David R. Roth

Androgen Receptor Gene Mutations are Rarely Associated with Isolated Penile Hypospadias

PURPOSE Hypospadias has no known single etiology but it has been linked to androgen insensitivity caused by mutations of the androgen receptor gene. The purpose of this study was to search for such mutations in cases of various degrees of isolated hypospadias to determine whether such an association exists and, if so, with any particular anatomical subgroup. MATERIALS AND METHODS Isolated deoxyribonucleic acid from the penile tissue of 40 patients undergoing reconstructive surgery was screened for mutations of the coding regions of the androgen receptor gene using single strand conformational polymorphism analysis. In cases with abnormal single strand conformational polymorphism findings sequence analysis of the deoxyribonucleic acid was performed to define the mutation. RESULTS A missense mutation of exon 2 of the androgen receptor gene was noted in 1 patient with isolated distal penile shaft hypospadias. Sequence analysis revealed that the mutation changed amino acid residue 546 from proline to serine. No abnormalities were detected in the other 39 patients. CONCLUSIONS Isolated distal shaft hypospadias is associated with mutations of the androgen receptor gene but these mutations appear to be a rare cause of hypospadias.

Comparison of Onlay and Tubularized Island Flaps of Inner Preputial Skin for the Repair of Proximal Hypospadias

PURPOSE Transverse island flaps of inner preputial skin have provided a reliable technique for the repair of proximal hypospadias. The flap may be used to create a neourethra by tubularizing the flap after urethral transection or applying the flap as an onlay patch onto an intact urethral plate. We retrospectively analyzed our experience with these 2 techniques to compare outcomes. MATERIALS AND METHODS During 11 years 132 patients underwent hypospadias repair by a single surgeon using an onlay (58) or tubularized (74) island flap technique. Surgical results were reviewed retrospectively. RESULTS At a mean followup of 20.3 months the overall complication rate was 36% for tubularized and 31% for onlay repair, and fistula rates were 14 and 17%, respectively. Despite similar fistula rates tubularized repairs tended to have larger fistulas that required more complex repair (p = 0.0147). In 9 patients who underwent tubularize repair diverticula developed, whereas no diverticula developed after onlay repair (p = 0.0162). The rates of urethral stricture, wound infection, residual chordee and cosmetic complications were not statistically significantly different between repairs. The use of double faced repair in 30 patients provided no difference in outcome in comparison to the overall study cohort. CONCLUSIONS Hypospadias repair using transverse island flaps offers reliable and durable outcomes. While overall complication rates were not greatly different between tubularized and onlay flap repairs, onlay repair tended to result in fistulas of smaller size and diverticula did not develop.

Analysis of homeobox gene HOXA10 mutations in cryptorchidism.

PURPOSE Cryptorchidism is the most common congenital abnormality of the genitalia. However, its exact etiology remains to be defined. Homeobox (HOX) containing genes have a key role in the morphogenesis of segmental structures along the primary body axis, including the urogenital mesenchyma. In male mice with a targeted deletion of the HOXA10 gene cryptorchidism manifests in the absence of other major defects. Because to our knowledge this gene has never been examined for alterations in humans, we evaluated whether mutations of HOXA10 are associated with cryptorchidism in humans. MATERIALS AND METHODS Genomic deoxyribonucleic acid (DNA) was extracted from human blood or tissue samples from 16 noncryptorchid control subjects and 45 cryptorchid boys. To screen for mutations exons 1 and 2 of the HOXA10 gene were amplified individually by polymerase chain reaction using 6 overlapping oligonucleotide primer pairs. Single strand conformational polymorphism (SSCP) analysis of the amplified radiolabeled DNA fragments was performed. Variant band shifts were detected due to abnormal migration of the denatured DNA fragment compared to controls, suggesting an alteration in the DNA sequence. Sequence analysis of these variant bands was then done to define any mutations. RESULTS SSCP analysis revealed variants in 2 controls. Of the 45 samples from cryptorchid patients 30 had SSCP variants in exon 1. No variants were found in other regions of the gene. Sequence analysis revealed several DNA polymorphisms in exon 1 in controls and boys with cryptorchidism. Other nucleotide changes (point mutations) were noted only in exon 1 in the DNA of 5 cryptorchid patients, of whom 1 had a 24 nucleotide deletion. CONCLUSIONS Our initial analysis of the HOXA10 gene in humans demonstrates that genetic alterations of this gene may be present in some boys with cryptorchidism. HOXA10 polymorphisms exist in normal control subjects as well as in cryptorchid patients. Further analysis of the function of the mutated protein will elucidate the role of this gene as a potential causative factor of testicular descent.

Treatment of Vesicoureteral Reflux Using Endoscopic Injection of Nonanimal Stabilized Hyaluronic Acid/Dextranomer Gel: Initial Experience in Pediatric Patients by a Single Surgeon

OBJECTIVE. Endoscopic injection of nonanimal stabilized hyaluronic acid/dextranomer gel is an increasingly recognized treatment option for vesicoureteral reflux. The procedure is minor compared with open surgery and, when successful, avoids the need for long-term antibiotic prophylaxis. We present data from our first 18 months using nonanimal stabilized hyaluronic acid/dextranomer gel to treat children with vesicoureteral reflux. PATIENTS AND METHODS. Pediatric patients aged ≤15 years with uncomplicated primary vesicoureteral reflux were recruited for endoscopic treatment with nonanimal stabilized hyaluronic acid/dextranomer gel. A follow-up voiding cystourethrogram was scheduled at ≥2 weeks after treatment, and vesicoureteral reflux resolution was defined as grade 0. Repeat nonanimal stabilized hyaluronic acid/dextranomer gel treatment was offered to patients with persistent vesicoureteral reflux. RESULTS. Of 120 patients treated, 6 were lost to follow-up, and 7 were yet to undergo posttreatment voiding cystourethrogram. The 107 remaining patients (efficacy population) had a mean age of 4.1 years (range: 0.5–15.0), and the median reflux grade was 2 (range: 1–5). The mean time to follow-up voiding cystourethrogram was 9.7 weeks (range: 2–26). Vesicoureteral reflux was resolved in 82.2% of patients and 86.9% of ureters after initial endoscopic treatment with nonanimal stabilized hyaluronic acid/dextranomer gel. The overall reflux resolution rate for patients increased to 90.7% after a second treatment in 14 patients. Two patients reported postoperative flank pain, although this was mild and transient in nature. No other adverse events were reported. No patients underwent open surgery for vesicoureteral reflux. CONCLUSIONS. Endoscopic treatment with nonanimal stabilized hyaluronic acid/dextranomer gel is effective in a high proportion of children with vesicoureteral reflux and, in our opinion, may be considered as a first-line treatment option.

Molecular Biology and Function of the Androgen Receptor in Genital Development

PURPOSE The rapidly growing field of molecular biology has caused exponential growth in our knowledge of the processes of embryogenesis. Since the cloning of the androgen receptor gene in 1988, investigators have been able to clarify many of the molecular events of male sexual differentiation that are mediated through the androgen receptor. We reviewed the current state of knowledge of the androgen receptor and its role in male genital development. MATERIALS AND METHODS An intensive literature search was conducted to review reports on the androgen receptor and sexual differentiation since 1988. This review also includes ongoing research from our laboratory on the role of the androgen receptor in human genital development, as well as collaboration with other investigators. RESULTS We reviewed the basic molecular biology of androgenic action mediated through the androgen receptor. This information has been integrated into the current understanding of human male sexual differentiation to clarify how androgens virilize the undifferentiated embryo. Defects in function of the androgen receptor may be manifested as a spectrum of phenotypes of the androgen insensitivity syndrome, and these phenotypes of male pseudohermaphroditism have been reviewed on a clinical and molecular basis. New molecular techniques have augmented the evaluation and diagnosis of the androgen insensitivity syndrome, and some groups have successfully diagnosed the condition prenatally. CONCLUSIONS Basic scientific research of androgen receptor function and its role in male sexual development has provided a clearer understanding of the mechanisms responsible for the spectrum of defects secondary to the androgen insensitivity syndrome. This knowledge will enable clinicians to offer more accurate diagnosis and insightful counseling to affected patients and their families.

Individualized Treatment of Ureteroceles

We reviewed 52 children with ureteroceles in an effort to evaluate the various facets of this disorder that influenced our surgical management. There were 12 single system ureteroceles and 40 duplex system ureteroceles. Total reconstruction was performed in 16 duplex system and 8 single system ureteroceles, of which 88 per cent required no further surgery. Upper pole heminephrectomy or ureteropyelostomy with partial ureterectomy was performed in 22 patients with duplex system ureteroceles with the goal of obviating lower tract surgery, of whom 12 (55 per cent) required subsequent surgery. In 6 patients, 4 with single system and 2 with duplex system ureteroceles transurethral incision of the ureterocele was the initial procedure with the expectation that improvement in function and hydronephrosis would facilitate subsequent lower tract surgery. Two of these patients required subsequent reconstruction. Recommendations regarding management are based on initial pathological condition, patient age and the presence of a single or duplex system ureterocele.

Pediatric pyeloplasty: outcome analysis based on patient age and surgical technique.

OBJECTIVES To analyze our experience with open pyeloplasty, with specific emphasis on procedural outcome on the basis of patient age, surgical technique, complication rate, and complication management. METHODS All patients from 1974 to 1994 who underwent pyeloplasty at our institution were included in our review. Charts were analyzed for age at presentation, presenting signs and symptoms, type of surgical reconstruction, complications and treatment, and final outcome. RESULTS From 1974 to 1994, 234 pyeloplasties were performed in 227 patients (108 less than 1 year old, 119 more than 1 year old). The percentage of children less than 1 year old increased throughout: 24% for 1975 to 1980, 37% for 1981 to 1990, and 69% for 1991 to 1994. Presenting signs and symptoms varied according to the age of the child at pyeloplasty. For children less than 1 year old, these were prenatal ultrasound in 86 (79%), urinary tract infection (UTI) in 9 (8%), and abdominal mass in 5 (4.6%). For children more than 1 year old, these were pain in 57 (48%), UTI in 29 (24%), hematuria in 12 (10%), and prenatal ultrasound in 3 (2.5%). Reconstruction was a dismembered pyeloplasty in all cases. The majority of patients in both age groups underwent a nonintubated repair (less than 1 year old, 99 of 114; more than 1 year old, 102 of 120). Postoperative results were evaluated by ultrasound or intravenous urography, with improvement or stable results in 95% of children less than 1 year old and in 96% of children more than 1 year old. Complications included UTI in 18 patients (7.7%), recurrent obstruction in 5 (2.1%), and persistent leak in 4 (1.7%). The complication rate was not related to age. CONCLUSIONS The nonintubated, dismembered pyeloplasty is an excellent technique for all age groups and has a low complication rate.

Management of ureteropelvic junction obstruction in infants.

The frequent use of fetal ultrasound is allowing early (prenatal) diagnosis of numerous uropathies previously delayed until the child either became symptomatic or had a palpable mass. We would anticipate an increasing number of neonates presenting for repair of obstructions, especially ureteropelvic junction obstruction. To evaluate our experience with this disorder in infants we reviewed our experience with ureteropelvic junction obstruction during the last 6 years in 16 infants less than 1 year old. Principles of evaluation, surgical techniques and results are presented. To date, no secondary procedures have been necessary and most neonates have shown dramatic improvement in the parenchymal mass and intrarenal anatomy.

ANDROGEN RECEPTOR GENE ALTERATIONS ARE NOT ASSOCIATED WITH ISOLATED CRYPTORCHIDISM

PURPOSE Multiple theories of testicular descent exist but there is no consensus. Cryptorchidism is a component of the androgen insensitivity syndrome, suggesting that testicular descent may be at least partially under the control of androgenic stimulation. To determine whether isolated cryptorchidism may be caused by androgen insensitivity, we screened a population of boys with isolated cryptorchidism for the presence of androgen receptor gene alterations. MATERIALS AND METHODS Deoxyribonucleic acid (DNA) was isolated from tissue collected from 21 patients with isolated cryptorchidism during orchiopexy. Patient selection was biased to maximize the likelihood of detection of a genetic etiology of cryptorchidism. The DNA was screened for androgen receptor gene alterations in exons 2 to 8 using single strand conformational polymorphism analysis. RESULTS No abnormalities in the androgen receptor gene were detected by single strand conformational polymorphism analysis in any patient. CONCLUSIONS Mutations of the androgen receptor gene in the hormone and DNA binding domains of the protein appear to be an unlikely cause of isolated cryptorchidism.

State of the art review in gonadal dysgenesis: challenges in diagnosis and management

Gonadal dysgenesis, a condition in which gonadal development is interrupted leading to gonadal dysfunction, is a unique subset of disorders of sexual development (DSD) that encompasses a wide spectrum of phenotypes ranging from normally virilized males to slightly undervirilized males, ambiguous phenotype, and normal phenotypic females. It presents specific challenges in diagnostic work-up and management. In XY gonadal dysgenesis, the presence of a Y chromosome or Y-chromosome material renders the patient at increased risk for developing gonadal malignancy. No universally accepted guidelines exist for identifying the risk of developing a malignancy or for determining either the timing or necessity of performing a gonadectomy in patients with XY gonadal dysgenesis. Our goal was to evaluate the literature and develop evidence-based medicine guidelines with respect to the diagnostic work-up and management of patients with XY gonadal dysgenesis. We reviewed the published literature and used the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system when appropriate to grade the evidence and to provide recommendations for the diagnostic work-up, malignancy risk stratification, timing or necessity of gonadectomy, role of gonadal biopsy, and ethical considerations for performing a gonadectomy. Individualized health care is needed for patients with XY gonadal dysgenesis, and the decisions regarding gonadectomy should be tailored to each patient based on the underlying diagnosis and risk of malignancy. Our recommendations, based on the evidence available, add an important component to the diagnostic and management armament of physicians who treat patients with these conditions.