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.

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.

Neurostimulation-guided Anal Intrasphincteric Botulinum Toxin Injection in Children With Hirschsprung Disease.

OBJECTIVES: In Hirschsprung disease (HD), despite successful surgical treatment, 50% of children experience long-term functional gastrointestinal problems, particularly chronic functional obstructive symptoms. We report our experience regarding clinical effects of neurostimulation-guided anal intrasphincteric botulinum toxin (BT) injections on postoperative obstructive symptoms attributed to a nonrelaxing anal sphincter complex in HD patients. METHODS: In this monocenter cohort study, 15 HD patients with postoperative functional intestinal obstructive symptoms received neurostimulation-guided anal intrasphincteric BT injections. Short-, medium-, and long-term effects were evaluated. The Bristol stool form scale was used to assess stool consistency, and the Jorge-Wexner (JW) score to assess fecal continence. RESULTS: The median age at first injection was 4 years. In the short-term, a significant improvement in stool consistency was noted in 12 of 14 patients (P = 0.0001) and JW score decreased for 14 of 15 patients (P = 0.001). In the medium-term, JW score significantly decreased for all patients (P = 0.0001), with an improvement of 50% or more for 10 patients (66.7%). In the long term, 83.3% of patients had normal stool consistency and JW score was <3 for all. Recurrent enterocolitis decreased from 86.7% to 8.3%. A complete resolution of all symptoms without further medication was observed in 66.7% of patients in the long term. CONCLUSIONS: Intrasphincteric BT injection was a safe, effective, and durable option for the management of postoperative functional intestinal obstructive symptoms in HD. The use of neurostimulator guidance for specific delivery of BT to muscular fibers of nonrelaxing anal sphincter complex takes into consideration the variability of patient's anatomy secondary to curative surgery.

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.

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.

Financial and relational impact of having a boy with posterior urethral valves.

Introduction: Childhood chronic diseases affect family functioning and well-being. The aim of this study was to measure the impact of caring for a child with PUV, and the factors that most impact the burden of care. Patients and method: We gave a questionnaire on the familial impact of having a child with posterior urethral valves to all parents of a child included in the CIRCUP trial from 2015 onwards. The questionnaire included questions about the parents' demographics, health, professional, financial and marital status and how these evolved since the child's birth as well as the "impact on family scale" (IOFS), which gives a total score ranging from 15 (no impact) to 60 (maximum impact). We then analyzed both the results of the specific demographic questions as well as the factors which influenced the IOFS score. Results: We retrieved answers for 38/51 families (74.5% response rate). The average IOFS score was 23.7 (15-51). We observed that the child's creatinine level had an effect on the IOFS score (p = 0.02), as did the parent's gender (p = 0.008), health status (p = 0.015), being limited in activity since the birth of the child (p = 0.020), being penalized in one's job (p = 0.009), being supported in one's job (p = 0.002), and decreased income (p = 0.004). Out of 38 mother/father binomials, 8/33 (24.2%) declared that they were no longer in the same relationship afterwards. Conclusion: In conclusion, having a boy with PUV significantly impacts families. The risk of parental separation and decrease in revenue is significant. Strategies aiming to decrease these factors should be put in place as soon as possible.

Risk factors for febrile urinary tract infection in boys with posterior urethral valves.

Objective: Boys with posterior urethral valves (PUV) present an increased risk of febrile urinary tract infection (fUTI). Identifying specific risk factors could allow for tailoring UTI prevention. The aim of this study was to use the data from the CIRCUP randomized controlled trial data to identify patient characteristics associated with a higher risk of fUTI. Patients and methods: We performed a secondary analysis of the data from the CIRCUP randomized trial which included boys with PUV, randomized to circumcision and antibiotic prophylaxis vs. antibiotic prophylaxis alone and followed for 2 years. There was only 1 episode of fUTI in the circumcision group vs. 17 in the uncircumcised group. We therefore only studied the antibiotic prophylaxis alone group and compared age at prenatal diagnosis, size and weight at birth, presence of dilating VUR at diagnosis, abnormal DMSA scan at 2 months, and nadir creatinine between children who presented a fUTI and those who did not, as well as age at first episode of fUTI. Results: The study group consisted of 42 patients of which 17 presented at least on fUTI. Presence of dilating VUR was significantly associated with risk of fUTI (p = 0.03), OR: 6 [CI 95% = (1.13-27.52)]. None of the other parameters were associated with increased risk of fUTI. We observed three distinct time periods for presenting a fUTI with a decrease in infection rate after the first 40 days of life, then at 240 days of life. Conclusion: In boys with PUV, presence of high-grade VUR is associated with a higher risk of presenting a fUTI. The rate of febrile UTIs seems to decrease after 9 months.

Torsion of otherwise healthy ovary Has a worse prognosis than torsion of pathologic ovary in children.

INTRODUCTION: To evaluate if torsion of an otherwise healthy ovary (THO) has a different prognosis than torsion with an underlying ovarian mass (TUOM) in children. MATERIAL AND METHODS: Children with an ovarian torsion who were treated in our department from 1997 to 2016 were studied retrospectively. Patients with prenatal ovarian torsion and isolated oviduct torsion were excluded. Trophicity of the ovary was assessed by ultrasonography at the end of follow-up. RESULTS: Fifty-four girls were included. Twenty-seven presented a TUOM; the others had a THO. Beside the deleterious effect of late surgical management, another prognostic factor was identified. THO was more prone to an ovarian hypotrophy or atrophy than TUOM (n = 20 vs n = 5, p < 0.01). This was confirmed by logistic regression analysis (OR = 5.08, p = 0.01). To explain this finding, we further compared TUOM and THO. The diagnosis of TUOM was more frequently suspected on US at the first visit (p = 0.005). TUOM also occurred more often after puberty (>12 years, 52.9% vs 11.1%, p < 0.001) than THO. CONCLUSION: THO is more frequently associated with an ovarian atrophy or hypotrophy than TUOM. A less obvious diagnosis at US and the early occurrence of THO before puberty with a less favorable hormonal climate may explain this finding. LEVEL OF EVIDENCE: III.

Survival of directly placed ormocer-based restorative materials: A systematic review and meta-analysis of clinical trials.

OBJECTIVES: In-vitro experiments on ormocers (ORganically MOdified CERamics) have provided controversial results. Consequently, the objectives of this meta-analysis were to (1) compare clinical performances of first generation ormocers versus conventional composite restorations, (2) explore the influence of various clinical factors and the impact of the quality of studies on published results. METHODS: The following databases were explored until 2017/01/08: Ovid MEDLINE In-Process, Pubmed, CENTRAL, HTA, DARE, LILACS and Google Scholar. Studies of more than two years with quantitative comparisons between ormocers and control groups were selected. Outcome was the failure of a restoration (need to repair, remove or replace). Multivariate random-effects Poisson's regression was used to obtain a summary estimate. RESULTS: 75% of the 8 included trials concerned Class I/II restorations. Although non-significant, the global failures were higher for ormocers (0.22 [-0.16; 0.61]). For Class I/II restorations, a significantly higher sensitivity was observed for ormocer-based materials compared to other composites (0.75 [0.01; 1.50]). An increase of the number of restorations per patient was associated with higher marginal adaptation failures for ormocers in Class I/II obturations (0.59 [0.11; 1.08]). SIGNIFICANCE: This study did not identify clear advantages of using the first generation of ormocer-based fillings rather than conventional composites. Given the recent development of new, dimethacrylate-diluent-free ormocer matrices, potentially more stable and resistant, new randomized clinical trials should be developed comparing this new family of pure ormocers with current composites.

[Pediatric pheochromocytoma and paraganglioma: an update]. / Pheochromocytomes et paragangliomes pédiatriques : revue de la littérature.

Pheochromocytomas and paragangliomas (PHEO/PGL) are neuroendocrine tumors that arise from sympathetic and parasympathetic paraganglia. Although well described in the adult population, diagnosis and treatment of these exceptionally rare neoplasms remains poorly characterized in children. This article reviews recent advances in clinical presentation, genetics, biochemistry, imaging and treatment of children with benign or malignant PHEO/PGL. Compared to adults, pediatric PHEO/PGL are more frequently familial, bilateral, multifocal and malignant. Approximately 50% of pediatric PHEO/PGL are associated with a mutation of one of the 12 known susceptibility genes. Von Hippel-Lindau disease, type 1 neurofibromatosis, type 2 multiple endocrine neoplasia and familial PGL syndrome are hereditary tumor syndromes associated with an increased risk of developing such diseases. Clinical presentation includes symptoms related to catecholamine hypersecretion and/or tumor mass effect. Plasma and/or urine metanephrine dosages are recommended as first-line diagnostic biochemical tests. Magnetic resonance imaging is useful as initial radiological approach. Most pediatric PHEO/PGLs are benign. Surgical resection, with appropriate perioperative management of catecholamine-related symptoms, remains the treatment of choice. In case of metastatic disease, surgical removal of metastases when possible and I-131-MIBG radiotherapy provide limited results whereas chemotherapy is reserved for more advanced stages.

Inguinal hernia in premature boys: should we systematically explore the contralateral side?

OBJECTIVE: Bilateral surgery has been largely advocated in premature boys with unilateral inguinal hernia owing to the high incidence of contralateral patent processus vaginalis. Recently, the potential morbidity of herniotomy in low birth-weight babies and the progress in pediatric anesthesia questioned this attitude. This study aims to evaluate the incidence of contralateral metachronous hernia in a large series of premature boys and to compare the morbidity of preventive versus elective surgery. METHODS: This retrospective multicenter analysis of 964 premature boys presenting with unilateral inguinal hernia operated from 1998 to 2012 included 557 infants who benefited from a unilateral herniotomy and 407 from a bilateral herniotomy (median follow-up 12months). RESULTS: Contralateral metachronous hernia after unilateral surgery occurred in 11% (n=60) without significant difference according to the initial symptomatic side (9.5% on right vs 13% on left, p>0.05). Postoperative morbidity on the contralateral side was higher after preventive surgery than elective surgery with metachronous hernia (2.45% versus 0.9%, p=0.05) especially for secondary cryptorchidism (1% vs 0%, p=0.03). Despite the risk of metachronous incarcerated hernia, elective surgery did not increase the rate of testicular hypotrophy on the opposite side (0.7%, vs 0.7%, p>0.05). CONCLUSION: Systematic bilateral herniotomy is unnecessary in almost 90% of patients and has a significant morbidity. Secondary surgery for metachronous hernia does not increase the risk of testicular lesion and even reduces the risk of secondary cryptorchidism. These results, along with the risk of hypofertility reported after bilateral surgery, may justify treating only the symptomatic side in premature boys.

Prenatal intrarenal neuroblastoma mimicking a mesoblastic nephroma: a case report.

Mesoblastic nephroma is by far the most frequent intrarenal fetal tumor. To the best of our knowledge, we report the first case of a newborn with an intrarenal neuroblastoma that was discovered prenatally. An intrarenal echogenic and homogenous mass was observed on routine prenatal ultrasonography, corroborated by magnetic resonance imaging, in a 30-week gestation fetus. A male weighing 3280 g was born with elevated blood pressure and cardiac failure. Postnatal ultrasound confirmed a left intrarenal tumor with microcalcifications and perirenal adenopathy. An open total left nephrectomy by laparotomy was performed. The pathologic study reported that the mass was an intrarenal neuroblastoma with local and regional invasion. Immediate postoperative urine analysis revealed a high level of vanillylmandelic acid, and blood samples showed high levels of normetanephrine. The purpose of this report is to demonstrate that prenatal intrarenal neuroblastoma can clinically and radiologically mimick a mesoblastic nephroma. High blood pressure, calcifications, and lymphadenopathy on ultrasound should raise the index of suspicion for a possible malignant process. Preoperative measurement of urinary vanillylmandelic acid (VMA) and metanephrines should be performed if the diagnosis is in doubt.