Endoscopic injection of bulking agents in pediatric vesicoureteral reflux: a narrative review of the literature.

In the last 20 years, endoscopic injection (EI) has affirmed as a valid alternative to open surgery for management of pediatric vesicoureteral reflux (VUR). This study aimed to investigate and discuss some debated aspects such as indications, bulking agents and comparison, techniques of injection and comparison, predictive factors of success, use in specific situations. EI is minimally invasive, well accepted by patients and families, with short learning curve and low-morbidity profile. It provides reflux resolution rates approaching those of open reimplantation, ranging from 69 to 100%. Obviously, the success rate may be influenced by several factors. Recently, it is adopted as first-line therapy also in high grade reflux or complex anatomy such as duplex, bladder diverticula, ectopic ureters. The two most used materials for injection are Deflux and Vantris. The first is absorbable, easier to inject, has lower risk of obstruction, but can lose efficacy over time. The second is non-absorbable, more difficult to inject, has higher risk of obstruction, but it is potentially more durable. The two main techniques are STING and HIT. To date, the ideal material and technique of injection has not yet clearly established, but the choice remains dependent on surgeon's preference and experience.

Long-Term Functional Outcomes of an Anorectal Malformation French National Cohort.

OBJECTIVES: The present study aimed to assess long-term functional outcomes of children with anorectal malformations (ARMs) across a network of expert centers in France. METHODS: Retrospective cross-sectional study of patients ages 6-30 years that had been surgically treated for ARM. Patient and ARM characteristics (eg, level, surgical approach) and functional outcomes were assessed in the different age groups. RESULTS: Among 367 patients, there were 155 females (42.2%) and 212 males (57.8%), 188 (51.2%) cases with, and 179 (48.8%) higher forms without, perineal fistula. Univariate and multivariate statistical analyses with logistic regression showed correlation between the level of the rectal blind pouch and voluntary bowel movements (odds ratio [OR] = 1.84 [1.31-2.57], P < 0.001), or soiling (OR = 1.72 [1.31-2.25], P < 0.001), which was also associated with the inability to discriminate between stool and gas (OR = 2.45 [1.28-4.67], P = 0.007) and the presence of constipation (OR = 2.97 [1.74-5.08], P < 0.001). Risk factors for constipation were sacral abnormalities [OR = 2.26 [1.23-4.25], P = 0.01) and surgical procedures without an abdominal approach (OR = 2.98 [1.29-6.87], P = 0.01). Only the holding of voluntary bowel movements and soiling rates improved with age. CONCLUSION: This cross-sectional study confirms a strong association between anatomical status and functional outcomes in patients surgically treated for ARM. It specifically highlights the need for long-term follow-up of all patients to help them with supportive care.

Phenotypic switch of smooth muscle cells in paediatric chronic intestinal pseudo-obstruction syndrome.

Smooth Muscle Cells (SMC) are unique amongst all muscle cells in their capacity to modulate their phenotype. Indeed, SMCs do not terminally differentiate but instead harbour a remarkable capacity to dedifferentiate, switching between a quiescent contractile state and a highly proliferative and migratory phenotype, a quality often associated to SMC dysfunction. However, phenotypic plasticity remains poorly examined in the field of gastroenterology in particular in pathologies in which gut motor activity is impaired. Here, we assessed SMC status in biopsies of infants with chronic intestinal pseudo-obstruction (CIPO) syndrome, a life-threatening intestinal motility disorder. We showed that CIPO-SMCs harbour a decreased level of contractile markers. This phenotype is accompanied by an increase in Platelet-Derived Growth Factor Receptor-alpha (PDGFRA) expression. We showed that this modulation occurs without origin-related differences in CIPO circular and longitudinal-derived SMCs. As we characterized PDGFRA as a marker of digestive mesenchymal progenitors during embryogenesis, our results suggest a phenotypic switch of the CIPO-SMC towards an undifferentiated stage. The development of CIPO-SMC culture and the characterization of SMC phenotypic switch should enable us to design therapeutic approaches to promote SMC differentiation in CIPO.

Diethylstilbestrol exposure during pregnancy with primary clear cell carcinoma of the cervix in an 8-year-old granddaughter: a multigenerational effect of endocrine disruptors?

To date, vaginal/cervical clear cell adenocarcinoma (CCAC) has not been reported in the granddaughters of women treated with diethylstilbestrol (DES) during pregnancy. We present an 8-year-old girl with a history of severe vaginal bleeding who was diagnosed with cervical CCAC. She underwent fertility-sparing surgery and radiotherapy. No sign of recurrence was detected throughout a 10-year follow-up. Her grandmother had received DES therapy during pregnancy with the patient's mother. Although no direct causal link is demonstrated, this case raises for the first time, the hypothesis of multigenerational effects of DES in girls and strongly suggests the need to follow the granddaughters of DES-treated women.

A cover flap reduces the rate of fistula after urethroplasty whatever the severity of hypospadias.

OBJECTIVE: To determine which patients should benefit from the interposition of a well-vascularized flap between the neourethra and the penile skin and if it should be performed even in mild hypospadias. PATIENTS AND METHODS: A retrospective study on patients with a primary hypospadias repair was performed (2003-2017). Only patients undergoing urethroplasty based on the principle of a tubularization were selected to ensure comparable groups. Patients were assigned in two groups according to the use or not of a cover flap. Univariate analysis and adjusted logistic regression were used to evaluate the relation between postoperative complications, the severity of hypospadias, the use of flap and patients' characteristics. RESULTS: Three-hundred and seventy-six patients were included with anterior (59.3%), midshaft (27.4%) and posterior hypospadias (13.3%). The median follow-up was 54 months (24 months-17 years). The overall rate of fistula was 11.7% (n = 44). Comparing the outcome in children with flap (n = 217) to controls (n = 159) showed that the use of a flap reduces the rate of fistula (6.5 vs 18.9%, p < 0.001). Stratification of the study according to the phenotype reveals that the more severe the hypospadias, the more protective was the flap (OR = 2.6 for anterior, 5.5 for midpenile, 7.1 for posterior hypospadias). The flap remains nevertheless significantly effective whatever the phenotype (p < 0.05 for anterior, p = 0.01 for midpenile, p = 0.02 for posterior hypospadias). CONCLUSIONS: The more severe the hypospadias, the more effective is the cover flap to avoid fistula. It remains nevertheless suitable even in anterior hypospadias and the use of a cover flap should not be limited to the surgery of severe phenotypes.

Multigenerational endometriosis : consequence of fetal exposure to diethylstilbestrol ?

BACKGROUND: Endometriosis, which affects 10-15 % of women of reproductive age, is an estrogen-driven condition influenced by environmental and genetic factors. Exposition to estrogen-like endocrine-disrupting chemicals (EDCs) has been reported to contribute to the fetal origin of this disease. CASE PRESENTATION: We report here an informative family in which all prenatally DES-exposed daughters and subsequent granddaughters presented endometriosis, whereas the unexposed first daughter and her progeny presented no gynecological disorders. Moreover, the only post-pubertal great-granddaughter, who presents chronic dysmenorrhea that remains resistant to conventional therapy, is at risk of developing endometriosis. The mother (I-2) was prescribed DES (30 mg/day for 3 months) to inhibit lactation after each delivery. CONCLUSIONS: Although a direct causal link between the grandmother's treatment with DES and the development of endometriosis in possibly three exposed generations remains speculative, this report strengthens the suspicion that fetal exposition to DES contributes to the pathogenesis of adult diseases, such as endometriosis. It also highlights a multigenerational and likely transgenerational effect of EDCs.

Experimental Evidence of 2,3,7,8-Tetrachlordibenzo-p-Dioxin (TCDD) Transgenerational Effects on Reproductive Health.

Previous studies have demonstrated that endocrine disruptors (EDs) can promote the transgenerational inheritance of disease susceptibility. Among the many existing EDs, 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) affects reproductive health, including in humans, following direct occupational exposure or environmental disasters, for instance the Agent Orange sprayed during the Vietnam War. Conversely, few studies have focused on TCDD multigenerational and transgenerational effects on human reproductive health, despite the high amount of evidence in animal models of such effects on male and female reproductive health that mimic human reproductive system disorders. Importantly, these studies show that paternal ancestral TCDD exposure substantially contributes to pregnancy outcome and fetal health, although pregnancy outcome is considered tightly related to the woman's health. In this work, we conducted a systematic review of the literature and a knowledge synthesis in order (i) to describe the findings obtained in rodent models concerning TCDD transgenerational effects on reproductive health and (ii) to discuss the epigenetic molecular alterations that might be involved in this process. As ancestral toxicant exposure cannot be changed in humans, identifying the crucial reproductive functions that are negatively affected by such exposure may help clinicians to preserve male and female fertility and to avoid adverse pregnancy outcomes.

Adolescent ovarian thecoma presenting as progressive hyperandrogenism: case report and review of the literature.

Hyperandrogenism is frequent and under investigated in adolescent girls. A 15-year-6-month-old French girl presented with oligomenorrhea and slowly progressing virilization 2 years post-menarche. Medical history revealed prenatal pesticide exposure through maternal professional activity and recurrent premature thelarche. Severe hirsutism, mild facial acne and clitoromegaly were noted. Serum androgens (testosterone: 94 ng/dL, 4-androstenedione: 8.23 ng/mL) were high and non-classic 21-hydroxylase deficiency was excluded. Pelvic ultrasonography showed a left ovarian mass, confirmed by computed tomography scan. Tumor markers were negative. Laparoscopic surgery was performed. The pathological diagnosis was benign luteinized thecoma. Postoperatively, the menstrual cycle and serum androgens became normal and hirsutism slowly improved. Hyperandrogenism 2 years after menarche should be systematically investigated, even if slowly progressive, since it may be a symptom of a rare virilizing ovarian tumor, like thecoma.

Predictors of the Performance of Early Antireflux Surgery in Esophageal Atresia.

OBJECTIVE: To identify predictors of and factors associated with the performance of antireflux surgery during the first year of life in children born with esophageal atresia. STUDY DESIGN: All patients were included in a French registry for esophageal atresia. All 38 multidisciplinary French centers completed questionnaires about perinatal characteristics and one-year outcome for children born with esophageal atresia. RESULTS: Of 835 infants with esophageal atresia born in France from 2010 to 2014, 682 patients, excluding those with long-gap esophageal atresia, were included. Three patients had type I, 669 had type III, and 10 had type IV esophageal atresia. Fifty-three children (7.8%) received fundoplication during the first year of life. The median age at the time of the end-to-end esophageal anastomosis was 1.1 day (range 0-15). Multivariate analysis identified three perioperative factors that predicted the need for early antireflux surgery: anastomotic tension (P = .004), associated malformations (P = .019), and low birth weight (P = .018). Six other factors, measured during the first year of life, were associated with the need for antireflux surgery: gastroesophageal reflux (P < .001), anastomotic stricture (P < .001), gastrostomy (P < .001), acute life-threatening event (P = .002), respiratory complications (P = .045), and poor nutritional status (P < .001). CONCLUSIONS: Gastroesophageal reflux disease, low birth weight, poor nutrition, and surgical anastomosis difficulties predicted the performance of antireflux surgery in the first year of life in infants with esophageal atresia.

Molecular genetics of hypospadias and cryptorchidism recent developments.

During the last decade, a tremendous amount of work has been devoted to the study of the molecular genetics of isolated hypospadias and cryptorchidism, two minor forms of disorders of sex development (DSD). Beyond the genes involved in gonadal determination and sex differentiation, including those underlying androgen biosynthesis and signaling, new genes have been identified through genome-wide association study and familial clustering. Even if no single genetic defect can explain the whole spectrum of DSD, these recent studies reinforce the strong role of the genetic background in the occurrence of these defects. The timing of signaling disruption may explain the different phenotypes.

Prenatal imaging of genital defects: clinical spectrum and predictive factors for severe forms.

OBJECTIVES: To report the clinical spectrum of genital defects diagnosed before birth, identify predictive factors for severe phenotypes at birth, and determine the rate of associated malformations. PATIENTS AND METHODS: A retrospective study (2008-2017) of 4580 fetuses, identified prenatally with abnormalities evaluated by our Reference Center for Fetal Medicine, included cases with fetal sonographic findings of abnormal genitalia or uncertainty of fetal sex determination. Familial, prenatal and postnatal data were collected via a standardised questionnaire. RESULTS: In all, 61 fetuses were included. The positive predictive value (PPV) of the prenatal diagnosis of genital defects was 90.1%. Most cases were 46,XY-undervirilized boys, 42 cases (68.8%), which included 29 with mid-penile or posterior hypospadias, nine with anterior hypospadias, and epispadias, micropenis, scrotal transposition, and buried penis (one each). In all, 46,XX-virilized girls were identified in seven cases (11.5%), which included four with congenital adrenal hyperplasia, two with isolated clitoromegaly, and one with ovotestis. Other defects included prune belly syndrome and persistent cloaca (six cases). Early detection during the second trimester (58.1% vs 18.8%, P = 0.03), intra-uterine growth restriction (IUGR) (45.2% vs 9.1%, P = 0.06), and curvature of the penis (38.7% vs 0%, P = 0.02), were more frequently related to severe defects in male newborns. Associated malformations (14 cases, 22.9%) and genetic defects (six) were frequent in undervirilized boys. CONCLUSION: Prenatal imaging of genital defects leads to a wide range of phenotypes at birth. Its PPV is high and extra-urinary malformations are frequent. Early diagnosis during the second trimester, associated IUGR, and curvature of the genital tubercle, should raise suspicion of a severe phenotype and may justify delivery near a multidisciplinary disorders/differences of sex development team.

Family History is Underestimated in Children with Isolated Hypospadias: A French Multicenter Report of 88 Families.

PURPOSE: While familial forms of complex disorders/differences of sex development have been widely reported, data regarding isolated hypospadias are sparse and a family history is thought to be less frequent. We aimed to determine the frequency of hypospadias in families of boys with hypospadias, to establish whether these familial forms exhibit a particular phenotype and to evaluate the prevalence of genetic defects of the main candidate genes. MATERIALS AND METHODS: A total of 395 boys with hypospadias were prospectively screened for a family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1. RESULTS: Family history of hypospadias was more frequent than expected (88 patients, 22.3%). In 17 instances (19.3%) familial hypospadias cases were multiple. Familial hypospadias was related to the paternal side in 59.1% of cases, consisting of the father himself (30.7%) as well as paternal uncles and cousins. Premature birth, assisted reproductive techniques, other congenital abnormalities and growth retardation were not more frequent in familial hypospadias than in sporadic cases. The severity of phenotype was similar in both groups. The results of genetic analysis combined with previous data on androgen receptor sequencing revealed that familial cases more frequently tend to demonstrate genetic defects than sporadic cases (5.68% vs 1.63%, p = 0.048). CONCLUSIONS: Familial forms of hypospadias are far more frequent than previously reported. Even minor and isolated forms justify a full clinical investigation of the family history. Detecting these hereditary forms may help to determine the underlying genetic defects, and may improve followup and counseling of these patients.

Ultrasound-guided pudendal nerve block in children: A new technique of ultrasound-guided transperineal approach.

BACKGROUND: Transperineal pudendal nerve block guided by nerve stimulator is used in pediatric anesthesia as an alternative to caudal analgesia in perineal surgery. The risk of rectal puncture or intravascular injection is inherent to this blinded technique. We described a new technique of transperineal pudendal nerve block, with ultrasound guidance, to improve safety of the technique. AIMS: The first goal of this study was to describe this new technique and to test its feasibility. The second objective was to evaluate intra operative effectiveness and postoperative pain control. METHODS: After parental and children consent, this prospective descriptive study included children aged 1-15 years, ASA status I-III, scheduled for general anesthesia associated with bilateral pudendal nerve block for an elective perineal surgery. After standardized general anesthesia, the anesthesiologist performed pudendal nerve block under ultrasound guidance with "out of plane" approach and evaluated the visualization of anatomical structures (ischial tuberosity, rectum, and pudendal artery), of the needle and of the local anesthetic spread. Pudendal nerve block failure was defined as an increase in mean arterial blood pressure or heart rate more than 20% compared to baseline values after surgical incision. In the postoperative period, the need for rescue analgesia was noted. RESULTS: During the study period, 120 blocks were performed in 60 patients, including 59 boys. Quality of the ultrasonographic image was good in 81% of blocks, with easy visualization of ischium and rectum in more than 95% of cases. Localization of the tip of the needle was possible for all pudendal nerve blocks, directly or indirectly. The spread of local anesthetic was seen in 79% of cases. The block was effective in 88% of cases. CONCLUSION: The new technique of ultrasound-guided pudendal nerve block, described in this study, seems to be easy to perform with a good success rate, and probably improves safety of the puncture and of the injection by real-time visualization of anatomical structures and local anesthetic spread.

Molecular analyses of juvenile granulosa cell tumors bearing AKT1 mutations provide insights into tumor biology and therapeutic leads.

Juvenile granulosa cell tumors (JGCTs) of the ovary are pediatric neoplasms representing 5% of all granulosa cell tumors (GCTs). Most GCTs are of adult type (AGCTs) and bear a mutation in the FOXL2 gene. The molecular basis of JGCTs is poorly understood, although mutations in the GNAS gene have been reported. We have detected in-frame duplications within the oncogene AKT1 in >60% of the JGCTs studied. Here, to evaluate the functional impact of these duplications and the existence of potential co-driver alterations, we have sequenced the transcriptome of four JGCTs and compared them with control transcriptomes. A search for gene variants detected only private alterations probably unrelated with tumorigenesis, suggesting that tandem duplications are the best candidates to underlie tumor formation in the absence of GNAS alterations. We previously showed that the duplications were specific to JGCTs. However, the screening of eight AGCTs samples without FOXL2 mutation showed the existence of an AKT1 duplication in one case, also having a stromal luteoma. The analysis of RNA-Seq data pinpointed a series of differentially expressed genes, involved in cytokine and hormone signaling and cell division-related processes. Further analyses pointed to the existence of a possible dedifferentiation process and suggested that most of the transcriptomic dysregulation might be mediated by a limited set of transcription factors perturbed by AKT1 activation. Finally, we show that commercially available AKT inhibitors can modulate the in vitro activity of various mutated forms. These results shed light on the pathogenesis of JGCTs and provide therapeutic leads for a targeted treatment.

Late surgical correction of hypospadias increases the risk of complications: a series of 501 consecutive patients.

OBJECTIVES: To evaluate the outcomes of hypospadias surgery according to age and to determine if some complications are age-related. PATIENTS AND METHODS: This retrospective study was based on 722 boys with hypospadias undergoing primary repair. A total of 501 boys underwent urethroplasty and were included in the study. Complications requiring an additional procedure (stenosis, fistula, dehiscence, relapse of curvature, urethrocele) were included in the analysis, as well as healing problems, infections, haematomas and detrusor-sphincter dyssynergy. Logistic regression analysis was performed. RESULTS: Hypospadias was anterior in 63.1%, mid-penile in 20.5%, posterior in 8.4% and scrotal in 7.9% of the boys. The median (range) age was 4 (1-16) years. The overall rates of re-intervention and complications were 22.8% and 36.2%, respectively. Age >2 years was a significant predictor of complications (P = 0.002, odds ratio 1.98 [95% confidence interval 1.26-3.13]). Some periods of time appeared to be associated with a specific complication: dyssynergy was more common between the ages of 24 and 36 months (12.5 vs 3.6%; P = 0.01) and healing problems were more common in boys aged >13 years (1.5 vs 28.5%; P = 0.06). CONCLUSION: Delayed surgery may be detrimental for patients. Factors related to age may influence the rate of complications. After the age of 2 years, urethral surgery may interfere with the normal toilet-training process. During puberty, endogenous testosterone may alter healing. Even if no specific data exist for severe hypospadias, it may be prudent to continue to advocate early surgery in patients with disorders of sex development.

Coccygeal polypoid eccrine nevus associated with imperforate anus and unilateral multicystic kidney dysplasia.

Eccrine nevi are rare hamartomas characterized by an increase in the number or size of eccrine glands. A polypoid form located in the coccygeal area has been described in a few cases and termed coccygeal polypoid eccrine nevus (CPEN). No association with internal malformations was reported in any of these cases. We describe herein a case of CPEN associated with imperforate anus and unilateral multicystic kidney dysplasia. We review the clinical and pathological characteristics of CPENs and discuss the differential diagnoses.

Advantages of robot-assisted surgery in anorectal malformations: Report of a case.

Laparoscopy has been widely used to repair anorectal malformations (ARMs) by paediatric surgeons in an attempt to be less invasive, offer better cosmetic results, enable a faster return of bowel function, decrease length of hospital stay and pain, and lately to improve functional results. Robotic technology assists the paediatric surgeon by increasing dexterity and precision of movement with a robotic wrist-like mechanism that allows up to 90° of articulation and 7° of freedom. This is important in ARM surgery, where the dissection of the fistula and the pull-through of the rectum into the muscular complex are crucial to achieve continence in future.

Sex-Cord Stromal Tumors in Children and Teenagers: Results of the TGM-95 Study.

BACKGROUND: We present the results of the TGM-95 study for gonadal sex-cord stromal tumors (SCT). METHODS: Between 1995 and 2005, children (<18 years) with gonadal SCT were prospectively registered. Primary gonadal resection was recommended whenever feasible. Patients with disseminated disease or an incomplete resection received neoadjuvant or adjuvant VIP chemotherapy (etoposide, ifosfamide, cisplatinum). RESULTS: Thirty-eight children with ovarian SCT were registered. Median age was 10.7y. Endocrine symptoms were present in 21 cases. The histological diagnoses were as follows: juvenile (23) and adult (3) granulosa cell tumors, Sertoli-Leydig cell tumors (11), and mixed germ cell SCT (1). An initial oophorectomy ± salpingectomy led to complete resection in 23 patients who did not receive adjuvant treatment; two of them relapsed: one achieved second complete remission whereas the other one died of disease. Fifteen patients had tumor rupture and/or malignant ascites: 11 received chemotherapy and did not relapse, four did not receive chemotherapy and relapsed with a fatal outcome in two cases. With a median follow-up of 5.9y, the 5-y EFS and OS rates were respectively 85% and 94%. Eleven patients had localized testicular tumors (median age 0.83y): juvenile granulosa cell tumors (4), Sertoli or Leydig cell tumors (5) and not otherwise specified SCT (2). Treatment was surgery alone with an inguinal orchiectomy. None have relapsed (median follow-up: 5.4y). CONCLUSIONS: Childhood SCT carry favorable prognosis. In ovarian SCT, surgery should be complete and non-mutilating. Adjuvant chemotherapy efficiently prevents recurrences in cases of tumor rupture. In childhood testicular SCT, the prognosis is excellent with an inguinal orchiectomy, prompting the debate on testis-sparing surgery.