Long-term follow-up of bladder outlet procedures in children with neurogenic urinary incontinence.

INTRODUCTION: Achieving continence in children with neurogenic sphincteric incompetence is a challenge. Awareness of the long-term outcome in this young patient population is important. In the past 25 years, the study institution has built experience in bladder outlet procedures such as bladder neck sling and bladder neck reconstructions. OBJECTIVE: The objective of this study was to evaluate the long-term outcome on continence and re-intervention rate of bladder outlet procedures in children with neurogenic urinary incontinence at the study institution. DESIGN: All children who underwent a bladder neck procedure between 1992 and 2017 at the study institution were retrospectively reviewed. Continence at the end of follow-up was the primary endpoint, defined as 'dry' when there was an interval of a minimum of 4 h without urinary leakage. Non-parametric tests were used for statistical analysis. RESULTS: During this 25-year period, a total of 60 children underwent a bladder outlet procedure, either a bladder neck sling (n = 43) or a bladder neck reconstruction (n = 17). The median age at surgery was 11.6 years (interquartile range [IQR] 7.8-13.9). Concomitant surgery consisted of bladder augmentation in 80% and continent catheterizable urinary channel in 97% of children. Dry rate within 1 year was 38%. After a median follow-up of 10.4 years (IQR 6.5-15.5), 77% of all children were dry. Twenty-five children (42%) needed one or more re-interventions, including redo of the bladder outlet procedure, other type of outlet procedure, bulking agents, bladder augmentation, and bladder neck closure. DISCUSSION: This study confirms that achieving continence is a challenge. The inconsistent use of the definition of urinary continence creates confusion in the literature and makes comparison of outcome with other studies difficult. Openness of (long-term) results in achieving urinary continence is important and helpful for future patients. CONCLUSION: On the long term, the majority of children with neurogenic urinary incontinence were dry after a bladder outlet procedure, but a considerable number of patients had a re-intervention. The initial outcome on continence was slightly disappointing. Reporting long-term results is essential and helpful for patient counseling.

Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling.

STUDY QUESTION: What is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT? SUMMARY ANSWER: No GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333). WHAT IS KNOWN ALREADY: Many adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown. STUDY DESIGN, SIZE, DURATION: This multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology. PARTICIPANTS/MATERIALS, SETTING, METHODS: Material from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14-54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies. MAIN RESULTS AND ROLE OF CHANCE: The earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT-associated SNPs. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: A limited number of cases were included. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests.

Clitoral hoodplasty in females with disorders of sex development.

INTRODUCTION: The surgical management of girls with masculinized genitalia is gradually changing towards a more conservative approach. Reports on loss of clitoral sensitivity and related impairment of sexual function in women after feminizing genital surgery in childhood have been pivotal in this evolution. An exposed clitoral glans is occasionally seen at follow-up, and while patients may complain of aesthetics, no clitoral discomfort secondary to glans exposure has been reported. A technique has been developed to reconstruct the clitoral hood and the present study reports the preliminary results. OBJECTIVES: To report the novel technique and preliminary results of clitoral hood reconstruction to cover an exposed glans after previous clitoroplasty in patients with congenital adrenal hyperplasia (CAH). PATIENTS AND METHODS: Six female patients (mean age 13, range 4-21 years) with CAH sought medical help for clitoral concerns after previous reduction clitoroplasty. In two of the six patients, the main complaint was clitoral hypersensitivity or even pain. The clitoral glans was completely exposed in all patients, who were subsequently treated with a bi-laminar V-Y clitoral hoodplasty to create a mobile and natural-looking clitoral hood composed of an inner and outer preputial skin layer. RESULTS: Postoperative covering of the glans was complete in five patients, and partial in one. The two patients with pre-operative pain became asymptomatic; all six patients were pleased with the cosmetic postoperative results. CONCLUSION: Clitoral hoodplasty provides simple, yet effective, relief for women with cosmetic concerns or clitoral discomfort after previous feminizing surgery.

Gonadal dysgenesis in disorders of sex development: Diagnosis and surgical management.

Recent studies on gonadal histology have improved the understanding of germ cell malignancy risk in patients with disorders of sex development (DSD), and evidence-based gonadal management strategies are gradually emerging. Especially in 46,XY DSD and 45,X/46,XY DSD, which are characterized by gonadal dysgenesis, the risk of germ cell malignancy is significantly increased. This paper summarized the progress over the past 10 years in malignancy risk assessment in patients with DSD, and its implications for optimal surgical handling of the involved gonads.

Breaking the vicious circle: Onabotulinum toxin A in children with therapy-refractory dysfunctional voiding.

INTRODUCTION: An increased activity of the external urethral sphincter or pelvic floor muscles during voluntary voiding leads to dysfunctional voiding. Frequently reported symptoms are urinary incontinence, urinary tract infections and high post-void residuals. Dysfunctional voiding is a common problem in school-aged children and despite various treatment options, 10-40% of the children remain therapy-refractory. OBJECTIVE: The aim of this study is to evaluate the effectiveness of Onabotulinum toxin-A (BTX-A) injections in the external urethral sphincter in children with therapy-refractory dysfunctional voiding. PATIENTS AND METHODS: Patients with therapy-refractory dysfunctional voiding who have received BTX-A injections in the external urethral sphincter from 2010 to 2013 were analysed. Children with known neuropsychiatric disorders were excluded. All children had abnormal flow patterns and increased pelvic floor tone during uroflowmetry/EMG studies. They had received at least five sessions of urotherapy and two sessions of pelvic floor physical therapy prior to treatment. A total of 100 IU of BTX-A was injected in the external urethral sphincter at the 3, 9 and 12 o'clock positions. Our main outcome measures were urinary incontinence, recurrent urinary tract infections and post-void residual. RESULTS: A total of twenty patients, of whom 16 girls, with a median age of 9 years (range 5-14) were treated with BTX-A. The median follow-up was 13 months (range 5-34). Post-void residual decreased by 75% after BTX-A, from a median of 47.5 ml (16.3-88.5 ml) to 0 ml (0.0-28.0 ml) (p = 0.001) Six patients had a post-void residual < 20 ml prior to treatment. After BTX-A sixteen patients had a post-void residual <20 ml (Figure). No significant changes in uroflowmetry results was seen. Sixteen children are no longer daily incontinent, of whom 9 became completely dry (p = 0.0001). Eleven patients suffered from recurrent urinary tract infections prior to treatment. After BTX-A five children remained infection free, while the other six experienced only one urinary tract infection during follow-up (p = 0.003). Fourteen patients received additional urotherapy after BTX-A. Repeat injections were necessary in four patients after initial satisfactory results, with repeated good clinical responses. Two children showed no improvement after first BTX-A injection. No serious adverse events were reported. DISCUSSION: The results in this homogenous group of patients confirm the conclusions of previous studies in opting BTX-A in the external urethral sphincter to be a viable treatment option for the therapy-refractory group of patients with dysfunctional voiding. What is new, is that in most of our patients post-injection urotherapy was used to amplify the BTX-A effect. During our long-term follow-up the satisfactory results were sustained, similar to the results of the long-term follow-up presented by Vricella et al. [1]. The retrospective character and relative small sample size are limitations of this study. CONCLUSIONS: This study shows safe and persistent satisfactory results during our average 13-month follow-up in 90% of our patients with therapy-refractory dysfunctional voiding. A prospective study using validated and standardized measurements will be performed to affirm our results and evaluate the exact role of post-injection urotherapy.

Testes in infants with Prader-Willi syndrome: human chorionic gonadotropin treatment, surgery and histology.

PURPOSE: Boys with Prader-Willi syndrome often have undescended testes. Prospective studies on the treatment of cryptorchidism in these patients are lacking. We evaluated the effects of human chorionic gonadotropin administration on testis position in 16 males with Prader-Willi syndrome. In patients who subsequently underwent orchiopexy biopsy was taken and testis histology was evaluated. MATERIALS AND METHODS: A total of 16 boys (median age 1.6 years, IQR 1.2 to 1.8) with Prader-Willi syndrome and cryptorchidism underwent human chorionic gonadotropin stimulation test. After a positive test human chorionic gonadotropin treatment was initiated. Patients received 250 to 500 IU (depending on age) intramuscularly twice weekly for 6 weeks. RESULTS: We found 1 testis in a stable scrotal position, 1 vanished testis and 1 atrophic abdominal testis. Of 29 testes responding to human chorionic gonadotropin 23% reached a stable scrotal position, 62% reached a lower position and 14% did not change position. Thus, 22 testes required orchiopexy. Of 17 obtained biopsies in 12 patients 2 showed germ cells in more than 60% of seminiferous tubules, 3 in 30% to 60% and 7 in less than 30%. In addition, 4 boys had Sertoli cell only syndrome and 1 had a vanished testis. In patients undergoing orchiopexy younger age and increased inhibin B and testosterone levels after human chorionic gonadotropin stimulation were associated with a greater number of germ cell containing tubules. CONCLUSIONS: Human chorionic gonadotropin administration resulted in an anatomically lower testis position in most of our patients with Prader-Willi syndrome, and 23% of testes reached a stable scrotal position. Of the cases 76% required orchiopexy to ensure a stable position in the scrotum.

A novel AMH missense mutation in a patient with persistent Müllerian duct syndrome.

Persistent Müllerian duct syndrome (PMDS) is characterized by the presence of a uterus, fallopian tubes, and the upper part of the vagina in phenotypic normal male patients. Here, we report a patient diagnosed with PMDS with a novel homozygous missense mutation in the anti-Müllerian hormone (AMH) gene (single nucleotide insertion (C) at position 208 (c.208dup, p.Leu70fs)) leading to a frameshift and the introduction of a premature stop codon. Biopsy of both gonads revealed that germ cells were present in an irregular distribution. However, the absence of OCT3/4, PLAP and c-KIT expression indicated physiological maturation.

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth.

OBJECTIVE: Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty and on germ cell tumor risk in patients with SF-1 mutations. This study reports on the natural course during puberty and on gonadal histology in two adolescents with SF-1 mutations and predominantly female phenotype at birth. DESIGN AND METHODS: Clinical and hormonal data and histopathological studies are reported in one male and one female adolescent with, respectively, a nonsense mutation (c.9T>A, p.Tyr3X) and a deletion of the first two coding exons (NCBI36/hg18 Chr9:g.(126306276-126307705)_(126303229-126302828)del) of NR5A1, both predicted to fully disrupt gene function. RESULTS: LH and testosterone concentrations were in the normal male range, virilization was disproportionate to the neonatal phenotype. In the girl, gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ. In the boy, at the age of 12, numerous germ cells without signs of malignancy were present in bilateral testicular biopsy specimen. CONCLUSIONS: In SF-1 mutations, the neonatal phenotype poorly predicts virilization at puberty. Even in poorly virilized cases at birth, male gender assignment may allow spontaneous puberty without signs of hypogonadotropic hypogonadism, and possibly fertility. Patients with SF-1 mutations are at increased risk for malignant germ cell tumors. In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted. The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation.

Gonadal development and tumor formation at the crossroads of male and female sex determination.

Malignant germ cell tumor (GCT) formation is a well-known complication in the management of patients with a disorder of sex development (DSD). DSDs are defined as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. DSD patients in whom the karyotype - at least at the gonadal level - contains (a part of) the Y chromosome are at increased risk for neoplastic transformation of germ cells, leading to the development of the so-called 'type II germ cell tumors'. However, tumor risk in the various forms of DSD varies considerably between the different diagnostic groups. This contribution integrates our actual knowledge on the pathophysiology of tumor development in DSDs, recent findings on gonadal (mal)development in DSD patients, and possible correlations between the patient's phenotype and his/her risk for germ cell tumor development.

Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism.

CONTEXT: Gonadectomy is avoided whenever possible in boys with 45,X/46,XY. However, no clinical markers are currently available to guide clinicians in predicting gonadal tumor risk or hormone production. OBJECTIVE: The objective of the study was to test the hypothesis that gonadal histology and risk for development of a malignant germ cell tumor are reflected by the clinical presentation of a 45,X/46,XY individual. DESIGN: The design of the study was the correlation of clinical data [external masculinization score (EMS), pubertal outcome] with pathology data (gonadal phenotype, tumor risk). SETTING: This was a multicenter study involving two multidisciplinary disorder of sex development teams. PATIENTS: Patients included genetically proven 45,X/46,XY (and variants) cases, of whom at least one gonadal biopsy or gonadectomy specimen was available, together with clinical details. INTERVENTIONS: Patients (n = 48) were divided into three groups, based on the EMS. Gonadal histology and tumor risk were assessed on paraffin-embedded samples (n = 87) by morphology and immunohistochemistry on the basis of established criteria. MAIN OUTCOME MEASURES: Gonadal differentiation and tumor risk in the three clinical groups were measured. Clinical outcome in patients with at least one preserved gonad was also measured. RESULTS: Tumor risk in the three groups was significantly related to the gonadal differentiation pattern (P < 0.001). In boys, hormone production was sufficient and was not predicted by the EMS. CONCLUSIONS: The EMS reflects gonadal differentiation and tumor risk in patients with 45,X/46,XY. In boys, testosterone production is often sufficient, but strict follow-up is warranted because of malignancy risk, which appears inversely related to EMS. In girls, tumor risk is limited but gonads are not functional, making gonadectomy the most reasonable option.

Tumor risk in disorders of sex development.

Certain patients with disorders of sex development (DSD), who bear Y chromosome material in their karyotype, are at increased risk for the development of type II germ cell tumors (GCT), which arise from early fetal germ cells. DSD gonads frequently harbor immature germ cells which express early fetal germ cell markers. Some of them (e.g. OCT3/4 and NANOG) seem to be of pathogenetic relevance in GCT development providing cells with the ability of pluripotency, proliferation and apoptosis suppression. Also TSPY (testis-specific protein Y-encoded), the main candidate for the so-called gonadoblastoma locus on Y chromosome, is overexpressed in germ cells of DSD patients and possibly contributes to their survival and proliferation. Nowadays, the use of immunohistochemical methods is highly relevant in identifying DSD gonads at risk. The risk for GCT development varies. While the prevalence of GCT is 15% in patients with partial androgen insensitivity, it may reach more than 30% in patients with gonadal dysgenesis. Patients with complete androgen insensitivity and ovotesticular DSD develop malignancies in 0.8% and 2.6% of cases, respectively. However, these data may be biased for various reasons. To better estimate the risk in individual groups of DSD, further investigations on large patient series are needed.

Potential for recovery in bladder function after removing a urethral obstruction.

AIMS: We examined the relation between the loss of bladder function during obstruction and the potential for recovery of function after de-obstruction. METHODS: Guinea pigs received a partial urethral obstruction. Bladder pressure, urine flow rate, detrusor overactivity (DO), compliance and contractility were examined weekly for 2-4 weeks (short), 6-8 weeks (medium), or 9-12 weeks (long). Then the obstruction was removed and bladder function followed up to 7 weeks. The groups were compared to animals receiving only obstruction or a sham operation. RESULTS: During obstruction the three de-obstruction groups and the obstruction group progressively lost bladder function. Flow rate remained stable, compliance decreased, pressure, contractility and DO increased. After de-obstruction the response in the three de-obstruction groups varied. In S, bladder pressure and compliance normalized, contractility initially increased then decreased towards high normal values, DO remained high normal and flow rate increased. In M, bladder pressure and DO decreased to above average normal levels. Compliance improved but did not normalize. Contractility initially stabilized, then decreased to just above the normal range. Flow-rate increased. In L, bladder pressure and DO decreased to high normal. Compliance did not improve. Contractility decreased directly after de-obstruction, stabilizing at an above normal level, flow-rate increased. CONCLUSIONS: The potential for functional recovery decreases with increasing loss of bladder function. At all stages of bladder dysfunction, voiding pressure appears to normalize after de-obstruction. However, contractility remains high and compliance low. Such a bladder may be more vulnerable to new events of outflow obstruction than a low contractile, normal compliant bladder.

Stem cell factor as a novel diagnostic marker for early malignant germ cells.

Carcinoma in situ (CIS) of the testis is the pre-invasive stage of type II testicular germ cell tumours (TGCTs) of adolescents and adults. These tumours are the most frequently diagnosed cancer in Caucasian adolescents and young adults. In dysgenetic gonads, the precursor of type II GCTs can be either CIS or a lesion known as gonadoblastoma (GB). CIS/GB originates from a primordial germ cell (PGC)/gonocyte, ie an embryonic cell. CIS can be cured by local low-dose irradiation, with limited side effects on hormonal function. Therefore, strategies for early diagnosis of CIS are essential. Various markers are informative to diagnose CIS in adult testis by immunohistochemistry, including c-KIT, PLAP, AP-2gamma, NANOG, and POU5F1 (OCT3/4). OCT3/4 is the most informative and consistent in presence and expression level, resulting in intense nuclear staining. In the case of maturational delay of germ cells, frequently present in gonads of individuals at risk for type II (T)GCTs, use of these markers can result in overdiagnosis of malignant germ cells. This demonstrates the need for a more specific diagnostic marker to distinguish malignant germ cells from germ cells showing maturation delay. Here we report the novel finding that immunohistochemical detection of stem cell factor (SCF), the c-KIT ligand, is informative in this context. This was demonstrated in over 400 cases of normal (fetal, neonatal, infantile, and adult) and pathological gonads, as well as TGCT-derived cell lines, specifically in cases of CIS and GB. Both membrane-bound and soluble SCF were expressed, suggestive of an autocrine loop. SCF immunohistochemistry can be a valuable diagnostic tool, in addition to OCT3/4, to screen for precursor lesions of TGCTs, especially in patients with germ cell maturation delay.

FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD).

The transcription factors SOX9 and FOXL2 are required for male and female mammalian gonadal development. We have used specific antibodies to investigate the role of these key proteins in disorders of sex development (DSD), specifically inter-sex states. In normal gonads, SOX9 was found to be restricted to the presence of (pre-)Sertoli cells, while FOXL2 was found in granulosa cells, and in stromal cells interpreted as early ovarian stroma. Both proteins were found within a single patient, when testicular and ovarian development was present; and within the same gonad, when both differentiation lineages were identified, as in ovotesticular DSD (ie hermaphrodite). Especially SOX9 was informative to support the presence of early testicular development (ie seminiferous tubules), expected based on morphological criteria only. In a limited number of DSD cases, FOXL2 was found within reasonably well-developed seminiferous tubules, but double staining demonstrated that it was never strongly co-expressed with SOX9 in the same cell. All seminiferous tubules containing carcinoma in situ (CIS), the malignant counterpart of a primordial germ cell, ie the precursor of type II germ cell tumours of the testis, seminomas and non-seminomas, showed the presence of SOX9 and not FOXL2. In contrast, gonadoblastomas (GBs), the precursor of the same type of cancer, in a dysgenetic gonad, showed expression of FOXL2 and no, or only very low, SOX9 expression. These findings indicate that gonadal differentiation, ie testicular or ovarian, determines the morphology of the precursor of type II germ cell tumours, CIS or GB, respectively. We show that in DSD patients, the formation of either ovarian or/and testicular development can be visualized using FOXL2 and SOX9 expression, respectively. In addition, it initiates a novel way to study the role of the supportive cells in the development of either CIS or GB.

Abnormal urine flow in boys with distal hypospadias before and after correction.

PURPOSE: We established the urine flow rate and the effect of surgical correction on that rate in patients with hypospadias. MATERIALS AND METHODS: The urine flow rate, voided volume and residual urine were measured using an ultrasound flow probe and bladder scan in boys with distal hypospadias before operative correction in 42 with a mean age of 16 months, 3 and 9 months after operative correction in 28 and 11, respectively, and in a control group of 51 boys 0 to 3 years old (mean age 11 months). Long-term flow data were obtained retrospectively from the records of 63 patients with hypospadias 1 to 10 years after operation. RESULTS: Of the controls 37% had mainly intermittent and sometimes fractionated flows, 4% had a plateau phase flow and 59% had mainly bell-shaped flow curves. The average maximum flow rate +/- SD was 6.8 +/- 4.1 ml per second and maximum flow rate/voided volume was 0.26 +/- 0.11 l per second. Of the boys with distal hypospadias 76% produced intermittent flows (fractionated in the majority) before correction. After correction this percent decreased to 50%. The average maximum flow rate was 7.5 +/- 2.5 ml per second before correction, and 6.6 +/- 2.8 and 7.2 +/- 1.8 ml per second 3 and 9 months after operation, respectively. Average maximum flow rate/voided volume was 0.22 +/- 0.12 l per second before, and 0.16 +/- 0.09 and 0.16 +/- 0.09 l per second 3 and 9 months after operation, respectively. In the long-term group maximum flow rate/voided volume was 0.13 +/- 0.11 l per second. The number of patients voiding with a plateau phase increased from 6% before to 13% and 17% after correction, respectively. An obstructive pattern was also observed in 41% of the long-term followup group. CONCLUSIONS: An intermittent flow pattern is common in 0 to 3-year-old boys. It appears to be more common and more pronounced or fractionated in boys with distal hypospadias at the same ages. In relation to voided volume patients with hypospadias already produce an abnormally low urine flow rate before correction and even more so thereafter in the short and intermediate term. The corrective procedure increases the occurrence of flows with an obstructive pattern.

Testicular germ cell tumors in children: management and outcome in a series of 20 patients.

Testicular germ cell tumors occurring during childhood are extremely rare. This study reports the clinical presentation, pathological diagnosis, treatment methods and outcome in a series of 20 boys, aged between 3.5 months and 16 years (median: 1.5 years; 19 were prepubertal), who were treated between 1963 and 2003. Histologically, mature teratoma was present in seven, immature teratoma in four and yolk sac tumor in nine. Nineteen patients were stage I; only one patient was stage IV. Of the 11 teratomas, 10 were treated by orchiectomy and one by testis-sparing tumor excision only. All 11 patients have survived and show no evidence of disease between 10 and 28 years after surgery. The nine patients with yolk sac tumor were managed by orchiectomy, in two plus retroperitoneal lymphadenectomy, and in eight plus chemotherapy. One patient is in remission for 10 months, seven are alive with no evidence of disease for 5.5-23 years, and one patient died from a T-cell acute lymphoblastic leukemia, 2 years after the end of treatment of the testicular tumor. A gradual switch towards less invasive treatment has been observed over the years. This study confirms the excellent cure rates obtained in children with testicular germ cell tumor, provided diagnosis is prompt and treatment accurate.

Sonographic genital ambiguity in a fetus due to a mosaic 45,X/46,X,idic(Y)(qter-p11.32::p11.32-qter) karyotype.

Nowadays, improved ultrasound techniques enable the detection of more subtle congenital abnormalities at an earlier stage of fetal development. Current cytogenetic techniques can characterize a chromosomal abnormality in greater detail. These advancements in both diagnostic possibilities have helped to answer many questions but have also created new issues and dilemmas in counselling. This is illustrated by this case report of a 35-year-old woman, who presented at the end of the second trimester of her first pregnancy. Sonographic examination indicated an abnormal external genital in a male fetus. A differential diagnosis of hypospadia was made. During follow-up, an amniocentesis was performed, and this showed a 45,X/46,X,idic(Y)(qter-p11.32::p11.32-qter) karyotype as the cause of the sonographic findings. Cytogenetic characterization of the isodicentric Y chromosome and pre- and post-natal findings in the child are reported. Cases with a similar karyotype reported in the literature are reviewed.

Mild renal pyelectasis in the second trimester: determination of cut-off levels for postnatal referral.

OBJECTIVE: To establish guidelines for postnatal referral of fetuses presenting with mild pyelectasis in the second trimester of pregnancy. METHODS: In a retrospective study, 87 fetuses with a renal pelvis anteroposterior (RPAP) diameter of > or = 4 mm and < or = 10 mm before 28 weeks of gestation were included. All patients had a third-trimester scan and fetuses with an RPAP diameter of > or = 10 mm at that stage were referred for postnatal assessment. The family practitioner of all infants with an RPAP of < 10 mm in the third trimester was contacted for follow-up information. The RPAP diameter most predictive of renal pathology was determined with receiver-operating characteristics (ROC) curve analysis for both the first and second scans. RESULTS: In 36 of 87 infants, 49 abnormal kidneys were diagnosed. Seven infants required surgery on eight renal tracts. The ROC curves of the first scan, second scan and differences between scans resulted in an area under the curve of 0.60, 0.87 and 0.85, respectively. The sensitivities and specificities for a cut-off level of 8, 9 and 10 mm at the second scan were 80%, 71% and 61% and 79%, 90% and 93%, respectively. At a cut-off level of 10 mm, only cases of insignificant minimal dilatation and a case of vesicoureteric reflux (VUR) requiring surgery were not detected. CONCLUSION: After establishing a diagnosis of mild pyelectasis before 28 weeks, a second scan is mandatory to determine which infants need postnatal evaluation. A cut-off level of 8 mm has a low specificity but includes most cases of pathology. A cut-off level of 10 mm detects most significant pathology; however, VUR may not be detected.

Raman spectroscopic analysis identifies testicular microlithiasis as intratubular hydroxyapatite.

PURPOSE: As diagnosed by ultrasonography, testicular microlithiasis is associated with various benign and malignant conditions. The molecular constitution of these microliths is largely unknown. Raman spectroscopy provides detailed in situ information about the molecular composition of tissues and to our knowledge it has not been applied to gonadal microliths. We analyzed the molecular composition of gonadal microlithiasis and its surrounding region using Raman spectroscopy in malignant and benign conditions. MATERIALS AND METHODS: Multiple microliths from 6 independent samples diagnosed with gonadal microlithiasis by ultrasound and histologically confirmed were investigated by Raman spectroscopy. The samples included 4 testicular parenchyma samples adjacent to a germ cell tumor (4 seminomas), a gonadoblastoma of a dysgenetic gonad and testicular biopsy of a subfertile male without malignancy. RESULTS: Raman spectroscopic mapping demonstrated that testicular microliths were located within the seminiferous tubule. Glycogen surrounded all microliths in the samples associated with germ cell neoplasm but not in the benign case. The molecular composition of the 26 microliths in all 6 conditions was pure hydroxyapatite. CONCLUSIONS: Microliths in the testis are located in the seminiferous tubules and composed of hydroxyapatite. In cases of germ cell neoplasm they co-localize with glycogen deposits.