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User-centered models for the development of digital health interventions are not consistently applied in healthcare settings. This study used a five-phase, user-centered approach to develop HEARTPrep © , a psychosocial intervention delivered via mobile app and telehealth to mothers expecting a baby with congenital heart disease (CHD) to promote maternal, family, and child well-being. Phases of intervention development were: (I) establishing partnerships; (II) creating content; (III) developing prototype and testable intervention; (IV) conducting think-aloud testing; and (V) completing beta testing. Partnerships with parents, clinicians, and design/technology experts were integral throughout the development of HEARTPrep © . Parents of children with CHD also served as participants in Phases II-V, contributing to the creation of content and providing feedback to inform the iterative refinement of HEARTPrep © . These five phases produced a refined digital health intervention with promising feasibility, usability, and acceptability results. This user-centered approach can be used to develop digital health interventions targeting various health outcomes., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Prenatal diagnosis of congenital heart disease (CHD) often leads to anxiety, depression, and traumatic stress in expectant mothers, with long-term implications for the child and family. However, psychosocial intervention is rarely incorporated into prenatal care. HEARTPrep is a virtually delivered psychosocial intervention aimed at reducing distress and social isolation and increasing parenting self-efficacy and hope for mothers expecting a baby with CHD to promote long-term child/family well-being. This study evaluated the feasibility and acceptability of HEARTPrep. Participants were mothers receiving cardiology care for a fetal CHD diagnosis. Partners could participate with the mother. HEARTPrep was delivered through a mobile app and telehealth. Feasibility was assessed through enrollment/retention rates. Acceptability was assessed through 20 Likert-scale and five open-ended questions. Of 39 recruited mothers, 35 (90%) enrolled. Half of partners (48%) also participated. Twenty-seven of 35 enrolled mothers (77%) completed HEARTPrep. On a scale from 0 (Not at All) to 4 (Very), mean item acceptability scores ranged from 3.5 to 3.9. Mothers reported HEARTPrep helped them feel less distressed (mean: 3.74), less alone (3.84), more prepared (3.89), and more hopeful (3.84). Opportunities to process emotions, develop coping skills, learn with their partner, navigate relationships, understand they are not alone, connect with peer support, access resources, and prepare for stressors were described as helpful. HEARTPrep is feasible and acceptable for mothers expecting a baby with CHD. Future research will evaluate its efficacy in preventing/reducing maternal mental health problems and improving postnatal clinical outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study., Methods: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey., Results: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results., Conclusions: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.

Background: Anomalous aortic origin of a coronary artery (AAOCA) is associated with sudden cardiac death. High-risk characteristics are most commonly assessed using a 2-dimensional (2D) echocardiogram (echo) or cardiac computed tomography (CT). We hypothesize that these characteristics will be more accurately assessed when they are presented in the form of a 3D digital model., Methods: Fourteen participants, including cardiothoracic surgeons and cardiac imaging specialists, assessed image representations, including echo, CT images, and a 3D digital model, from 6 patients who had undergone AAOCA repair. Accuracy of assessment was evaluated by comparing responses with operative findings (the gold standard)., Results: The reported type of AAOCA was most accurately assessed on CT (100%) and 3D models (92.31%) compared with echo (80.77%). The accuracy of the AAOCA course was highest on CT (91.03%), followed by the 3D model (80.77%), and lowest on echo (61.54%). The accuracy of intramurality was low across all imaging modalities (17.95% echo, 29.49% CT, and 21.79% 3D model). Accurate assessment of a separate AAOCA ostium was highest on 3D models (97.40%). Ostial stenosis was more accurately assessed on 3D models (56.41%). When accuracy was separated by subspecialty, CT and 3D models were more accurately assessed by all participants regardless of training., Conclusions: Cardiac imagers and congenital cardiothoracic surgeons most accurately assessed AAOCA presence, type, and course on cardiac CT and 3D models. 3D models were superior in representation of ostial characteristics. CT and 3D models are overall more accurately assessed by specialists regardless of training., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Congenital heart disease (CHD) is the most common major congenital anomaly with an incidence of ∼1% of live births and is a significant cause of birth defect-related mortality. The genetic mechanisms underlying the development of CHD are complex and remain incompletely understood. Known genetic causes include all classes of genetic variation including chromosomal aneuploidies, copy number variants, and rare and common single-nucleotide variants, which can be either de novo or inherited. Among patients with CHD, ∼8%-12% have a chromosomal abnormality or aneuploidy, between 3% and 25% have a copy number variation, and 3%-5% have a single-gene defect in an established CHD gene with higher likelihood of identifying a genetic cause in patients with nonisolated CHD. These genetic variants disrupt or alter genes that play an important role in normal cardiac development and in some cases have pleiotropic effects on other organs. This work reviews some of the most common genetic causes of CHD as well as what is currently known about the underlying mechanisms., (Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.)

Pulmonary hypertension (PH) is common in premature infants with bronchopulmonary dysplasia (BPD) and is associated with significant mortality. Despite expert consensus suggesting the use of targeted therapies such as phosphodiesterase inhibitors, endothelin receptor antagonists, and prostanoids, there is little data on safety and outcomes in infants with BPD-associated PH (BPD-PH) treated with these medications. We sought to describe the pharmacologic management of BPD-PH and to report outcomes at our institution. Premature infants with BPD-PH born between 2005 and 2016 were included. Follow-up data were obtained through January 2020. A total of 101 patients (61 male, 40 female) were included. Of these, 99 (98.0%) patients were treated with sildenafil, 13 (12.9%) with bosentan, 35 (34.7%) with inhaled iloprost, 12 (11.9%) with intravenous epoprostenol, and nine (8.9%) with subcutaneous treprostinil. A total of 33 (32.7%) patients died during the study period and 10 (9.9%) were secondary to severe to pulmonary hypertension. Of the surviving patients, 57 (83.8%) had follow-up data at a median of 5.1 (range 0.38-12.65) years and 44 (77.2%) were weaned off PH medications at a median 2.0 (range 0-8) years. Mortality for BPD-PH remains high mostly due to co-morbid conditions. However, for those patients that survive to discharge, PH therapies can frequently be discontinued in the first few years of life.

The genetic mechanisms underlying congenital heart disease (CHD) are complex and remain incompletely understood. The majority of patients with CHD have an isolated heart defect without other organ system involvement, but the genetic basis of isolated CHD has been even more difficult to elucidate compared to syndromic CHD. Our understanding of the genetics of isolated CHD is advancing in large part due to advances in next generation sequencing, and the list of genes associated with CHD is rapidly expanding. Variants in hundreds of genes have been identified that may cause or contribute to CHD, but a genetic cause can still only be identified in about 20-30% of patients. Identifying a genetic cause for CHD can have an impact on clinical outcomes and prognosis and thus it is important for clinicians to understand when and what to test in patients with isolated CHD. This chapter reviews some of the known genetic mechanisms that contribute to isolated inherited and sporadic CHD as well as recommendations for evaluation and genetic testing in patients with isolated CHD., (© 2019 Wiley Periodicals, Inc.)

Objective: To assess the demographics, treatment algorithm, and outcomes in a large cohort of children treated with sildenafil., Study Design: A retrospective cohort study of children with pulmonary hypertension (PH) treated with sildenafil at a single institution between 2004 and 2015. Baseline and follow-up data collected by chart review., Results: There were 269 children included in this study: 47 with idiopathic pulmonary arterial hypertension, 53 with congenital heart disease, 135 with bronchopulmonary dysplasia, 24 with congenital diaphragmatic hernia, and 7 with other causes. Sildenafil was initial monotherapy in 84.8% and add-on therapy in 15.2%. Median follow-up time was 3.1 years (2  weeks-12.4 years). On follow-up, 99 (37%) remained on sildenafil or transitioned to tadalafil, 93 (35%) stopped sildenafil for improvement in PH, 54 (20%) died, and 20 (7%) were lost to follow-up. PH was most likely to improve in those with bronchopulmonary dysplasia, allowing for the discontinuation of sildenafil in 45%. Eighteen deaths were related to PH and 36 from other systemic causes. Two patients stopped sildenafil owing to airway spasm with desaturation. Overall survival was significantly lower in World Health Organization group 3 PH (bronchopulmonary dysplasia and congenital diaphragmatic hernia) vs group 1 (idiopathic pulmonary arterial hypertension and congenital heart disease), P = .02., Conclusions: In this retrospective experience in children with mainly World Health Organization groups 1 and 3 PH, low-dose sildenafil was well-tolerated, safe, and had an acceptable side effect profile. Although patients with group 3 PH have high mortality, survivors have a high likelihood of PH improving., (Published by Elsevier Inc.)

Objectives: Anomalous aortic origin of a coronary artery (AAOCA) from the opposite sinus of Valsalva is a rare cardiac anomaly associated with sudden cardiac death (SCD). Single-center studies describe surgical repair as safe, although medium- and long-term effects on symptoms and risk of SCD remain unknown. We sought to describe outcomes of surgical repair of AAOCA., Methods: We reviewed institutional records for patients who underwent AAOCA repair, from 2001 to 2016, at 2 affiliated institutions. Patients with associated heart disease were excluded., Results: In total, 60 patients underwent AAOCA repair. Half of the patients (n = 30) had an anomalous left coronary artery arising from the right sinus of Valsalva and half had an anomalous right. Median age at surgery was 15.4 years (interquartile range, 11.9-17.9 years; range, 4 months to 68 years). The most common presenting symptoms were chest pain (n = 38; 63%) and shortness of breath (n = 17; 28%); aborted SCD was the presenting symptom in 4 patients (7%). Follow-up data were available for 54 patients (90%) over a median of 1.6 years. Of 53 patients with symptoms at presentation, 34 (64%) had complete resolution postoperatively. Postoperative mild or greater aortic insufficiency was present in 8 patients (17%) and moderate supravalvar aortic stenosis in 1 (2%). One patient required aortic valve replacement for aortic insufficiency. Two patients required reoperation for coronary stenosis at 3 months and 6 years postoperatively., Conclusions: Surgical repair of AAOCA is generally safe and adverse events are rare. Restenosis, and even sudden cardiac events, can occur and long-term surveillance is critical. Multi-institutional collaboration is vital to identify at-risk subpopulations and refine current recommendations for long-term management., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: There has been hesitancy to use dextranomer/hyaluronic acid copolymer (DHXA, Deflux for vesicoureteral reflux (VUR) in the setting of lower urinary tract (LUT) dysfunction because of the limited number of published studies, the possibility of less success, and the manufacturer's recommendations contraindicating its use in patients with active LUT dysfunction. We report on our experience using DXHA in this subset of patients whose VUR persisted despite targeted therapy for their LUT condition., Materials and Methods: We reviewed patients diagnosed with both a LUT condition and VUR who underwent subureteric DXHA while still undergoing treatment for their LUT dysfunction. Persistence of VUR was confirmed by videourodynamic studies (VUDS)/VCUG (voiding cystourethrogram) and all patients were on targeted treatment (TT) and antibiotic prophylaxis prior to and during DXHA injection. VUR was reassessed post-injection., Results: Fifteen patients (22 ureters; 21F,1M) met inclusion criteria (mean age 6.1 years, range 4-12). Following one to three DXHA injections, VUR resolved in 17 ureters (77%) including eight of nine ureters in dysfunctional voiding (DV) patients, five of nine in idiopathic detrusor overactivity disorder (IDOD), and four of four in detrusor underutilization disorder (DUD) patients., Conclusions: DXHA is safe and effective in resolving VUR in children with associated LUT dysfunction, even before their LUT condition has fully resolved. Highest resolution rates were noted in patients with either DV or DUD or who were least symptomatic prior to injection., (Copyright © 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

The prevalence of varicocoeles is 15% in the general adolescent and adult male population and in 35-40% of men evaluated for infertility. While varicocelectomy can be performed using various methods and techniques, the laparoscopic approach allows for clear visualization of the testicular artery and lymphatics. Amongst urologists, particularly paediatric urologists, and andrologists there is much debate regarding the significance of testicular artery sparing when performing a varicocelectomy, with some believing that ligating the testicular artery impairs catch-up growth and future fertility. On the other hand, several studies have reported higher failure rates with artery preservation. To help resolve the debate regarding the significance of artery sparing, we sought to compare varicocoele recurrence rate and catch-up growth in patients who underwent artery sparing laparoscopic varicocelectomy compared with those who had the artery sacrificed. We identified 524 laparoscopic varicocelectomies in 425 patients from our adolescent varicocoele database. Only patients who had ultrasound determined testicular volume measurements pre-operatively and at least 6 months post-operatively were included. Post-operative persistence/recurrence of varicocoele, testicular atrophy and repeat varicocelectomy were noted. Catch-up growth was compared between procedures in those with significant pre-operative asymmetry. Four hundred and forty primary laparoscopic varicocelectomies were performed in 355 patients (mean age: 15.5 years, range 9.3-20.6; mean follow-up: 32.9 months, range 6.0-128.9) who had both pre- and post-varicocelectomy scrotal Duplex Doppler ultrasound performed. The testicular artery was preserved in 54 varicocoeles (41 patients) and ligated in 384 varicocoeles (312 patients). We observed an increased rate of persistent/recurrent varicocoele in the artery-sparing vs. artery ligating patients (12.2% vs. 5.4%, p = 0.09). In addition, there was no difference in catch-up growth and no instance of testicular atrophy. As artery sparing varicocelectomy offered no advantage in regards to catch-up growth and was associated with a higher incidence of recurrent varicocoele, preservation of the artery does not appear to be routinely necessary in adolescent varicocelectomy., (© 2013 American Society of Andrology and European Academy of Andrology.)

Objective: Varicoceles occur in 15% of adult and adolescent males and are generally considered to be an extratesticular phenomenon. However, an intratesticular component has been reported in up to 2% of adult and 2% of adolescent varicoceles. We sought to determine the incidence of intratesticular varicoceles (ITV) in adolescents in our practice, its significance, associated findings and response to treatment., Materials and Methods: We retrospectively reviewed 684 adolescent males who were diagnosed with varicoceles and had at least one Doppler ultrasound (DUS) prior to any surgery to identify those with an intratesticular component. Testicular volumes, maximum vein diameter (MVD) and peak retrograde flow (PRF) were determined by DUS and recorded., Results: A total of 6 (0.9%) patients were found to have an intratesticular component with a mean PRF of 43.7 cm/s, mean MVD of 3.3 mm and mean asymmetry of 20%. Mean PRF, MVD, and asymmetry of those without an intratesticular component who underwent surgery was 44.8 cm/s, 2.9 mm, and 21.8%, respectively (PNS for all parameters). Four of the 6 patients had 2 or more DUS, and all 4 had worsening testicular asymmetry and PRF over time. Five patients underwent laparoscopic varicocelectomy and all five had catch-up testicular growth. One patient refused surgical repair and has had subsequent worsening testicular asymmetry and softening of the testicle., Conclusions: Our findings suggest that adolescents who present with an intratesticular varicocele in association with testicular asymmetry will develop worse asymmetry over time. Therefore, adolescents with intratesticular varicoceles and initial asymmetry should be scheduled for surgery rather than followed., (Copyright © 2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Purpose: There is a known association between nonneurogenic lower urinary tract conditions and vesicoureteral reflux. Whether reflux is secondary to the lower urinary tract condition or coincidental is controversial. We determined the rate of reflux resolution in patients with lower urinary tract dysfunction using targeted treatment for the underlying condition., Materials and Methods: Patients diagnosed and treated for a lower urinary tract condition who had concomitant vesicoureteral reflux at or near the time of diagnosis were included. Patients underwent targeted treatment and antibiotic prophylaxis, and reflux was monitored with voiding cystourethrography or videourodynamics., Results: Vesicoureteral reflux was identified in 58 ureters in 36 females and 5 males with a mean age of 6.2 years. After a mean of 3.1 years of treatment reflux resolved with targeted treatment in 26 of 58 ureters (45%). All of these patients had a history of urinary tract infections before starting targeted treatment. Resolution rates of vesicoureteral reflux were similar for all reflux grades. Resolution or significant improvement of reflux was greater in the ureters of patients with dysfunctional voiding (70%) compared to those with idiopathic detrusor overactivity disorder (38%) or detrusor underutilization (40%)., Conclusions: Vesicoureteral reflux associated with lower urinary tract conditions resolved with targeted treatment and antibiotic prophylaxis in 45% of ureters. Unlike the resolution rates reported in patients with reflux without a coexisting lower urinary tract condition, we found that there were no differences in resolution rates among grades I to V reflux in patients with lower urinary tract conditions. Patients with dysfunctional voiding had the most improvement and greatest resolution of reflux. Additionally grade V reflux resolved in some patients., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood., Methods: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies., Results: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases., Conclusions: We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

Purpose: Varying incidences and levels of persistent retrograde venous flow have been reported following adult and adolescent varicocelectomy but the significance remains unclear. We sought to determine the incidence and natural history of persistent flow and whether it had any effect on postoperative testicular catch-up growth., Materials and Methods: We retrospectively analyzed pre-varicocelectomy and post-varicocelectomy Doppler duplex ultrasound findings. Peak retrograde venous flow, maximum vein diameter, flow quality and varicocele grade were recorded at each visit. Catch-up growth was defined as less than 15% testicular asymmetry at final visit., Results: Of 330 patients (median age 15.4 years) undergoing varicocelectomy (laparoscopic in 247, open in 83) 145 had residual retrograde venous flow after Valsalva maneuver with a mean peak of 13.3 cm per second. Of 290 patients with repeat Doppler duplex ultrasound (median followup 2.6 years) 124 had initial peak retrograde venous flow less than 20 cm per second (43%) and only 17 (6%) had flow 20 cm per second or greater. Incidence of post-varicocelectomy retrograde venous flow at last visit (48%) was similar to that at initial postoperative visit (49%). Of 330 boys 20 had recurrence of palpable varicocele (grade 2 or 3), of whom 18 (90%) had initial retrograde venous flow. Catch-up growth was more likely in patients with no retrograde venous flow, and rates of catch-up growth decreased as peak retrograde venous flow increased. All 5 patients with initial testicular asymmetry and persistent retrograde venous flow at levels greater than 30 cm per second had continued testicular asymmetry (ie none had catch-up growth)., Conclusions: Retrograde venous flow is frequently present after varicocelectomy and is almost always associated with peak retrograde venous flow rates significantly lower than those seen in patients who are recommended for initial varicocelectomy. Retrograde venous flow tends to persist during followup at stable peak retrograde venous flow rates. Palpable recurrence and persistent testicular asymmetry are most often associated with postoperative peak retrograde venous flow rates 20 cm per second or greater., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein receptor (LDLRs) molecules expressed on the cell surface. Gene inactivation of PCSK9 reduces the areas of atherosclerotic lesions in mice, and the effect is mainly dependent on LDLRs. Furthermore, a positive relationship between PCSK9 and cholesterol accumulation in the wall of the aorta has been established. However, the mechanism remains unknown. As PCSK9 is mainly expressed in atherosclerotic plaque and in the liver, we hypothesize that PCSK9 might increase oxidized LDL uptake and impair macrophage-mediated reverse cholesterol transport, contributing to the development of atherosclerosis., (Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Purpose: The main objective of this study was to investigate the prevalence of complementary and alternative medicine (CAM) use, types and reasons for use, and determinants of use among survivors of childhood cancer., Methods: An interviewer-based survey of CAM use was administered to 197 survivors or their guardians. Demographic data, CAM therapies used, purpose and referral for use, and communication about use was collected., Results: A total of 115 (58%) survivors reported using CAM in survivorship, 72% of which used biologically based therapies. The majority of therapies were used for relaxation and stress management (15%), referred for use by the parent (25%), reported as very effective (62%), and initiated 0 to 4 years after completion of cancer treatment (41%). Among CAM users, young adults used manipulative and body-based therapies [odds ratio (OR)=3.3; 95% confidence interval (CI), 1.4-7.8] and mind-body therapies (OR=2.8, 95% CI: 1.2-6.4) more than children. Use of mind-body therapies was associated with not attending religious services regularly (OR=2.4; P<0.01). Half (51%) of all CAM therapies were disclosed to the physician., Conclusions: Survivors of childhood cancer frequently use CAM for health promotion and mitigation of physical and psychological conditions. Clinicians should consider the role of CAM in the adoption of healthy lifestyles among this population.

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: There is wide variation in the reported incidence of hydrocele after varicocelectomy (0% to 29%). We determined the incidence of hydroceles and hydrocelectomy following adolescent varicocelectomy, the time it took for them to manifest, and the results of aspiration and surgical correction., Materials and Methods: Our adolescent varicocele registry was reviewed to identify patients with a post-varicocelectomy hydrocele. We evaluated physical examination and ultrasound findings, postoperative interval to development and treatment results., Results: A total of 400 patients with at least 6 months of postoperative followup underwent 521 varicocelectomies (16 redo, 1 right, 104 bilateral) from 1987 to 2010. Mean followup was 32 months (range 6 to 182). Hydrocele was detected in 80 of 521 (15.4%) at a mean of 2 years after surgery. The incidence of hydrocele was higher in open vs laparoscopic (p <0.001), bilateral vs unilateral (p = 0.013), nonlymphatic sparing vs lymphatic sparing (p = 0.043) and Palomo vs laparoscopic nonlymphatic sparing (p = 0.001) procedures. Eight patients underwent aspiration for a large postoperative hydrocele. In all 8 patients fluid returned to pre-aspiration status. There were 29 patients (5.6%) who underwent Jaboulay bottleneck hydrocelectomy and none had recurrence., Conclusions: Hydroceles are a common sequela of varicocelectomy, with the fewest hydroceles occurring after laparoscopic lymphatic sparing varicocelectomy. Patients should be followed for at least 2 years after varicocelectomy to examine for the presence of hydroceles. Although there have been reports on the use of aspiration for post-varicocelectomy hydrocele, we have not had success in those with a single aspiration. Jaboulay bottleneck hydrocelectomy had a 100% success rate in this select group., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Appropriate management for adolescent varicocele with testicular symmetry is rarely discussed. We examined the natural history of varicocele in patients presenting with testicular symmetry to achieve better understanding of the clinical course., Materials and Methods: Our varicocele registry was queried for adolescent boys who presented with varicocele in association with less than 15% testicular asymmetry and who underwent at least 1 testicular asymmetry assessment 12 or more months later. Patients were stratified into 2 groups based on an initial testicular asymmetry measurement of less than 10% vs 10.0% to 14.9%. Logistic regression modeling was used to analyze the association of Tanner stage, varicocele grade, peak retrograde flow and maximum vein diameter at presentation with increased testicular asymmetry at followup. Kaplan-Meier methodology was applied to compare testicular asymmetry progression rates., Results: We identified 89 adolescents, of whom 52 (58.4%) and 37 (41.6%) presented with less than 10.0% and 10.0% to 14.9% testicular asymmetry, respectively. Of the patients 37 (41.6%) showed testicular asymmetry progression at a median 18-month followup. The overall 3-year testicular asymmetry progression-free rate was 48% while in patients with peak retrograde flow 30 cm per second or greater it was 23%. On multivariate analysis controlled for age, Tanner stage and varicocele grade a peak retrograde flow of 30 cm per second or greater was associated with worsening testicular asymmetry (OR 4.87, 95% CI 1.6-8.0)., Conclusions: Adolescents with varicocele and less than 15% testicular asymmetry are at risk for asymmetry during followup. Those with peak retrograde flow 30 cm per second or greater are at increased risk for early asymmetry while those with peak retrograde flow less than 30 cm per second may still show asymmetry but tend to do so after longer followup., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

To identify gene loci associated with steroid-resistant nephrotic syndrome (SRNS), we utilized homozygosity mapping and exome sequencing in a consanguineous pedigree with three affected siblings. High-density genotyping identified three segments of homozygosity spanning 33.6 Mb on chromosomes 5, 10, and 15 containing 296 candidate genes. Exome sequencing identified two homozygous missense variants within the chromosome 15 segment; an A159P substitution in myosin 1E (MYO1E), encoding a podocyte cytoskeletal protein; and an E181K substitution in nei endonuclease VIII-like 1 (NEIL1), encoding a base-excision DNA repair enzyme. Both variants disrupt highly conserved protein sequences and were absent in public databases, 247 healthy controls, and 286 patients with nephrotic syndrome. The MYO1E A159P variant is noteworthy, as it is expected to impair ligand binding and actin interaction in the MYO1E motor domain. The predicted loss of function is consistent with the previous demonstration that Myo1e inactivation produces nephrotic syndrome in mice. Screening 71 additional patients with SRNS, however, did not identify independent NEIL1 or MYO1E mutations, suggesting larger sequencing efforts are needed to uncover which mutation is responsible for the phenotype. Our findings demonstrate the utility of exome sequencing for rapidly identifying candidate genes for human SRNS.