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STUDY QUESTION What are the genetic loci that increase susceptibility to nonsyndromic cryptorchidism, or undescended testis? SUMMARY ANSWER A genome-wide association study (GWAS) suggests that susceptibility to cryptorchidism is heterogeneous, with a subset of suggestive signals linked to cytoskeleton-dependent functions and syndromic forms of the disease. WHAT IS KNOWN ALREADY Population studies suggest moderate genetic risk of cryptorchidism and possible maternal and environmental contributions to risk. Previous candidate gene analyses have failed to identify a major associated locus, although variants in insulin-like 3 (INSL3), relaxin/insulin-like family peptide receptor 2 (RXFP2) and other hormonal pathway genes may increase risk in a small percentage of patients. STUDY DESIGN, SIZE, DURATION This is a case-control GWAS of 844 boys with nonsyndromic cryptorchidism and 2718 control subjects without syndromes or genital anomalies, all of European ancestry. PARTICIPANTS/MATERIALS, SETTING, METHODS All boys with cryptorchidism were diagnosed and treated by a pediatric specialist. In the discovery phase, DNA was extracted from tissue or blood samples and genotyping performed using the Illumina HumanHap550 and Human610-Quad (Group 1) or OmniExpress (Group 2) platform. We imputed genotypes genome-wide, and combined single marker association results in meta-analyses for all cases and for secondary subphenotype analyses based on testis position, laterality and age, and defined genome-wide significance as P = 7 × 10(-9) to correct for multiple testing. Selected markers were genotyped in an independent replication group of European cases (n = 298) and controls (n = 324). We used several bioinformatics tools to analyze top (P < 10(-5)) and suggestive (P < 10(-3)) signals for significant enrichment of signaling pathways, cellular functions and custom gene lists after multiple testing correction. MAIN RESULTS AND THE ROLE OF CHANCE In the full analysis, we identified 20 top loci, none reaching genome-wide significance, but one passing this threshold in a subphenotype analysis of proximal testis position (rs55867206, near SH3PXD2B, odds ratio = 2.2 (95% confidence interval 1.7, 2.9), P = 2 × 10(-9)). An additional 127 top loci emerged in at least one secondary analysis, particularly of more severe phenotypes. Cytoskeleton-dependent molecular and cellular functions were prevalent in pathway analysis of suggestive signals, and may implicate loci encoding cytoskeletal proteins that participate in androgen receptor signaling. Genes linked to human syndromic cryptorchidism, including hypogonadotropic hypogonadism, and to hormone-responsive and/or differentially expressed genes in normal and cryptorchid rat gubernaculum, were also significantly overrepresented. No tested marker showed significant replication in an independent population. The results suggest heterogeneous, multilocus and potentially multifactorial susceptibility to nonsyndromic cryptorchidism. LIMITATIONS, REASONS FOR CAUTION The present study failed to identify genome-wide significant markers associated with cryptorchidism that could be replicated in an independent population, so further studies are required to define true positive signals among suggestive loci. WIDER IMPLICATIONS OF THE FINDINGS As the only GWAS to date of nonsyndromic cryptorchidism, these data will provide a basis for future efforts to understand genetic susceptibility to this common reproductive anomaly and the potential for additive risk from environmental exposures. STUDY FUNDING/COMPETING INTERESTS This work was supported by R01HD060769 (the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD)), P20RR20173 (the National Center for Research Resources (NCRR), currently P20GM103464 from the National Institute of General Medical Sciences (NIGMS)), an Institute Development Fund to the Center for Applied Genomics at The Children's Hospital of Philadelphia, and Nemours Biomedical Research. The authors have no competing interests to declare.

INTRODUCTION: In testicular torsion, ischemia time from pain onset impacts testicular salvage. A tunica albuginea fasciotomy to relieve compartment pressure followed by a tunica vaginalis flap (TVF) may enhance salvage. OBJECTIVE: To define the optimal window of ischemia time during which TVF may be most beneficial to avoid orchiectomy. STUDY DESIGN: A retrospective cohort study of males presenting with testicular torsion at a single tertiary-care institution from January, 2003 to March, 2017. Ischemia time was defined as duration of pain from onset to surgery. Because TVF would be an option to orchiectomy, and it was found that ischemia time was longer in testicles that underwent orchiectomy, matching was performed. Cases of torsion treated with TVF were matched 1:1 with cases treated with orchiectomy on age at surgery, and ischemia time. Outcomes included postoperative viability, defined as palpable testicular tissue with normal consistency, and atrophy, defined as palpable decrease in size relative to contralateral testicle. Sensitivity analyses were performed restricting to the subgroups with postoperative ultrasound, >6 months’ follow-up, and additionally matching for degrees of twist. RESULTS: A total of 182 patients met eligibility criteria, of whom 49, 36, and 97 underwent orchiectomy, TVF, and septopexy alone, respectively. Median follow-up was 2.7 months; 26% of patients had postoperative ultrasound (61% of TVF group). In the orchiectomy, TVF, and septopexy groups, respectively, median ischemia times were 51, 11, and 8 hours, postoperative viability rates were 0, 86, and 95%, and postoperative atrophy rates were 0, 68, and 24%. After matching, 32 patients with TVF were matched to 32 patients who underwent orchiectomy. In the TVF group, postoperative viability occurred in 95% (19/20) vs 67% (8/12) of patients with ischemia times ≤24 and >24 hours, respectively (Summary table). Atrophy occurred in 67% (12/18) vs 83% (10/12) of these same respective patients. Sensitivity analysis by ultrasound and longer follow-up found similar viability results, although atrophy rates were higher. Additional matching for degrees of twist showed lower viability and higher atrophy rates for increasing ischemia times. DISCUSSION: Patients who presented with testicular torsion with ischemia times ≤24 hours and who were being considered for orchiectomy may have benefitted most from TVF, albeit at high risk of atrophy. However, for ischemia times >24 hours, TVF may still have preserved testicular viability in two-thirds of cases. A limitation was short follow-up. CONCLUSION: A TVF was a valid alternative to orchiectomy for torsed testicles, albeit with high testicular atrophy rates.

We present a case of bilateral multifocal Wilms tumor in a nonsyndromic 12-month-old male. Our management approach included 12 weeks of preoperative chemotherapy for maximal tumor shrinkage and, despite the central location of the tumors, successful staged bilateral nephron-sparing surgery. We advocate for a broader application of nephron-sparing surgery in Wilms tumor cases with the goal of preserving renal function without compromising oncologic outcomes.

Summary Introduction Prior studies of outcomes following genitoplasty have reported high rates of surgical complications among children with atypical genitalia. Few studies have prospectively assessed outcomes after contemporary surgical approaches. Objective The current study reported the occurrence of early postoperative complications and of cosmetic outcomes (as rated by surgeons and parents) at 12 months following contemporary genitoplasty procedures in children born with atypical genitalia. Study design This 11-site, prospective study included children aged ≤2 years, with Prader 3–5 or Quigley 3–6 external genitalia, with no prior genitoplasty and non-urogenital malformations at the time of enrollment. Genital appearance was rated on a 4-point Likert scale. Paired t-tests evaluated differences in cosmesis ratings. Results Out of 27 children, 10 were 46,XY patients with the following diagnoses: gonadal dysgenesis, PAIS or testosterone biosynthetic defect, severe hypospadias and microphallus, who were reared male. Sixteen 46,XX congenital adrenal hyperplasia patients were reared female and one child with sex chromosome mosaicism was reared male. Eleven children had masculinizing genitoplasty for penoscrotal or perineal hypospadias (one-stage, three; two-stage, eight). Among one-stage surgeries, one child had meatal stenosis (minor) and one developed both urinary retention (minor) and urethrocutaneous fistula (major) ( Summary Figure ). Among two-stage surgeries, three children developed a major complication: penoscrotal fistula, glans dehiscence or urethral dehiscence. Among 16 children who had feminizing genitoplasty, vaginoplasty was performed in all, clitoroplasty in nine, external genitoplasty in 13, urethroplasty in four, perineoplasty in five, and total urogenital sinus mobilization in two. Two children had minor complications: one had a UTI, and one had both a mucosal skin tag and vaginal mucosal polyp. Two additional children developed a major complication: vaginal stenosis. Cosmesis scores revealed sustained improvements from 6 months post-genitoplasty, as previously reported, with all scores reported as good or satisfied. Discussion In these preliminary data from a multi-site, observational study, parents and surgeons were equally satisfied with the cosmetic outcomes 12 months after genitoplasty. A small number of patients had major complications in both feminizing and masculinizing surgeries; two-stage hypospadias repair had the most major complications. Long-term follow-up of patients at post-puberty will provide a better assessment of outcomes in this population. Conclusion In this cohort of children with moderate to severe atypical genitalia, preliminary data on both surgical and cosmetic outcomes were presented. Findings from this study, and from following these children in long-term studies, will help guide practitioners in their discussions with families about surgical management. Download : Download high-res image (236KB) Download : Download full-size image Summary Figure . Surgical complications at 12-month postoperative follow-up, n = 27. *Among the six complications in the masculinizing surgery group, one patient developed both urinary retention (minor) and urethrocutaneous fistula (major). ǂAmong the five complications in the feminizing surgery group, one patient had both a mucosal skin tag (minor) and vaginal mucosal polyp (minor).

PURPOSE: We examined the psychological adjustment of parents of children born with moderate to severe genital atypia 12 months after their child underwent genitoplasty. MATERIALS AND METHODS: Parents were recruited longitudinally from a multicenter collaboration of 10 pediatric hospitals with specialty care for children with disorders/differences of sex development and/or congenital adrenal hyperplasia. Parents completed measures of depressive and anxious symptoms, illness uncertainty, quality of life, posttraumatic stress and decisional regret. RESULTS: Compared to levels of distress at baseline (before genitoplasty) and 6 months after genitoplasty, data from 25 mothers and 20 fathers indicated significant improvements in all psychological distress variables. However, a subset of parents continued endorsing clinically relevant distress. Some level of decisional regret was endorsed by 28% of parents, although the specific decision that caused regret was not specified. CONCLUSIONS: Overall the majority of parents were coping well 1 year after their child underwent genitoplasty. Level of decisional regret was related to having a bachelor’s level of education, increased levels of illness uncertainty preoperatively and persistent illness uncertainty at 12 months after genitoplasty but was unrelated to postoperative complications.

Cryptorchidism is one of the most common pediatric disorders of the male endocrine glands and the most common genital disorder identified at birth. This guideline is intended to provide physicians and non-physician providers (primary care and specialists) with a consensus of principles and treatment plans for the management of cryptorchidism (typically isolated non-syndromic).A systematic review and meta-analysis of the published literature was conducted using controlled vocabulary supplemented with key words relating to the relevant concepts of cryptorchidism. The search strategy was developed and executed by reference librarians and methodologists to create an evidence report limited to English-language, published peer-reviewed literature. This review yielded 704 articles published from 1980 through 2013 that were used to form a majority of the guideline statements. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence-based data.Guideline statements were created to inform clinicians on the proper methods of history-taking, physical exam, and evaluation of the boy with cryptorchidism, as well as the various hormonal and surgical treatment options.Imaging for cryptorchidism is not recommended prior to referral, which should occur by 6 months of age. Orchidopexy (orchiopexy is the preferred term) is the most successful therapy to relocate the testis into the scrotum, while hormonal therapy is not recommended. Successful scrotal repositioning of the testis may reduce but does not prevent the potential long-term issues of infertility and testis cancer. Appropriate counseling and follow-up of the patient is essential.

Background Infertility is an unfortunate treatment-related consequence for some pediatric malignancies as well as some non-malignant conditions treated with stem cell transplant. Unlike pubertal males, prepubertal males cannot produce semen for cryopreservation. This manuscript reports on the acceptability and safety of a multi-institutional protocol for offering testicular tissue cryopreservation to families of prepubertal male children at highest risk for infertility. Data on decision influences, decision-making control, and emotional state when considering this option are described. Procedure Prepubertal males facing gonadotoxic therapy were offered testicular cryopreservation. Post-biopsy, patients were followed for acute side effects. In addition, parents and patients were asked to complete questionnaires, whether or not they chose to cryopreserve tissue. Results Seventy-four prepubertal male children were approached. Fifty-seven families (77%) consented to the testicular biopsy; 48 of 57 underwent the procedure. There was one post-operative side effect. Parents who agreed to testicular cryopreservation and those that did not felt in control of this decision. Parents who consented to the biopsy and refusers were not deterred by the experimental nature of the protocol. An important decision-making influence was the risk of the biopsy. Conclusion Biopsy and cryopreservation of testicular tissue from prepubertal male children was performed successfully and safely at three institutions. Parents faced with this option at diagnosis can make an informed decision and weigh carefully the risks and benefits. Although asked to make a decision soon after they were given a difficult diagnosis, parents uniformly felt in control of this decision. Pediatr Blood Cancer 2014;61:1673–1678. © 2014 Wiley Periodicals, Inc.

There are few normative data on semen analyses in youths at risk for but not presenting with infertility. Standard practice among infertility specialists includes evaluation of 2 separate semen samples, given the degree of within subject variability. We hypothesized that males transitioning from pediatric to adult care who are at risk for infertility would similarly have this variability.We retrospectively reviewed patients with a history of cryptorchidism or varicocele who submitted 2 semen samples for evaluation of fertility potential. The within subject coefficient of variation and intraclass correlation coefficient were calculated for each semen parameter to evaluate reproducibility and reliability, respectively.A total of 79 subjects were studied. Mean ± SD age was 18.8 ± 1.2 years (range 17.8 to 24.7). The within subject coefficient of variation was high for each semen parameter, ranging from 36% for volume and motility to 82% for total motile count. Intraclass correlation coefficient for a single semen analysis ranged from 0.55 for motility to 0.88 for total count. Intraclass correlation coefficient for total motile count was 0.78 (95% CI 0.67-0.85), consistent with substantial reliability.Although we observed within patient variability of individual semen analysis parameters, overall there was substantial agreement between consecutive semen analyses in this population at risk for infertility, particularly regarding total motile count, which is the most important determinant of fertility from a semen analysis. Therefore, it is possible to appropriately classify some young men based on the result of a single measurement as they transition from pediatric to adult care.

Summary Background The birth of a child with a disorder of sex development (DSD) and atypical genitalia can be traumatizing and isolating for families. Parents of children with DSD are at risk for increased levels of psychological distress, including depression, anxiety, illness uncertainty (IU), post-traumatic stress symptoms (PTSS), and impairments in quality of life (QOL). Our previous report indicated that although the majority of parents of children with atypical genitalia were coping well prior to the child's genitoplasty, approximately 25% of them reported experiencing some type of psychological distress. Objective The current study sought to examine the trajectory of parental psychological distress prior to, and 6 months after their child underwent genitoplasty. Methods Parents were recruited as part of an ongoing, prospective, multi-site study involving 10 pediatric hospitals with specialized care for children with atypical genitalia. Results from 49 parents (27 mothers, 22 fathers) of 28 children (17 female sex of rearing, 11 male sex of rearing) born with atypical genitalia (Prader rating of 3–5 in 46,XX DSD or by a Quigley rating of 3–6 in 46,XY DSD or 45,XO/46,XY) were included in the study. Results There were no significant changes in level of depressive or anxious symptoms or quality of life between baseline and 6-month post-operative follow-up, although mothers continued to report significantly higher levels of depressive symptoms than fathers, and as a group, these parents reported lower QOL than published norms. The level of PTSS significantly decreased for all parents, suggesting that parents may have come through the acute stress phase associated with their child's diagnosis. Finally, while there were no significant changes in IU over the time period, the level of IU for parents of boys actually increased, while parents of girls reported no change (Figure). Conclusion Six months after their child has undergone genitoplasty, the majority of parents report minimal levels of psychological distress. However, a subset of these parents continue to experience significant distress related to their child's diagnosis. Specifically, parents of boys appear to be at increased risk for difficulties, which may be related to either the lack of clinical diagnosis for almost half of these children or the necessity of two-stage surgeries for the majority of them. We will continue collecting data on these families to better understand the trajectory of these adjustment variables. Download : Download high-res image (173KB) Download : Download full-size image Figure . Graphs of significant changes.

International audience; Ten years after the consensus meeting on disorders of sex development (DSD), genital surgery continues to raise questions and criticisms concerning its indications, its technical aspects, timing and evaluation. This standpoint details each distinct situation and its possible management in 5 main groups of DSD patients with atypical genitalia: the 46,XX DSD group (congenital adrenal hyperplasia); the heterogeneous 46,XY DSD group (gonadal dysgenesis, disorders of steroidogenesis, target tissues impairments …); gonosomic mosaicisms (45,X/46,XY patients); ovo-testicular DSD; and "non-hormonal/non chromosomal" DSD. Questions are summarized for each DSD group with the support of literature and the feed-back of several world experts. Given the complexity and heterogeneity of presentation there is no consensus regarding the indications, the timing, the procedure nor the evaluation of outcome of DSD surgery. There are, however, some issues on which most experts would agree: 1) The need for identifying centres of expertise with a multidisciplinary approach; 2) A conservative management of the gonads in complete androgen insensitivity syndrome at least until puberty although some studies expressed concerns about the heightened tumour risk in this group; 3) To avoid vaginal dilatation in children after surgical reconstruction; 4) To keep asymptomatic mullerian remnants during childhood; 5) To remove confirmed streak gonads when Y material is present; 6) It is likely that 46,XY cloacal exstrophy, aphallia and severe micropenis would do best raised as male although this is based on limited outcome data. There is general acknowledgement among experts that timing, the choice of the individual and irreversibility of surgical procedures are sources of concerns. There is, however, little evidence provided regarding the impact of non-treated DSD during childhood for the individual development, the parents, society and the risk of stigmatization. The low level of evidence should lead to design collaborative prospective studies involving all parties and using consensual protocols of evaluation.

Summary Introduction Disorders of sex development (DSD) are a heterogeneous group of complex conditions that can affect chromosomal, gonadal, and/or phenotypical sex. In addition to impacts on internal and external genitalia,these conditions can affect fertility potentialto various degrees. In this review we discuss fertility issues including gonadalpreservation and reproductive outcomes based on specific DSD conditions. Methods and Materials A systematic literature review was performed on Embase™, PubMed®, and Google Scholar™ for disordersof sex development and infertility. Original research articles and relevant reviews were examinedand a synopsis of these data was generated for a comprehensive review of fertility potential in disorders of sex development. Results While patients with some DSDs may have functioning gonads with viable germ cells but an inability to achieve natural fertility secondary to incongruent internal or external genitalia, other patients may have phenotypically normal genitalia but infertility due to abnormal gonad development. Fertility rates in females with congenital adrenal hyperplasia (CAH) depend on phenotype and are inversely proportionalto the severity of the disease. Men with classic CAH have reduced fertility and due to the presence of testicular adrenal rest tumors and to suppression of the hypothalamic-pituitary-gonadal axis by high systemic levels of androgens. Infertility is seen in complete androgen insensitivity and subfertility is common in partial cases. Fertility is rare in pure or mixed gonadal dysgenesis, ovotesticular disorder, Klinefelter syndrome, and XX males. Conclusion Fertility potential appears to be the highest in patientswith XX or XY CAH, especially non-classic forms. Advancements in assisted reproduction techniques has in rare cases produced offspring in some diagnoses thought to be universally infertile. Discussion of fertility issues with the patient and family is essential to the optimal treatment of each patient and an important part of the multi-disciplinary approach to evaluating and counseling these families.

Little data exist about the surgical interventions taking place for children with disorders of sex development (DSD). Most studies that have evaluated cosmetic outcomes after genitoplasty have included retrospective ratings by a physician at a single center.The present study aimed to: 1) describe frequency of sex assignment, and types of surgery performed in a cohort of patients with moderate-to-severe genital ambiguity; and 2) prospectively determine cosmesis ratings by parents and surgeons before and after genital surgery.This prospective, observational study included children aged2 years of age, with no prior genitoplasty at the time of enrollment, moderate-to-severe genital atypia, and being treated at one of 11 children's hospitals in the United States of America (USA). Clinical information was collected, including type of surgery performed. Parents and the local pediatric urologist rated the cosmetic appearance of the child's genitalia prior to and 6 months after genitoplasty.Of the 37 children meeting eligibility criteria, 20 (54%) had a 46,XX karyotype, 15 (40%) had a 46,XY karyotype, and two (5%) had sex chromosome mosaicism. The most common diagnosis overall was congenital adrenal hyperplasia (54%). Thirty-five children had surgery; 21 received feminizing genitoplasty, and 14 had masculinizing genitoplasty. Two families decided against surgery. At baseline, 22 mothers (63%), 14 fathers (48%), and 35 surgeons (100%) stated that they were dissatisfied or very dissatisfied with the appearance of the child's genitalia. Surgeons rated the appearance of the genitalia significantly worse than mothers (P 0.001) and fathers (P ≤ 0.001) at baseline. At the 6-month postoperative visit, cosmesis ratings improved significantly for all groups (P 0.001 for all groups). Thirty-two mothers (94%), 26 fathers (92%), and 31 surgeons (88%) reported either a good outcome, or they were satisfied (see Summary Figure); there were no significant between-group differences in ratings.This multicenter, observational study showed surgical interventions being performed at DSD centers in the USA. While parent and surgeon ratings were discordant pre-operatively, they were generally concordant postoperatively. Satisfaction with postoperative cosmesis does not necessarily equate with satisfaction with the functional outcome later in life.In this cohort of children with genital atypia, the majority had surgery. Parents and surgeons all rated the appearance of the genitalia unfavorably before surgery, with surgeons giving worse ratings than parents. Cosmesis ratings improved significantly after surgery, with no between-group differences.

Verkauskasa et al. are to be commended on the depth of their investigation on hormonal parameters and histological changes in boys with cryptorchidism [1]. The overall finding of the study, which is that Ad spermatogonia counts decrease with age of cryptorchid testis biopsy, is consistent with other studies and highlights the need for prompt treatment of cryptorchid patients after 6 months of age [2]. In the subgroup that had a high risk of infertility because of absence of Ad spermatogonia stem cells, the LH levels were lower than expected, consistent with this subgroup having a hypogonadotropic hypogonadism. However, this group is small, less than 20% of the total sample. While the Ad numbers were low in the patients studied, it appears that the count was zero in only 21/51 pts (i.e. the majority of testes showed some germ cell maturation). The authors claim that transformation of gonocytes into Ad spermatogonia is testosterone dependent; however, there are also contrary animal and human studies which show that, even in complete androgen insensitivity, Ad spermatogonia appear normal initially. This would suggest that gonocyte transformation into Ad spermatogonia may be androgen-independent. Furthermore, several recent studies in animals and humans show that the pathogenesis and etiology of isolated cryptorchidism is likely multifactorial and in most cases unknown [3]. The bottom line is this: while men with a history of unilateral cryptorchidism tend to have lower sperm counts than the normal

Background Copy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population. Methods Genome wide genotyping were performed in 559 cases and 1772 controls (Group 1) using Illumina HumanHap550 v1, HumanHap550 v3 or Human610-Quad platforms and in 353 cases and 1149 controls (Group 2) using the Illumina Human OmniExpress 12v1 or Human OmniExpress 12v1-1. Signal intensity data including log R ratio (LRR) and B allele frequency (BAF) for each single nucleotide polymorphism (SNP) were used for CNV detection using PennCNV software. After sample quality control, gene- and CNV-based association tests were performed using cleaned data from Group 1 (493 cases and 1586 controls) and Group 2 (307 cases and 1102 controls) using ParseCNV software. Meta-analysis was performed using gene-based test results as input to identify significant genes, and CNVs in or around significant genes were identified in CNV-based association test results. Called CNVs passing quality control and signal intensity visualization examination were considered for validation using TaqMan CNV assays and QuantStudio® 3D Digital PCR System. Results The meta-analysis identified 373 genome wide significant (p

Purpose: Cryptorchidism has been associated with infertility. We hypothesize that a positive correlation exists between testicular histopathology at orchiopexy and future fertility potential in patients with cryptorchidism.Materials and Methods: Patients with cryptorchidism who underwent orchiopexy with bilateral testis biopsies were followed into adulthood. Testis histology was stratified into groups based on total germ cells per tubule and adult dark spermatogonia per tubule. After age 18 years, patients underwent hormonal testing and semen analysis. Mean semen analysis parameters and hormone levels were compared among histopathology groups.Results: A total of 91 patients with unilateral undescended testes and 19 with bilateral undescended testes had data for review. No significant differences in semen analysis parameters were seen among the germ cells per tubule groups. In unilateral undescended testis, sperm density and sperm count in the abnormal adult dark spermatogonia per tubule group remained wit...

Purpose Partial nephrectomy is increasingly used in children with bilateral Wilms' tumor (BWT) or contralateral recurrence. Nephron-sparing surgery seeks to achieve complete tumor removal while preserving functional renal parenchyma. Previous series have documented high rates of complications, recurrence, and mortality. Methods Twelve patients (4 boys and 8 girls aged 9-42 months) with BWT or contralateral recurrence were treated at our institution with unilateral or bilateral partial nephrectomy. Preoperative imaging, operative notes, and pathology reports were reviewed. Outcomes analyzed included complications, recurrence, readmission rate, postoperative glomerular filtration rate (GFR), and survival. Results All patients underwent successful nephron-sparing resection using standard techniques, with only 2 patients requiring unilateral nephrectomy. Median length of stay was 3 days. There were no major complications or urine leaks. Two patients were lost to follow-up. The remaining 10 were followed up for a median of 36 months (range, 3-79 months). There have been no recurrences or unplanned readmissions. Mean GFR is 107.7 (±32.8) mL/min per 1.73 m 2 , with no patient having a GFR below the lower limit of normal for age. Conclusion Nephron-sparing resection is a safe and effective approach for children with BWT or contralateral recurrence and should be part of the multimodality therapeutic approach to this disease.

Congenital absence of the testis is believed to be secondary to prenatal torsion, differing from the isolated undescended testis. We determined whether congenital absence of the testis is associated with abnormal histology in the solitary contralateral descended testis.A total of 239 boys with a primary diagnosis of unilateral absent testis underwent orchiectomy and testis biopsy. Germ cell counts were compared between solitary contralateral descended testes and contralateral descended testes in a randomly selected, age matched cohort of patients with unilateral undescended testes. Subanalyses evaluating hypertrophic testes and hypertrophic prepubertal testes between the study groups were performed.The solitary contralateral descended testis group exhibited a significantly greater volume (p0.001) and a significantly greater germ cell count (p = 0.001). In the hypertrophied testes there was a greater gonocyte count (p = 0.02), greater percentage of gonocytes (p = 0.02), greater primary spermatocyte count (p = 0.04) and greater percentage of primary spermatocytes (p = 0.03). No significant differences in adult dark spermatogonia or Leydig cells were detected. Primary spermatocytes did not differ significantly in prepubertal patients.The solitary contralateral descended testis exhibits increased volume, increased germ cell proliferation and dissimilar maturation patterns compared to the contralateral descended testis in unilateral cryptorchidism. These findings support prenatal torsion rather than endocrinopathy as the etiology for the congenitally absent testis. In the postpubertal solitary contralateral descended testis more germ cell maturation is seen and primary spermatocytes account for the increased total germ cell count. Patients with a solitary testis are likely not at additional risk for infertility.

Summary Introduction Re-operative penile reconstruction is challenging and requires tension-free skin closure. The repair popularized by Cecil and Culp in the 1940s, using the scrotum to provide a temporary vascularized bed for complex hypospadias repairs, fell out of favor due to temporal trends towards single-stage repairs and concern for utilizing hair-bearing skin on the penile shaft. Objective It was hypothesized that a modified Cecil-Culp (CC) concept of penile scrotalization, leaving the penis attached to the scrotum for 1 year rather than 6 weeks as originally described, improves outcomes with this reconstruction for ventral skin deficiency or poor vascular support. Methods Institutional Review Board-approved registries were reviewed to identify patients who underwent a CC repair during 1987–2016 at two institutions. Cecil-Culp technique was utilized in multi-stage hypospadias complication repairs or for insufficient ventral penile shaft skin coverage. Anatomic abnormality, number and type of prior surgeries, and complications before and after CC were recorded. Results Thirty-nine patients underwent CC: 23 failed hypospadias repairs, three hypospadias after bladder exstrophy, 10 penile curvature following circumcision, and three with skin loss from trauma. Mean age at CC was 61.8 months (hypospadias), and 59.8 months (non-hypospadias). Hypospadias patients underwent a mean of 3.6 surgeries (range 1–9) prior to CC. Four of the 39 patients (10.3%) had perioperative complications after CC, including scrotal abscess, skin infections, and difficulty removing the urethral stent. Eight of 37 (21.6%) patients had longer-term complications related to their hypospadias repair, including fistulae, diverticula, dehiscence, and stricture. Mean time from CC placement to release was 345 and 473 days for hypospadias and non-hypospadias cases, respectively. There was no apparent scrotal skin transferred to the penile shaft at the final take-down. Mean follow-up was 22.3 months. Discussion Embedding the penis into the scrotum for added vascularity and ventral skin coverage has been used effectively in cases of the most tenacious fistulas and for significant skin loss and trauma. Limitations of this study were its retrospective approach at two institutions over an extended period of time by multiple surgeons, so patient selection and procedure may have varied. Conclusions Modification of CC repair by delaying 9–12 months before CC take-down enhanced the benefits of a robust vascular bed for wound healing, and helped to avoid transfer of hair-bearing scrotal skin to the penile shaft. The CC technique is an important tool for penile reconstructive surgery of complex hypospadias repairs with inadequate skin, and for traumatic injuries.

Cryptorchidism is a common genital anomaly diagnosed at birth or during childhood. Genetic and/or environmental factors that alter expression or function of hormones crucial for testicular descent, insulin-like 3, and testosterone, may contribute to cryptorchidism. When identified at birth, surgical treatment is indicated by 6 months of age if testes fail to descend, or at the time of diagnosis in older children. A laparoscopic approach is preferred for abdominal testes. Early surgical therapy may reduce the risk of subfertility and/or malignancy.

The evaluation and management of neonates with ambiguous genitalia requires sensitivity, efficiency, and accuracy. The approach to these neonates is facilitated by a multidisciplinary team including urology, endocrinology, genetics, and psychiatry or psychology. Disorders of sex development (DSD) encompass chromosomal DSD, 46,XX DSD, and 46,XY DSD. The 46,XX DSD is the most common DSD and in the majority of these children congenital adrenal hyperplasia is the underlying etiology. The 46,XY DSD is a heterogeneous disorder that often results from a disruption in the production or response to testosterone, dihydrotestosterone, or Mullerian inhibitory substance. Chromosomal DSD includes conditions resulting from abnormal meiosis, including Klinefelter syndrome (47, XXY) and Turner syndrome. The evaluation of children with DSD demands a thorough physical examination, medical history, karyotype, metabolic panel, 17-OH progesterone, testosterone, luteinizing hormone, follicle stimulation hormone, and urinalysis. A radiographic evaluation should begin with an abdominal and pelvic ultrasound but may include magnetic resonance imaging, endoscopy, or laparoscopy.

In the human testis, beginning at ≈2 months of age, gonocytes are replaced by adult dark (Ad) and pale (Ap) spermatogonia that make up the spermatogonial stem cell (SSC) pool. In mice, the SSC pool arises from gonocytes ≈6 days after birth. During puberty in both species, complete spermatogenesis is established by cells that differentiate from SSCs. Essentially pure populations of prepubertal human spermatogonia and mouse gonocytes were selected from testis biopsies and validated by confirming the presence of specific marker proteins in cells. Stem cell potential of germ cells was demonstrated by transplantation to mouse testes, following which the cells migrated to the basement membrane of the seminiferous tubule and were maintained similar to SSCs. Differential gene expression profiles generated between germ cells and testis somatic cells demonstrated that expression of genes previously identified as SSC and spermatogonial-specific markers (e.g., zinc-finger and BTB-domain containing 16, ZBTB16) was greatly elevated in both human spermatogonia and mouse gonocytes compared to somatic cells. Several genes were expressed at significantly higher levels in germ cells of both species. Most importantly, genes known to be essential for mouse SSC self-renewal (e.g., Ret proto-oncogene, Ret ; GDNF-family receptor α1, Gfr α 1 ; and B-cell CLL/lymphoma 6, member B, Bcl6b ) were more highly expressed in both prepubertal human spermatogonia and mouse gonocytes than in somatic cells. The results indicate remarkable conservation of gene expression, notably for self-renewal genes, in these prepubertal germline cells between two species that diverged phylogenetically ≈75 million years ago.

Gonadal damage is a consequence of therapy for pediatric malignancies. Prepubertal males have no semen or mature spermatozoa, posing a challenge for fertility preservation. Testicular tissue cryopreservation is a potential option but is still experimental. We report on a pilot protocol that offered testicular biopsy cryopreservation to families of prepubertal boys with newly diagnosed malignancy. The aims were to determine the acceptability and safety of this procedure.Parents of prepubertal boys with diagnoses at highest risk for treatment-related gonadal damage were offered the option of testicular cryopreservation. Half of the biopsy was frozen for the subject's potential future use and the remainder used for research. Data on negative intraoperative and/or 7 day post-operative sequelae of testicular biopsies were assessed. Two to four weeks later, parents were asked to complete a questionnaire on factors influencing their decision to have the biopsy or not.Since January 2008, 24 boys have met the eligibility criteria but three required immediate treatment and were excluded. Sixteen of 21 families (76%) consented to testicular biopsy, indicating the prospective acceptability of this option to parents of boys aged 3 months to 14 years; 14 underwent the procedure without any negative intra- or post-operative sequelae. Although the time at diagnosis is stressful, families can give thoughtful consideration to this option. Factors such as religion, finance, ethics and the experimental nature of cryopreservation did not play a major role in decision-making.Parents of prepubertal boys with cancer are willing to pursue testicular tissue cryopreservation at diagnosis, and testicular biopsy caused no acute adverse effects.

Normal human sexual development occurs in a highly regulated process that comprises three distinct phases: establishment of chromosomal sex, development of the sex-specific gonads and phenotypic differentiation of the internal ductal anatomy and external genitalia. The latter two phases are mediated by specific hormonal effector molecules, including anti-Müllerian hormone and testosterone, and their dysregulation often leads to the development of a phenotypic disorder of sexual differentiation. This review describes the hormonal mediators that are involved in sexual development and the disorders of sexual differentiation that arise from their dysfunction.

We assessed the testicular growth of adolescent males followed nonsurgically for the presence of left varicocele.We retrospectively reviewed the charts of adolescent males with a diagnosis of unilateral left varicocele and ultrasound testis volume measurements seen during a 10-year period. A total of 161 boys underwent at least 2 testicular ultrasounds as part of the evaluation for left varicocele. Patients were excluded from study for a history of inguinal/scrotal pathology or endocrinopathy that could affect testicular size. Sonographic testicular volume was calculated using the Lambert volume (length x width x height x 0.71). The resulting volumes were compared to previously published criteria for surgical repair (15%, 20% and 2 cc size differentials).Of the 71 boys with 3 followup ultrasounds 38 (54%) initially had a 15% or greater volume differential. After nonsurgical followup with ultrasounds for 2 years 60 boys (85%) had testicular volume differentials in the normal range (less than 15%). Of the patients 71% were spared potential surgery by size criteria and 50% were spared surgery by the same 15% volume differential criteria.Adolescent males with unilateral left varicocele often demonstrate asynchronous testicular growth that usually equalizes in time. Therefore, sonographic testicular size measurement at a single point during adolescence is insufficient to determine the need for varicocelectomy. When contemplating varicocelectomy we recommend at least 2, and preferably 3, testicular volume measurements 1 year apart to establish accurately decreased left testicular volume compared to a normal right testis.

We present a newborn infant with ovotesticular disorder of sex development and sex chromosome mosaicism with a supernumerary ring(Y), and a normal female cell line (47,XXr(Y)[10]/46,XX[40]. The ring (Y) was inherited from the child's father, and was transmitted following assisted reproductive technology and intracytoplasmic sperm injection (ICSI). The father presented with infertility and oligospermia, but cytogenetic analysis had not been carried out as part of the infertility workup. The Y containing cell line had not been seen on amniocentesis, which had shown a 46,XX apparently normal female karyotype in all cells studied. Molecular analysis using polymorphic probes from the X chromosome demonstrated that the 47,XXr(Y) cell line in the child was consistent with inheritance from the father, following meiosis I paternal non-disjunction. This report underscores the need to obtain chromosome analysis in couples with infertility who undergo assisted reproduction.

Laparoscopic transvesical ureteral reimplantation with or without robot assisted surgical devices is being developed as an alternative to open surgery. We sought to review our experience with an extravesical robotic technique, to determine whether postoperative voiding dysfunction might be avoided with pelvic plexus visualization and to evaluate the overall feasibility of this approach to ureteral surgery.A total of 41 patients underwent robotic extravesical reimplantation for bilateral vesicoureteral reflux. The patients were divided into groups based on bladder capacity as measured by voiding cystourethrogram. The operation was performed via a transperitoneal approach with robotic assistance using the da Vinci Surgical System.Operative success rates were 97.6%. There were no complications. There were no episodes of urinary retention documented by bladder scanning.Robotic extravesical reimplantation is in its infancy, and visualization of the pelvic plexus appears to be paramount in avoiding postoperative voiding complications. This approach appears to be a feasible and reasonable option for vesicoureteral reflux correction.

In human sexual development, the female phenotype represents the default pathway. Therefore, a failure of testis determination results in the development of the female phenotype, while genetic alterations resulting in partial testicular development can give rise to a wide spectrum of masculinization. In addition to defects in peptide hormones and their receptors, timing of hormonal exposure is also critical to appropriate development. Although much work remains to be done, recent advances in our knowledge have begun to unravel the molecular basis of disorders of sexual development. Consensus statements from investigators have recommended changes in the nomenclature, and further investigations have examined the role of the female and male psyche in patients with these disorders. This review focuses on the diagnosis and management of conditions related to disorders of sexual development.

Objective Advancements in oncologic therapy have increased long-term survival rates for children with childhood cancers. As survival has increased, the secondary effects of treatment have come into focus for patients and family. Infertility preservation in prepubertal children is a particularly difficult task as options are limited compared to adult counterparts with mature gametes. Methods A systematic review of the published literature was conducted using keywords relevant to fertility preservation in the pediatric population undergoing oncologic treatment. Results We review the impact of cancer therapy upon gonadal function and identify the risk factors for future infertility in the prepubertal population. Treatment modifications that could modify the degree of potential damage to reproductive organs yet maintain oncologic principles were highlighted. Pubertal males and females have the opportunity to donate mature sperm or oocytes as do their adult counterparts; however, for the prepubertal child this is not the case. The options for these patients are considered investigational at this point and center on testicular tissue cryopreservation in males and oophorectomy vs ovarian cortical tissue cryopreservation in females. Conclusion Infertility is an unfortunate side effect of oncologic treatment. Options are limited in the prepubertal population but tissue preservation and potential fertility should be discussed with all at-risk patients and their parents.

Varicocele is one of the most common genital conditions referred to pediatric urologists. Most adolescents with varicocele are asymptomatic and their fertility future (and surgery benefit) is largely unknown. This review assesses varicocele evaluation, management and indications for repair, as well as types and success of varicocelectomy.A systematic literature review was performed on Embase™, PubMed® and Google Scholar™ for adolescent varicocele. Original research articles and relevant reviews were examined, and a synopsis of these data was generated for a comprehensive review of clinical adolescent varicocele management.The prevalence of adolescent varicocele is similar to the adult population. While ultrasound is the most sensitive method for determining testicular volumes, orchidometer measurement may be adequate to gauge significant discordance. Significant hypotrophy of the affected testis with poor total testicular volume may indicate a testis at risk and warrant surgical repair. Similar findings have been noted with an associated high peak retrograde venous flow. Testicular hypotrophy often resolves following surgery but may also improve spontaneously if followed through adolescence. Continued scrotal pain despite adequate support or serial abnormal semen analysis in Tanner stage V boys is an indication for varicocelectomy. Artery and lymphatic sparing techniques (microscopic subinguinal or laparoscopic) are associated with the lowest risk of recurrence and complications.Overtreatment and under treatment are medically and financially costly. Abnormal serial semen analysis with or without testicular hypotrophy is an indication for varicocele repair. If observation remains the treatment, followup with an adult urologist should be encouraged until paternity is achieved.

Introduction The symptomatic calyceal diverticulum is a rare event in the pediatric population. In adults, surgical options include ureteroscopy, percutaneous ablation, and laparoscopic decortication but there is a lack of experience in the literature with these techniques. Objective We present our experience with both the ureteroscopic and laparoscopic approach to treating the pediatric calyceal diverticulum. Study design We performed a retrospective case series looking at patients who underwent treatment for calyceal diverticulum at our institution from January 2009 to May 2014. We reviewed patient demographics, indications for intervention, radiographic appearance, type of intervention, and perioperative outcomes. Ureteroscopic approach included dilation of infundibulum and ablation of diverticular cavity. Laparoscopic approach included ablation of the diverticulum with argon diathermy with or without surgical closure of the ostium. Results There were 13 patients who underwent 15 procedures for symptomatic calyceal diverticulum (Table). Median age was 11 years. Indications for intervention were: pain and increasing size of diverticulum (8/15, 55%), hematuria (3/15, 20%), UTI (3/15, 20%), and calculi (1/15, 5%). 11/15 (73%) procedures were managed endoscopically and 4/15 (27%) were managed with laparoscopic decortication. Ureteral stent was left in all patients for a mean duration of 51 days (15–120 days). Follow up imaging at median of 2.1 years (0.5–4 years) revealed an initial success rate of 85% (11/13 patients). Two patients failed initial intervention (persistent pain/increasing size) necessitating successful secondary minimally invasive procedures. There were 2 (13%) complications: a perinephric hematoma post endoscopic ablation which resolved spontaneously and a deep venous thrombosis in a patient with a coagulation disorder in the laparoscopic group. Discussion Limitations of our study include its retrospective design, lack of standardization of the treatment approach amongst the four treating surgeons, and the small number of patients requiring intervention for this relatively rare diagnosis. Our study is the largest to date in the pediatric population and is the first to report outcomes with ureteroscopic management of the calyceal diverticulum. Conclusions We found that the pediatric calyceal diverticulum can be successfully treated in a minimally invasive manner. The endoscopic approach should be the first line option for patients with small, endophytic diverticula, particularly those located in the upper and mid pole. The laparoscopic approach is more invasive but should be considered for large diverticula that are exophytic with thin overlying parenchyma. Table . Summary of patient data. Complications classified according to clavien-dindo system. Endoscopic Laparoscopic Number of patients 9/13 (73%) 4/13 (27%) Size: median cm (range) 2.3 (1.3–3.5) 5.8 (2–10) Median decrease in size (cm) 1.0 (0–2) 3.0 (2.4–7.2) Median OR time, minutes (range) 69 (13–97) 172 (107–197) Median length of stay, days (range) 0.25 (0.2–1.2) 2 (1.9–4) Failure of initial therapy 2/9 0/4 Complications Repeat procedure 2 (Clavien IIIb) Perinephric hematoma 1 (Clavien I) DVT 1 (Clavien II)

Based on a genome-wide association study of testicular dysgenesis syndrome showing a possible association with TGFBR3, we analyzed data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal.We excluded samples based on strict quality control criteria, leaving 844 cases and 2,718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform (ie Illumina® HumanHap550, version 1 or 3, or Human610-Quad, version 1 BeadChip in group 1 and Human OmniExpress 12, version 1 BeadChip platform in group 2). Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of data for groups 1 and 2, and selective genotyping of independent cases (330) and controls (324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum.We identified suggestive (p ≤ 1× 10(-4)) association of markers in/near TGFBR3, including rs9661103 (OR 1.40; 95% CI 1.20, 1.64; p = 2.71 × 10(-5)) and rs10782968 (OR 1.58; 95% CI 1.26, 1.98; p = 9.36 × 10(-5)) in groups 1 and 2, respectively. In subgroup analyses we observed strongest association of rs17576372 (OR 1.42; 95% CI 1.24, 1.60; p = 1.67 × 10(-4)) with proximal and rs11165059 (OR 1.32; 95% CI 1.15, 1.38; p = 9.42 × 10(-4)) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior genome-wide association study signal (rs12082710) was marginal (OR 1.13; 95% CI 0.99, 1.28; p = 0.09 for group 1), and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild-type and cryptorchid rat fetal gubernaculum.These data suggest complex or phenotype specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFβ signaling.

Cryptorchidism is a common anomaly treated by every pediatric urologist. The etiology is multifactorial and includes hormonal and molecular factors. Diagnostic abilities may be enhanced by radiologic advances. Hormonal and surgical treatment modalities are discussed herein, as well as the identification and prevention of long-term sequelae.

Sexual determination is a complex process that occurs in an organized sequential manner. When chromosomal, gonadal, or phenotypic sex determination goes awry,intersexuality develops. Advances in molecular biology have made it easier to understand the various phenotypes that are encountered. It is easy to be overwhelmed when reviewing the testosterone synthesis pathway and the intersex differential diagnosis. This article presents a useful approach to the evaluation of the newborn with ambiguous genitalia.

Concordant and discordant presentations of posterior urethral valves (PUV) in twins have been described. Twin gestation may complicate the diagnosis of PUV based on prenatal evaluation. A case series of 2 sets of twin births is presented, each of which was discordant for the diagnosis of PUV. A delay in diagnosis occurred in both cases, despite prenatal ultrasound abnormalities. This delay could result from failed sensitivity of prenatal ultrasound or from postnatal evaluation of the incorrect twin. Caution must be exercised during follow-up of abnormalities identified on prenatal ultrasound in diseases in which there are no external distinguishing characteristics.

Purpose: Inpatient stays of 3 to 5 days are common in the surgical management of vesicoureteral reflux and often include the use of bladder catheters, ureteral stents and perivesical drains. We reviewed our recent experience, in which patients undergoing routine ureteroneocystostomy were often discharged home on postoperative day 1 to determine the safety and efficacy of our management.Materials and Methods: Between July 1998 and March 2001 patients who underwent intravesical ureteroneocystostomy at 2 major tertiary care institutions were identified. Patients who also underwent simultaneous additional operative procedures, bilateral ureteral duplication or ureteral tapering were excluded from study. Data recorded included patient demographics, the procedure, operative and postoperative pain, nausea and bladder spasm management, hospital stay, post-hospital discharge problems and operative success.Results: Of the 113 patients with complete data available for analysis 101 received ketorolac postoperatively,...

Summary Introduction Adolescent males with varicoceles present a dilemma for surveillance and treatment. Testicular volumetrics have not been shown to predict SA outcomes. Serial SAs are thus recommended in asymptomatic adolescent males with varicoceles and normal testicular development, but the natural history of semen parameters is unknown. Objective To explore the natural history of semen parameters in adolescent boys with a left varicocele under active surveillance. Study design Adolescents with an asymptomatic unilateral left varicocele, Tanner V development, normal testicular volumes, and an initial SA were retrospectively reviewed in a single-institution prospectively followed cohort. Total motile count (TMC) was calculated. A cutoff of TMC Z 20 million was used to dichotomize SA results into “normal” or “poor.” Those with poor SA were offered repeat SA. Cumulative probabilities of normal TMC over successive rounds of SA were calculated. Bivariate models were used to explore associations of a second consecutive poor TMC with age and varicocele grade. Results A total of 216 patients provided an initial SA between 1992 and 2015. We excluded 17 for a history of cryptorchidism or incomplete SA data for a final cohort of 199 patients with median follow-up of 3.3 years (interquartile range 1.5–5.6 years). The mean age at initial SA was 17.9 years (range 14.8–21.8 years). One hundred and nine out of 199 had an initial normal TMC. Of the 90 out of 199 with an initially poor TMC, 51 had repeat SA and 24 of the 51 patients improved to normal TMC. Of the 27 patients with two consecutive poor TMCs, 15 had a third SA and five out of 15 improved to normal TMC. Thus, cumulatively, 55%, 67%, and 69% of all patients had a normal TMC after an initial, second, and third SA, respectively. However, fewer patients in each round of SA normalized their TMC ( Figure ). Neither age nor varicocele grade was associated with a second consecutive poor TMC. Discussion Two-thirds of Tanner V boys with an uncorrected varicocele and normal testicular volumes achieve a normal TMC regardless of varicocele grade or age. Despite Tanner V development, 47% with an initial “poor” SA will improve to normal status without surgery. However, a small subgroup of patients will have persistently poor TMC and thus should be targeted in future research for timely intervention. Conclusion Semen parameters improve over time. SA should be followed and repeated at least once in symptomatic Tanner V boys with varicoceles. Download : Download high-res image (98KB) Download : Download full-size image Figure . Semen analysis outcomes.

Summary Purpose The main indications for adolescent varicocelectomy are testicular hypotrophy or pain. However, we have previously shown that both serial total testicular volume and volume differential are weakly associated with semen quality. The ultimate patient goal is paternity, but semen analysis is critical to appropriate management of varicocele. We hypothesize that varicocelectomy improves total motile count (TMC) among patients who only have abnormal semen analysis (SA) parameters, but not among those with potential hormonal dysfunction such as Klinefelter syndrome or cryptorchidism. Methods We retrospectively reviewed our registry of adolescent males followed with a clinical left varicocele. For this study, subjects without sustained testicular asymmetry, who were Tanner V, and gave at least one preoperative SA were included. Subjects were excluded if they had embolization for their varicocele or no postoperative SA. Primary outcome was change in TMC before and after surgery, compared using the Wilcoxon signed rank test after stratifying by surgical indication. Secondary outcomes included rates of improved TMC and normalized TMC (>20 million) after surgery, compared across covariates using the Fisher exact test. Results Seventeen patients met the eligibility criteria, 11 of whom underwent repair for only abnormal preoperative TMC. Overall, median age (interquartile range [IQR]) at first preoperative SA was 17.6 (15.9–17.9) years. The median preoperative TMC across all SA was 2.8 (0.7–7.4) million. The median age at surgery was 18.2 (16.8–18.9) years. Postoperatively, the median TMC across all SA increased to 18.2 (3.6–18.2) million (Wilcoxon signed rank test, p Conclusions Adolescent varicocele patients should undergo SA after development of Tanner V. Varicocelectomy has a high success rate for improving TMC in adolescent or young adult males who only have abnormal TMC and no history of cryptorchidism. Download : Download high-res image (153KB) Download : Download full-size image Figure . Change in total motile count after varicocelectomy by patient.

Infertility is an unfortunate treatment-related consequence for some pediatric malignancies as well as some non-malignant conditions treated with stem cell transplant. Unlike pubertal males, prepubertal males cannot produce semen for cryopreservation. This manuscript reports on the acceptability and safety of a multi-institutional protocol for offering testicular tissue cryopreservation to families of prepubertal male children at highest risk for infertility. Data on decision influences, decision-making control, and emotional state when considering this option are described.Prepubertal males facing gonadotoxic therapy were offered testicular cryopreservation. Post-biopsy, patients were followed for acute side effects. In addition, parents and patients were asked to complete questionnaires, whether or not they chose to cryopreserve tissue.Seventy-four prepubertal male children were approached. Fifty-seven families (77%) consented to the testicular biopsy; 48 of 57 underwent the procedure. There was one post-operative side effect. Parents who agreed to testicular cryopreservation and those that did not felt in control of this decision. Parents who consented to the biopsy and refusers were not deterred by the experimental nature of the protocol. An important decision-making influence was the risk of the biopsy.Biopsy and cryopreservation of testicular tissue from prepubertal male children was performed successfully and safely at three institutions. Parents faced with this option at diagnosis can make an informed decision and weigh carefully the risks and benefits. Although asked to make a decision soon after they were given a difficult diagnosis, parents uniformly felt in control of this decision.

Purpose: Human chorionic gonadotropin (HCG) has a stimulatory effect on testicular steroidogenesis and has been widely used for evaluating male Leydig cell function. However, considerable variability exists in the protocols for HCG stimulation tests. In the most commonly used protocols HCG is administered daily for several days. We examine the circulating androgen response after 1 and 3-dose HCG regimens.Materials and Methods: We evaluated 77 prepubertal boys diagnosed with hypospadias, cryptorchidism or micropenis. In 60 boys who underwent 1 dose of 100 IU/kg. or 5,000 IU/1.7 m.2 HCG serum testosterone and dihydrotestosterone were sampled at 72 (28) and 96 (32) hours after injection, while in 17 who underwent 3 daily age adjusted doses hormone levels were determined on day 4. All blood specimens were obtained and injections were performed at 8:00 to 9:00 a.m. and all specimens were evaluated at the same endocrine reference laboratory.Results: Nonstimulated testosterone levels were prepubertal in all grou...

Approximately 10 to 30% of prenatal cases of hydronephrosis result in the postnatal diagnosis of vesicoureteral reflux. Using a new generic prenatal-postnatal data sheet developed by the Society for Fetal Urology the characteristics, natural history and outcome of prenatal hydronephrosis confirmed postnatally to be vesicoureteral reflux were documented at 3 centers.We performed a retrospective multicenter review of Society for Fetal Urology data sheets completed for each patient in whom prenatal hydronephrosis was proved to be postnatal vesicoureteral reflux from 1993 to 1998.In 56 male and 15 female patients with prenatal hydronephrosis a total of 116 refluxing renal units were confirmed postnatally. Of the 116 renal units 112 were hydronephrotic prenatally. During gestation increased hydronephrosis was noted with voiding in 4 cases. Of the 112 hydronephrotic renal units only 26 ureters in 15 patients were seen prenatally. The obstetrician considered the diagnosis of vesicoureteral reflux in only 24% of the cases. Postnatally 116 refluxing renal units were identified. Initial postnatal ultrasound was normal in 25% of the cases. Bilateral reflux was present in 36 male and 9 female patients. In 10 of the 19 uncircumcised patients (53%) urinary tract infection developed despite antibiotic prophylaxis. In 15 of the 74 renal units with grades III to V reflux the condition resolved at an average patient age of 0.9 and 2.1 years in boys and girls, respectively. A total of 27 refluxing renal units were reimplanted.The majority of prenatal reflux occurs in boys, and it is high grade and bilateral. The data sheets designed by the Society for Fetal Urology are useful data collection instruments. The presentation and natural history of vesicoureteral reflux are different in male and female individuals. In a significant number of renal units high grade reflux resolves spontaneously. Early circumcision may decrease the incidence of breakthrough urinary tract infection in this subpopulation. In addition, the effective management of prenatally detected reflux depends on multispecialty communication.

Purpose: Cryptorchidism is the most common congenital abnormality of the genitalia. However, its exact etiology remains to be defined. Homeobox (HOX) containing genes have a key role in the morphogenesis of segmental structures along the primary body axis, including the urogenital mesenchyma. In male mice with a targeted deletion of the HOXA10 gene cryptorchidism manifests in the absence of other major defects. Because to our knowledge this gene has never been examined for alterations in humans, we evaluated whether mutations of HOXA10 are associated with cryptorchidism in humans.Materials and Methods: Genomic deoxyribonucleic acid (DNA) was extracted from human blood or tissue samples from 16 noncryptorchid control subjects and 45 cryptorchid boys. To screen for mutations exons 1 and 2 of the HOXA10 gene were amplified individually by polymerase chain reaction using 6 overlapping oligonucleotide primer pairs. Single strand conformational polymorphism (SSCP) analysis of the amplified radiolabeled ...

Objective To discuss a case of asynchronous bilateral renal venous thrombosis with a review of current literature. Case A premature fraternal twin male was delivered via Cesarean section to a mother with a history of pre-eclampsia. He was initially diagnosed with a left renal venous thrombosis (RVT) but subsequently developed right RVT. Only intravenous fluids and supportive care were provided. Anticoagulation was withheld because of MRI findings of multiple areas of intracerebral bleeding. His serum creatinine concentration stabilized at 0.7 mg/dL, but follow-up renal ultrasound studies showed bilateral anechoic corticomedullary cysts. He also developed hypertension. Discussion Renal venous thrombosis usually occurs in neonates. Multiple clinical conditions are associated with RVT, two of which exist in this case. Recent work has focused on genetic prothrombotic risk factors, one of which our patient exhibits. Controversy exists over management, i.e. whether or not to initiate anticoagulation or antithrombotic therapy to decrease the development of renal atrophy, renal failure and hypertension. Conclusions This unusual case of asynchronous bilateral renal venous thrombosis recovered in the short term without antithrombotic therapy. Substantial insult early in life is reflected in the progressive worsening of his renal function, ultrasound findings and hypertension, highlighting the need for long-term vigilant observation of these patients.

We hypothesized that active surveillance of the adolescent varicocele is not associated with a high prevalence of suboptimal semen analysis and that patients with abnormal semen analysis have smaller testicular volumes and larger volume differentials.We conducted an institutional review board approved retrospective cohort study of adolescents with a clinically detected varicocele. Patients were initially observed by serial scrotal ultrasound evaluating testicular size and differential. Semen analysis was routinely collected in Tanner V cases, around age 18 years. Prevalence of normal semen analysis parameters was calculated, and logistic regression was used to model the ability of age at presentation and testicular volume parameters to predict a normal semen analysis.A cohort of 73 patients underwent surveillance with a mean ± SD age at presentation of 15.5 ± 2.3 years. Median followup was 2.7 years, during which time subjects underwent a median of 3 scrotal ultrasounds. A low total motile count was found in 48 patients (66%). Neither age at presentation nor testicular volume differential could predict normal semen volume, density, sperm motility or total motile count. Total testicular volume from the final ultrasound predicted total motile count (p = 0.008). However, the collective observations of volume during the entire period of surveillance could not predict total motile count (p = 0.847).There is a high prevalence of suboptimal semen analysis in adolescents with a varicocele who are followed with active surveillance. Total testicular volume can predict total motile count at the end of adolescence but not throughout.

With the increasing number of patients surviving cancer, there is increasing interest in long-term quality of life, especially with respect to cancer-related infertility. Although infertility most commonly occurs as the result of treatment with gonadotoxic agents, it can also manifest before treatment has commenced. Current fertility preservation strategies for the postpubertal male patient with cancer focus on sperm cryopreservation before therapy. Sperm acquisition techniques should be discussed with the patient as early as possible, by either an oncologist or a specialist in male reproduction. For patients rendered infertile by cancer treatment who did not cryopreserve sperm beforehand, there are no techniques currently available to restore fertility. For the prepubertal male patient, cryopreservation of sperm is impossible. However, emerging research--primarily in animal models--into promising fertility preservation and restoration strategies might provide a clinical solution in the future. Advances in the protection and cryopreservation of spermatogonial stem cells (SSCs) might translate into clinical options for fertility preservation before treatment. Restoring fertility after treatment might also be possible via SSC autotransplantation or in vitro maturation of SSCs. Before any of these techniques become clinically viable, a number of scientific, logistical and ethical issues will need to be resolved.