Biagio Zuccarello

Genetic Alterations Associated With Cryptorchidism

CONTEXT Cryptorchidism is the most frequent congenital birth defect in male children and represents an important risk factor for infertility and testicular cancer. Major regulators of testicular descent are the hormones insulin-like factor 3 (INSL3) and testosterone, and disruption of these pathways might cause cryptorchidism. OBJECTIVE To determine the frequency of genetic alterations in cryptorchidism. DESIGN AND SETTING Case-control study in 2 departments of pediatric surgery in Italy between January 2003 and March 2005. PATIENTS Six hundred male infants with cryptorchidism. Boys were followed up for 2 to 3 years (through January 2008) and orchidopexy was performed in those who were persistently cryptorchid. We analyzed 300 noncryptorchid male children aged 1 to 4 years as controls. MAIN OUTCOME MEASURES Karyotype anomalies and INSL3, INSL3 receptor, and androgen receptor gene mutations. RESULTS The frequency of genetic alterations in boys with cryptorchidism was low (17/600 [2.8%; 95% confidence interval {CI}, 1.7%-4.5%]) and was significantly higher in participants with persistent cryptorchidism (16/303 [5.3%; 95% CI, 3.0%-8.4%]; P = .001) and those with bilateral cryptorchidism (10/120 [8.3%; 95% CI, 4.1%-14.8%]; P = .001) than in controls (1/300 [0.3%; 95% CI, 0.1%-0.8%]). Boys with persistent cryptorchidism had a 17-fold greater odds of having a genetic alteration (odds ratio, 16.7; 95% CI, 2.2-126.5). The most common genetic findings in those with cryptorchidism were 8 cases of Klinefelter syndrome and 5 cases of mutations in the INSL3 receptor gene. Genetic alterations were not found in boys with low birth weight or low gestational age, who had frequent spontaneous descent of the testes. CONCLUSION In a small percentage of the study population, there was a statistically significant association between bilateral and persistent cryptorchidism and genetic alterations, including Klinefelter syndrome and INSL3 receptor gene mutations.

Disorders of the esophageal motor activity in atresia of the esophagus

Esophageal dysfunction has been reported after successful repair of esophageal atresia but its nature has not been clearly defined. We studied esophageal motility in 20 newborns with esophageal atresia by recording intraluminal pressure of both proximal and distal segments. The investigation was made by pressure monitoring of the upper pouch via the mouth and of the distal segment via the gastrostomy. In all cases we found motility disorders. Two patients (12.5%) showed incomplete relaxation of the upper esophageal sphincter. The resting pressure of the esophageal body in both segments was constantly positive in all cases. Lower esophageal sphincter (LES) function was normal in all but two patients (16.7%) in whom the LES pressure was reduced and one case (8.4%) with incomplete relaxation of the LES. These studies suggest that motility disorders are also present in esophageal atresia before surgery.

Prenatal testicular torsion: ultrasonographic features, management and histopathological findings.

Aim:  To highlight the ultrasonographic features of prenatal torsion of the testis in utero (IUTT) at presentation, the neonatal management and the histological findings postorchiectomy or biopsy.

Evidence for a Role of Mitogen-Activated Protein Kinase 3/Mitogen-Activated Protein Kinase in the Development of Testicular Ischemia-Reperfusion Injury

Abstract Mitogen-activated protein kinase (MAPK) 3/MAPK1 (also known as ERK1/ERK2) plays an important role in the signal transduction pathways. To our knowledge, however, its role in the development of testicular ischemia-reperfusion injury has not yet been investigated. Therefore, we studied the pattern of MAPK3/MAPK1 activation in a experimental model of testicular ischemia-reperfusion injury. We also investigated MAPK8 to understand whether an association exists between these two MAPKs. Adult male Sprague-Dawley rats were subjected to 1 h of testicular ischemia followed by 24 h of reperfusion or to a sham testicular ischemia-reperfusion. Animals were randomized to receive PD98059, which is an inhibitor of MAPK3/MAPK1 (10 mg/kg i.p. administered immediately after detorsion), or its vehicle. The time course of MAPK3/MAPK1, MAPK8, and tumor necrosis factor (TNF; also known as TNF alpha) expression and a histological examination in both the ischemic-reperfused testis and the contralateral one were performed. In both testes, MAPK3/MAPK1 and MAPK8 expression appeared following 10 min of reperfusion and reached their highest activation after 30 min. The MAPK levels slowly decreased, and no significant expression of either kinase was observed following 2 h of reperfusion. Expression of TNF was evident after 1 h of reperfusion and reached its maximum increase after 3 h. PD98059 blunted MAPK3/MAPK1 and MAPK8, reduced TNF expression, and improved the testicular damage caused by ischemia-reperfusion injury in both testes. These data emphasize that MAPK3/MAPK1 has a role in testicular damage and that its blockade might have a future therapeutic role for the management of patients with unilateral testicular torsion.

Gastrointestinal sequelae in survivors of congenital diaphragmatic hernia

Background: Gastrointestinal sequelae have been sporadically reported in survivors of congenital diaphragmatic hernia (CDH). The aim of the present paper was to evaluate the gastrointestinal morbidity in infant, adolescent and adult patients who had undergone repair of CDH.

Is a complete urological evaluation necessary in all newborns with asymptomatic renal ectopia

Aim:  To evaluate if a complete urological screening is justified by potential urological anomalies in newborns or infants with asymptomatic renal ectopia (RE).

Mutations in INSL3 and RXFP2 Genes in Cryptorchid Boys

Mutations in the INSL3 and RXFP2 genes have been associated with human cryptorchidism but with contrasting data. We analyzed the frequency of mutations in these genes in 600 newborns with cryptorchidism (396 unilateral and 204 bilateral) and 300 noncryptorchid subjects. We found five RXFP2 mutations in five bilateral cryptorchid boys, one INSL3 mutation in a unilateral cryptorchid boy, and one INSL3 mutation in a boy with unilateral cryptorchidism at birth and spontaneous descent during the first month of life. Overall, the frequency of INSL3 and RXFP2 mutations was therefore 7/600 at birth (1.2%) and 7/303 (2.3%) in persistent cryptorchid boys, with a higher prevalence of bilateral forms (5/120, 4.2%). No mutations were found in controls. This study confirmed the association between INSL3 and RXFP2 gene mutations and human cryptorchidism.

Surgical correction of penoscrotal transposition associated with hypospadias and bifid scrotum: our experience of two-stage repair

OBJECTIVE To assess the results of surgical correction of incomplete penoscrotal transposition and bifid scrotum using the Glenn-Anderson technique, and its impact on subsequent definitive urethroplasties and final outcome. PATIENTS AND METHODS We retrospectively reviewed 31 children that underwent two-stage repair for incomplete penoscrotal transposition with severe hypospadias and bifid scrotum. Patient age at stage 1 ranged from 12 to 24 months (average 16 months). The operative principle was based on achieving a normal anatomical position of the penis and scrotum using the Glenn-Anderson technique. In cases with associated scrotal or perineal hypospadias this was transformed into a penoscrotal hypospadias. Final stage urethroplasty was performed after a period of 6 months with a modified Thiersch-Duplay technique. RESULTS Cosmetic and functional results of the Glenn-Anderson operation were excellent. No major complications were observed. Of 31 patients, 12 (38%) had complications secondary to urethral repair. CONCLUSION The Glenn-Anderson technique for reconstruction of penoscrotal transposition and bifid scrotum is a simple technique, free of major complications. The purpose of this intervention is to improve the cosmetic appearance and function of the penis. A minimum period of 6 months between consecutive urethroplasties is important. The final stage guarantees good functional and cosmetic results preserving the prepuce.

Immunohistology of aquaporin-1 and stem cell factor-receptor in human undescended testes.

ObjectivesBoth aquaporin (AQP) 1 and the stem-cell factor/C-kit system seem to have a definite role in testis function, but very few studies have been reported in humans, especially in the paediatric age group. With the present study we wanted to investigate the expression of these proteins to better delineate their role in normal and pathologic testes.MethodsImmunohistology using AQP 1 and C-kit antibodies was performed on paraffin sections of open-testicular biopsies from 32 undescended testes. The testes of cryptorchid patients, with ages ranging from 2 to 15 years, were biopsied during an orchidopexy operation, after obtaining informed consent. Control biopsies, from 8 patients of matched age, were obtained during operations for inguinal hernia or hydrocele, always after obtaining informed consent. Positive results were recorded as diffuse or focal patterns and scored as weak, moderate or strong immunostaining.ResultsAQP 1 antibody strongly depicted microvessel endothelial cells, but was unlabeled in endotubular and interstitial cell lines, in both control and undescended testes. The C-kit immunostaining in normal testes revealed a diffuse, strong staining in the cytoplasm of spermatogonia and primary spermatocytes. However, in the undescended testes a focal C-kit immunolabelling was weakly recognized in both spermatogonial and immature Sertoli cells.ConclusionsThese results indicate a direct involvement of AQP 1 in the regulation of fluid transport across the endothelial cell membranes of testicular microvessels. A role of the C-kit receptor protein is also substantiated by its strong expression in the maturing spermatogonia of the normal testes, but was minimally or not recognizable in undescended prepubertal testes.

A case of bilateral prenatal testicular torsion: Ultrasonographic features, histopathological findings and management

OBJECTIVES The aim of this study was to demonstrate the ultrasonographic features of prenatal bilateral torsion of the testis, and its histological correlation and management. PATIENT A newborn presented at delivery with both testes enlarged, swollen and tender. Prenatal ultrasound (US) showed enlarged, hyperechoic testes. Colour Doppler US examination was performed. RESULTS US revealed both testes to be heterogeneous. Colour Doppler US did not reveal any flow signal. On inguinal exploration both testes appeared necrotic. Histology showed recognizable seminiferous tubules and Leydig cells. CONCLUSION We believe that both testes should be left in situ after bilateral detorsion even if their macroscopic appearance is necrotic.