as reconstructive treatment, with constipation occurring in 46% and 89% of the patients at 1 and 5-year follow-up. However, accurate evaluation of long-term functional outcomes remains challenging.
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Malformações Anorretais , Doenças Retais , Humanos , Pré-Escolar , Criança , Reto/cirurgia , Reto/anormalidades , Laxantes , Constrição Patológica/cirurgia , Doenças Retais/cirurgia , Malformações Anorretais/epidemiologia , Malformações Anorretais/cirurgia , Constipação Intestinal , Canal Anal/anormalidades , Estudos RetrospectivosRESUMO
Introduction: Posterior urethral valves (PUV) is a congenital disorder causing an obstruction of the lower urinary tract that affects approximately 1 in 4,000 male live births. PUV is considered a multifactorial disorder, meaning that both genetic and environmental factors are involved in its development. We investigated maternal risk factors for PUV. Methods: We included 407 PUV patients and 814 controls matched on year of birth from the AGORA data- and biobank and three participating hospitals. Information on potential risk factors (family history of congenital anomalies of the kidney and urinary tract (CAKUT), season of conception, gravidity, subfertility, and conception using assisted reproductive techniques (ART), plus maternal age, body mass index, diabetes, hypertension, smoking, and use of alcohol and folic acid) was derived from maternal questionnaires. After multiple imputation, adjusted odds ratios (aORs) were estimated using conditional logistic regression corrected for minimally sufficient sets of confounders determined using directed acyclic graphs. Results: A positive family history and low maternal age (<25 years) were associated with PUV development [aORs: 3.3 and 1.7 with 95% confidence intervals (95% CI) 1.4-7.7 and 1.0-2.8, respectively], whereas higher maternal age (>35 years) was associated with a lower risk (aOR: 0.7 95% CI: 0.4-1.0). Maternal preexisting hypertension seemed to increase PUV risk (aOR: 2.1 95% CI: 0.9-5.1), while gestational hypertension seemed to decrease this risk (aOR: 0.6 95% CI: 0.3-1.0). Concerning use of ART, the aORs for the different techniques were all above one, but with very wide 95% CIs including one. None of the other factors studied were associated with PUV development. Conclusion: Our study showed that family history of CAKUT, low maternal age, and potentially preexisting hypertension were associated with PUV development, whereas higher maternal age and gestational hypertension seemed to be associated with a lower risk. Maternal age and hypertension as well as the possible role of ART in the development of PUV require further research.
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BACKGROUND: Registries are important in rare disease research. The Anorectal Malformation Network (ARM-Net) registry is a well-established European patient registry collecting demographic, clinical, and functional outcome data. We assessed the quality of this registry through review of the structure, data elements, collected data, and user experience. MATERIAL AND METHODS: Design and data elements were assessed for completeness, consistency, usefulness, accuracy, validity, and comparability. An intra- and inter-user variability study was conducted through monitoring and re-registration of patients. User experience was assessed via a questionnaire on registration, design of registry, and satisfaction. RESULTS: We evaluated 119 data elements, of which 107 were utilized and comprised 42 string and 65 numeric elements. A minority (37.0%) of the 2278 included records had complete data, though this improved to 83.5% when follow-up elements were excluded. Intra-observer variability demonstrated 11.7% incongruence, while inter-observer variability was 14.7%. Users were predominantly pediatric surgeons and typically registered patients within 11-30 min. Users did not experience any significant difficulties with data entry and were generally satisfied with the registry, but preferred more longitudinal data and patient-reported outcomes. CONCLUSIONS: The ARM-Net registry presents one of the largest ARM cohorts. Although its collected data are valuable, they are susceptible to error and user variability. Continuous evaluations are required to maintain relevant and high-quality data and to achieve long-term sustainability. With the recommendations resulting from this study, we call for rare disease patient registries to take example and aim to continuously improve their data quality to enhance the small, but impactful, field of rare disease research. LEVEL OF EVIDENCE: V.
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Malformações Anorretais , Doenças Raras , Criança , Humanos , Sistema de Registros , Confiabilidade dos Dados , Inquéritos e Questionários , Coleta de DadosRESUMO
BACKGROUND: The etiology of congenital solitary functioning kidney (CSFK) is largely unknown but likely includes various risk factors. We performed a case-control study to compare exposure to environmental and parental risk factors during embryonic kidney development between children with CSFK and healthy controls. METHODS: We included 434 children with CSFK and 1302 healthy controls from the AGORA data- and biobank matched on year of birth. Exposure to potential risk factors was investigated using parental questionnaire data. Crude and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were estimated for each potential risk factor. Multiple imputation was used to deal with missing values. Confounders for each potential risk factor were selected using directed acyclic graphs. RESULTS: Maternal stress was newly identified as a risk factor for CSFK (aOR 2.1, 95% CI 1.2-3.5). Known associations with conception using in vitro fertilization/intracytoplasmic sperm injection (aOR 1.8, 95% CI 1.0-3.2), maternal infections during pregnancy (aOR 2.5, 95% CI 1.4-4.7), smoking during pregnancy (aOR 1.4, 95% CI 1.0-2.0), and parental CAKUT (aOR 6.6, 95% CI 2.9-15.1) were confirmed, but previous associations with diabetes and obesity could not be replicated. Folic acid supplement use and younger maternal age seemed to reduce the risk of CSFK (aORs 0.7, 95% CI 0.5-1.0, and 0.8, 95% CI 0.6-1.0, respectively). CONCLUSIONS: Environmental and parental risk factors are likely to be involved in the development of CSFK and future studies should combine genetic, environmental, and gene-environment interaction analyses. Women wanting to become pregnant should consider optimizing their health and lifestyle. A higher-resolution version of the Graphical abstract is available as Supplementary information.
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Rim Único , Gravidez , Criança , Masculino , Humanos , Feminino , Estudos de Casos e Controles , Sêmen , Fatores de Risco , PaisRESUMO
Congenital solitary functioning kidney (CSFK) is a birth defect that occurs in 1:1500 children and predisposes them to kidney injury. Its aetiology is likely multifactorial. In addition to known monogenic causes and environmental risk factors, common genetic variation may contribute to susceptibility to CSFK. We performed a genome-wide association study among 452 patients with CSFK and two control groups of 669 healthy children and 5363 unaffected adults. Variants in two loci reached the genome-wide significance threshold of 5 × 10-8, and variants in 30 loci reached the suggestive significance threshold of 1 × 10-5. Of these, an identified locus with lead single nucleotide variant (SNV) rs140804918 (odds ratio 3.1, p-value = 1.4 × 10-8) on chromosome 7 was most promising due to its close proximity to HGF, a gene known to be involved in kidney development. Based on their known molecular functions, both KCTD20 and STK38 could explain the suggestive significant association with lead SNV rs148413365 on chromosome 6. Our findings need replication in an independent cohort of CSFK patients before they can be established definitively. However, our analysis suggests that common variants play a role in CSFK aetiology. Future research could enhance our understanding of the molecular mechanisms involved.
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Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.
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Extrofia Vesical , Neoplasias da Bexiga Urinária , Humanos , Animais , Camundongos , Extrofia Vesical/genética , Extrofia Vesical/complicações , Estudo de Associação Genômica Ampla , Neoplasias da Bexiga Urinária/genética , Transcriptoma , Efrina-A1/genéticaRESUMO
BACKGROUND: Outcome of patients operated for anorectal malformation (ARM) type rectovestibular fistula (RVF) is generally considered to be good. However, large multi-center studies are scarce, mostly describing pooled outcome of different ARM-types, in adult patients. Therefore, counseling parents concerning the bowel function at early age is challenging. Aim of this study was to evaluate bowel function of RVF-patients at preschool/early childhood age and determine risk factors for poor functional outcome. METHODS: A multi-center cohort study was performed. Patient characteristics, associated anomalies, sacral ratio, surgical procedures, post-reconstructive complications, one-year constipation, and Bowel Function Score (BFS) at 4-7 years of follow-up were registered. Groups with below normal (BFS < 17; subgroups 'poor' ≤ 11, and 'fair' 11 < BFS < 17) and good outcome (BFS ≥ 17) were formed. Univariable analyses were performed to detect risk factors for outcome. RESULTS: The study included 111 RVF-patients. Median BFS was 16 (range 6-20). The 'below normal' group consisted of 61 patients (55.0%). Overall, we reported soiling, fecal accidents, and constipation in 64.9%, 35.1% and 70.3%, respectively. Bowel management was performed in 23.4% of patients. Risk factors for poor outcome were tethered cord and low sacral ratio, while sacral anomalies, low sacral ratio, prior enterostomy, post-reconstructive complications, and one-year constipation were for being on bowel management. CONCLUSIONS: Although median BFS at 4-7 year follow-up is nearly normal, the majority of patients suffers from some degree of soiling and constipation, and almost 25% needs bowel management. Several factors were associated with poor bowel function outcome and bowel management. LEVEL OF EVIDENCE: Level III.
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Malformações Anorretais , Fístula Retal , Adulto , Canal Anal/anormalidades , Canal Anal/cirurgia , Malformações Anorretais/complicações , Malformações Anorretais/epidemiologia , Malformações Anorretais/cirurgia , Criança , Pré-Escolar , Estudos de Coortes , Constipação Intestinal/complicações , Seguimentos , Humanos , Fístula Retal/epidemiologia , Fístula Retal/etiologia , Fístula Retal/cirurgia , Reto/cirurgia , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Anorectal malformation (ARM) is a relatively frequently occurring congenital anomaly of hindgut development with a prevalence of 1 in 3,000 live births. ARM may present as an isolated anomaly, but it can also be associated with other anomalies, sometimes as part of a recognizable syndrome. After birth, much medical attention is given to the treatment and restoring of bowel function in children with ARM. Effort should also be given to studying the etiology of the ARM in these patients. This information is important to both the medical community and the family, because it can help guide treatment and provides information on the long-term prognosis of the patient and recurrence risk in the family.In this article, we will review the current knowledge on the (genetic) etiology of (syndromic) ARM and provide guidelines for (family) history taking and clinical and genetic studies of ARM patients and their families, which is needed to study the causal factors in an ARM patient and for genetic counseling of the families.
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Malformações Anorretais , Criança , Aconselhamento Genético , Humanos , PrevalênciaRESUMO
BACKGROUND: Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development. OBJECTIVE: To identify genetic variants associated with kidney injury in patients with obstructive uropathy. DESIGN SETTING AND PARTICIPANTS: We included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Signs of kidney injury were defined as dialysis, nephrectomy, kidney transplantation, estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at <45%. We used χ2 tests to calculate p values and odds ratios for >600 000 single-nucleotide polymorphisms (SNPs) in the discovery sample comparing patients with and without signs of kidney injury within 5 yr after surgery. We performed stratified analyses for PUV and UPJO and Kaplan-Meier and Cox regression analyses in the discovery and two replication samples for the associated SNPs, and RNA and protein expression analyses for the associated gene in fetal tissues. RESULTS AND LIMITATIONS: Despite the small and nonhomogeneous sample, we observed suggestive associations for six SNPs in three loci, of which rs6874819 in the CDH12 gene was the most clear (p = 7.5 × 10-7). This SNP also seemed to be associated with time to kidney injury in the PUV discovery and replication samples. RNA expression analyses showed clear CDH12 expression in fetal kidneys, which was confirmed by protein immunolocalization. CONCLUSIONS: This study identified CDH12 as a candidate gene for kidney injury in PUV. PATIENT SUMMARY: We found that variants of the CDH12 gene increase the risk of kidney injury in patients with extra flaps of tissue in the urethra (posterior urethral valves). This is the first report on this gene in this context. Our study provides interesting new information about the pathways involved and important leads for further research for this condition.
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BACKGROUND/PURPOSE: Parental decisional conflict and decisional regret are aspects in parental adjustment to childhood elective surgery. This study assessed correlates of parental decisional regret in parents of young boys treated for hypospadias. METHODS: Parents of 261 boys treated for hypospadias at the Radboudumc between 2006 and 2014 were approached to complete questionnaires on socio-demographics, clinical details, postoperative outcomes, decisional conflict and decisional regret. RESULTS: Of the 97 participating parents, 50.5% reported some form of decisional regret, in 11.3% this was moderate to strong. Decisional conflict (ß = .68, p < .001) and psychosocial behavior problems of the child (ß = .20, p < .05) significantly predicted decisional regret. Demographic and medical variables did not correlate with parental decisional regret. CONCLUSIONS: A substantial number of parents report some form of decisional regret regarding the elective surgery for hypospadias in their child. Although most parents only show mild forms of regret, in the perspective of discussions on this surgery in early childhood, future research could shed more light on the interrelationship between medical and psychosocial factors in the process of decision-making around surgery, in boys with hypospadias and their parents.
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Hipospadia , Criança , Pré-Escolar , Tomada de Decisões , Emoções , Humanos , Hipospadia/cirurgia , Masculino , Pais , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The VACTERL association (VACTERL) includes at least three of these congenital anomalies: vertebral, anal, cardiac, trachea-esophageal, renal, and limb anomalies. Assisted reproductive techniques (ART), pregestational diabetes mellitus, and chronic lower obstructive pulmonary disorders (CLOPD) have been associated with VACTERL. We aimed to replicate these findings and were interested in additional maternal risk factors. METHODS: A case-control study using self-administered questionnaires was performed including 142 VACTERL cases and 2,135 population-based healthy controls. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). RESULTS: Parents who used invasive ART had an increased risk of VACTERL in offspring (aOR 4.4 [95%CI 2.1-8.8]), whereas the increased risk for mothers with CLOPD could not be replicated. None of the case mothers had pregestational diabetes mellitus. Primiparity (1.5 [1.1-2.1]) and maternal pregestational overweight and obesity (1.8 [1.2-2.8] and 1.8 [1.0-3.4]) were associated with VACTERL. Consistent folic acid supplement use during the advised periconceptional period may reduce the risk of VACTERL (0.5 [0.3-1.0]). Maternal smoking resulted in an almost twofold increased risk of VACTERL. CONCLUSION: We identified invasive ART, primiparity, pregestational overweight and obesity, lack of folic acid supplement use, and smoking as risk factors for VACTERL.
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Deformidades Congênitas dos Membros , Traqueia , Canal Anal/anormalidades , Estudos de Casos e Controles , Esôfago/anormalidades , Feminino , Cardiopatias Congênitas , Humanos , Rim/anormalidades , Deformidades Congênitas dos Membros/epidemiologia , Deformidades Congênitas dos Membros/etiologia , Coluna Vertebral/anormalidades , Traqueia/anormalidadesRESUMO
Aim: Male patients with anorectal malformations (ARM) are classified according to presence and level of the recto-urinary fistula. This is traditionally established by a preoperative high-pressure distal colostogram that may be variably interpreted by different surgeons. The aim of this study was to evaluate the inter- and intraobserver variation in the assessment by pediatric surgeons of preoperative colostograms with respect to the level of the recto-urinary fistula. Materials and Methods: Sixteen pediatric surgeons from 14 European centers belonging to the ARM-Net Consortium twice scored 130 images of distal colostograms taken in sagittal projection at a median age of 66 days of life (range: 4-1,106 days). Surgeons were asked to classify the fistula in bulbar, prostatic, bladder-neck, no fistula, and "unclear anatomy" example. Their assessments were compared with the intraoperative findings (kappa) for two scoring rounds with an interval of 6 months (intraobserver variation). Agreement among the surgeons' scores (interobserver variation) was also calculated using Krippendorff's alpha. A kappa over 0.75 is considered excellent, between 0.40 and 0.75 fair to good, and below 0.40 poor. Surgeons were asked to score the images in "poor" and "good" quality and to provide their years of experience in ARM treatment. Results: Agreement between the image-based rating of surgeons and the intraoperative findings ranges from 0.06 to 0.45 (mean 0.31). Interobserver variation is higher (Krippendorff's alpha between 0.40 and 0.45). Years of experience in ARM treatment does not seem to influence the scoring. The mean intraobserver variation between the two rounds is 0.64. Overall, the quality of the images is considered poor. Images categorized as having a good quality result in a statistically significant higher kappa (mean: 0.36 and 0.37 in the first and second round, respectively) than in the group of bad-quality images (mean: 0.25 and 0.23, respectively). Conclusions: There is poor agreement among experienced pediatric colorectal surgeons on preoperative colostograms. Techniques and analyses of images need to be improved in order to generate a homogeneous series of patients and make comparison of outcomes reliable.
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Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
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INTRODUCTION: Several medical and surgical improvements in the treatment of congenital diaphragmatic hernia (CDH) patients have led to a higher survival rate. However, some of these improvements also lead to an increased morbidity rate. This study aims to determine the contribution different medical and surgical treatments have had on the development of surgical complications. METHOD: All CDH patients treated in a single centre between 2000 and 2015 were retrospectively evaluated. Multivariate logistic regression was used to estimate the independent effects of several treatment options that could influence the surgical outcome by adjustment for multiple risk factors. RESULTS: Sixty of the 197 surgically repaired CDH patients had surgical complications. There were more haemorrhagic complications in the ECMO compared to non-ECMO group (27% vs. 2%, p < 0.001). The use of inhaled nitric oxide was also significantly related to haemorrhage (OR = 13.0 (95% CI 1.1-159)). After adjustment for other risk factors, chylothorax was neither significantly associated with ECMO treatment (OR = 1.6 (95% CI 0.5-5.2) nor with patch repair (OR = 2.1: 95% CI 0.7-6.1). A recurrence occurred more often in patients with pulmonary hypertension (OR = 10.0 (95% CI 1.5-65.8) and after treatment with an abdominal patch (OR = 11.3: 95% CI 1.5-84.4). CONCLUSION: ECMO treatment and the inhalation of nitric oxide are used in the most severe CDH patients but are associated with a higher risk on surgical haemorrhage. The recurrence rate is associated with both the use of an abdominal patch and the presence of pulmonary hypertension, regardless of medical treatment.
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Perda Sanguínea Cirúrgica , Quilotórax/etiologia , Oxigenação por Membrana Extracorpórea/efeitos adversos , Hérnias Diafragmáticas Congênitas/cirurgia , Complicações Pós-Operatórias/etiologia , Anestésicos Inalatórios/efeitos adversos , Feminino , Humanos , Hipertensão Pulmonar/complicações , Lactente , Recém-Nascido , Masculino , Análise Multivariada , Óxido Nítrico/efeitos adversos , Recidiva , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
PURPOSE: Since pediatric surgeons aim to follow their patients with anorectal malformations (ARM) into adulthood the aim of this study was to investigate how pediatric surgeons deal with sexual issues related to ARM. METHODS: In 2018, a questionnaire was developed by the working group "Follow-up and sexuality" of the ARM-Net consortium and sent to all consortium-linked pediatric surgeons from 31 European pediatric surgical centers. Obtained data were statistically analyzed. RESULTS: Twenty-eight of 37 pediatric surgeons (18 males/10 females) answered the questionnaire. The majority of pediatric surgeons (82%) think they should talk about sexual issues with their patient. More than 50% of pediatric surgeons do not feel at all or only moderately confident discussing the topic of sexuality. Most pediatric surgeons require more support (96%) and wish to be trained in sexuality and sexual issues (78%) to feel confident towards their ARM-patients/parents. For optimal care, sexual issues with ARM-patients should be managed by a multidisciplinary team. CONCLUSIONS: Pediatric surgeons feel that sexuality is an important issue for their ARM-patients, which they are primarily responsible of but should be managed in concert with a multidisciplinary team. A training in sexuality is wished to feel more confident about this specific issue.
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Malformações Anorretais/cirurgia , Atitude do Pessoal de Saúde , Encaminhamento e Consulta/estatística & dados numéricos , Sexualidade/estatística & dados numéricos , Cirurgiões/estatística & dados numéricos , Inquéritos e Questionários , Criança , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PediatriaRESUMO
We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.
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Alelos , Sequência de Bases , Fenda Labial/genética , Fissura Palatina/genética , Mutação com Perda de Função , Deleção de Sequência , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Adulto , Substituição de Aminoácidos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido IncorretoRESUMO
BACKGROUND: Preoperative illnesses might induce immunosuppression and subsequently increase morbidity after surgery. Several studies have tried to identify risk factors for complications after hypospadias correction, but effects of illnesses in the weeks just before surgery are unknown. We aimed to determine the associations between preoperative illnesses not severe enough to postpone surgery and short-term complications after hypospadias repair in children. METHODS: In this retrospective cohort study, data were collected from 681 children with anterior or middle type hypospadias that had initial 1-stage repair in the period 1983-2012 in the Radboudumc, The Netherlands. The associations between common illnesses, such as common cold, fever and ear infection, within 2 weeks before repair, and postoperative complications, such as urethrocutaneous fistula, wound dehiscence and stenosis, within 2 months and 1 year after surgery, were analyzed using multivariable logistic regression analyses. RESULTS: Of the 681 boys, 22% had preoperative illnesses, most often common cold, and 14% had postoperative complications. Children with preoperative illnesses had fewer postoperative complications within 2 months (n = 13, 9%) than children without preoperative illnesses (n = 79, 16%), resulting in a 50% risk reduction (odds ratio: 0.49; 95% confidence interval: 0.26-0.93). Preoperative infections (common cold, fever and ear infection), in particular, reduced the risk of postoperative infections (wound and urinary tract infections; odds ratio: 0.37; 95% confidence interval: 0.14-0.98). Results were similar for complications within 1 year. CONCLUSIONS: Common preoperative illnesses not severe enough to postpone surgery did not increase the postoperative complication risk and even seemed to have a protective effect, especially for postoperative infections. Consequently, there is no reason to alter preoperative screening.
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Hipospadia/complicações , Procedimentos de Cirurgia Plástica , Período Pré-Operatório , Adolescente , Criança , Pré-Escolar , Resfriado Comum , Febre , Humanos , Lactente , Masculino , Países Baixos , Otite , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Nephronophthisis is an autosomal recessive ciliopathy and important cause of end-stage renal disease (ESRD) in children and young adults. Diagnostic delay is frequent. This study investigates clinical characteristics, initial symptoms, and genetic defects in a cohort with nephronophthisis-related ciliopathy, to improve early detection and genetic counseling. METHODS: Forty patients from 36 families with nephronophthisis-related ciliopathy were recruited at university medical centers and online. Comprehensive clinical and genotypic data were recorded. Patients without molecular diagnosis were offered genetic analysis. RESULTS: Of 40 patients, 45% had isolated nephronophthisis, 48% syndromic diagnosis, and 7% nephronophthisis with extrarenal features not constituting a recognizable syndrome. Patients developed ESRD at median 13 years (range 5-47). Median age of symptom onset was 9 years in both isolated and syndromic forms (range 5-26 vs. 5-33). Common presenting symptoms were fatigue (42%), polydipsia/polyuria (33%), and hypertension (21%). Renal ultrasound showed small-to-normal-sized kidneys, increased echogenicity (65%), cysts (43%), and abnormal corticomedullary differentiation (32%). Renal biopsies in eight patients showed nonspecific signs of chronic kidney disease (CKD). Twenty-three patients (58%) had genetic diagnosis upon inclusion. Thirteen of those without a genetic diagnosis gave consent for genetic testing, and a cause was identified in five (38%). CONCLUSIONS: Nephronophthisis is genetically and phenotypically heterogeneous and should be considered in children and young adults presenting with persistent fatigue and polyuria, and in all patients with unexplained CKD. As symptom onset can occur into adulthood, presymptomatic monitoring of kidney function in syndromic ciliopathy patients should continue until at least age 30.
Assuntos
Ciliopatias/diagnóstico , Aconselhamento Genético , Testes Genéticos , Doenças Renais Císticas/congênito , Falência Renal Crônica/prevenção & controle , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Idade de Início , Biópsia , Criança , Ciliopatias/complicações , Ciliopatias/genética , Ciliopatias/patologia , Proteínas do Citoesqueleto , Diagnóstico Tardio/prevenção & controle , Feminino , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Falência Renal Crônica/etiologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Países Baixos , Sistema de Registros/estatística & dados numéricos , Fatores de Tempo , Ultrassonografia , Sequenciamento do Exoma , Adulto JovemRESUMO
BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. © 2016 Wiley Periodicals, Inc.