John S. Wiener

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.

LONG-TERM EFFICACY OF SIMPLE BEHAVIORAL THERAPY FOR DAYTIME WETTING IN CHILDREN

PURPOSE Behavioral therapy has proved benefit for children with daytime wetting but most studies have used biofeedback techniques and provide no long-term assessment of results. We previously reported similar results using simple behavioral therapy without biofeedback. We report the long-term efficacy of behavioral therapy for daytime wetting. MATERIALS AND METHODS Our program of behavioral therapy included timed voiding, modification of fluid intake, positive reinforcement techniques and pelvic floor (Kegel) exercises to promote pelvic floor strengthening and relaxation. Questionnaires to assess therapeutic efficacy were mailed to patients who had completed therapy more than 1 year previously. RESULTS A total of 48 patients responded. Mean ages at the time of the initial clinic visit and questionnaire were 8.2 and 12.9 years, respectively. Improvement in symptoms was noted in approximately 74% of the cases during the first year following therapy. At a mean of 4. 7 years after treatment 59.4% of the patients had improved daytime urinary control, 51.1% improved daytime urinary frequency and 45.6% improved daytime urinary urgency. The frequency of urinary tract infections decreased in 56.4% of the cases. Measures of psychological well-being were also noted to be improved in a majority of patients. A total of 77.3% of the patients stated that they would recommend the program to others. CONCLUSIONS Simple behavioral therapy without biofeedback techniques is an effective and durable first line therapy for children with daytime wetting.

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.

GENITOURINARY COMPLICATIONS OF SICKLE CELL DISEASE

PURPOSE In the last half century the molecular biology, pathophysiology and natural history of sickle cell disease have been well defined. Sickle cell disease causes microvascular occlusion, which is manifested in most organ systems. The genitourinary tract is most commonly affected by hematuria, urinary tract infection and priapism but other more serious sequelae have been identified. MATERIALS AND METHODS We performed a computerized MEDLINE search from 1965 to the present and a bibliographic review of cross references. These references were analyzed for meaningful findings and case reports. RESULTS The diagnosis and management of sickle cell disease have advanced rapidly with a significant increase in the life expectancy of affected patients and recognition of a greater number of genitourinary complications. Renal function may be mildly altered or lost completely. Patients with sickle cell disease are at increased risk for urinary tract infection. Priapism is a painful complication of sickle cell disease that is poorly understood and challenging to treat and prevent. Testicular infarction has also been noted. Furthermore, renal medullary carcinoma, a highly lethal tumor, develops almost exclusively in young patients with sickle cell trait. CONCLUSIONS Heightened awareness of the genitourinary complications of sickle cell disease may prevent end stage disease, including renal failure and impotence. New forms of therapy for sickle cell disease, such as hydroxyurea, may prevent these complications in the future.

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.

Evaluating Outcomes of Enterocystoplasty in Patients With Spina Bifida: A Review of the Literature

PURPOSE The urological complications of spina bifida impose a significant burden of disability and disease. Therapy is focused on the bladder to achieve the primary goals of maintaining normal renal function and attaining urinary continence. When medical management fails, surgical intervention, including enterocystoplasty, is frequently performed. However, practice patterns for enterocystoplasty show significant variation. Given this context, we examined outcome measures for enterocystoplasty in patients with spina bifida. MATERIALS AND METHODS A MEDLINE search was performed for articles on enterocystoplasty in patients with spina bifida. A total of 226 articles were identified and manually reviewed for relevant studies. Additional articles were selected based on a cited reference search. RESULTS Almost all studies are retrospective, single institution case series of a relatively small number of patients. Few uniform or validated outcome measures for enterocystoplasty exist but reported measures typically include urodynamic, continence and satisfaction parameters. Interinstitutional variability in urodynamic measurements and in definitions of continence makes a comparison of outcomes difficult. The complication rate following enterocystoplasty is significant, well described and primarily related to the use of gastrointestinal segments for urine storage. CONCLUSIONS Medical management is the mainstay of neurogenic bladder therapy in the spina bifida population. Enterocystoplasty remains an important option to prevent or reverse upper tract deterioration, and/or improve or cure socially unacceptable incontinence despite poorly defined outcome measures. The development of appropriate and validated outcomes measures may enable more uniform, effective and safe urological care of patients with spina bifida.

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.

Oncogenic human papillomaviruses are rarely associated with squamous cell carcinoma of the bladder : evaluation by differential polymerase chain reaction

While a strong association between oncogenic human papillomaviruses and squamous cell cancers of the genital tract (penis, urethra and cervix) is known to exist, there is substantial controversy regarding the association of human papillomaviruses and cancers of the bladder. Technical issues regarding assay technique and concern about potential contamination have marred interpretation of previous work. Moreover, because human papillomavirus has been associated predominantly with squamous cell cancers at other sites, any involvement of human papillomavirus and bladder epithelial carcinogenesis must address whether any association between human papillomavirus and squamous cell carcinoma of the bladder exists. Differential polymerase chain reaction and a rigorous protocol to avoid crossover contamination were used to analyze archival bladder carcinoma specimens (22 squamous cell carcinomas and 20 transitional cell carcinomas). Type specific primers for human papillomavirus types 16 and 18 were used as were general primers to detect types 6b, 11, 13, 16, 18, 31, 32, 33, 35, 45 and 51. Only 1 of 22 squamous cell carcinoma specimens (4.4%) was positive (human papillomavirus type 18)--a cadaveric renal transplant patient on chronic immunosuppression. Cervical specimens were human papillomavirus negative in this patient. No human papillomavirus deoxyribonucleic acid was detected in the 20 transitional cell carcinoma cohort. Our results confirm that these human papillomavirus types appear to have little association with invasive transitional cell cancers. Of greater significance, despite this (to our knowledge) first reported case of human papillomavirus type 18 detected in squamous cell carcinoma of the bladder (seen in an immunocompromised patient), we conclude that these oncogenic human papillomavirus types do not have a significant role in squamous cell carcinogenesis of the bladder.

Squamous Cell Carcinoma of the Prostate: 2 Cases of a Rare Malignancy and Review of the Literature

Primary squamous cell carcinoma of the prostate is an extremely uncommon malignancy, accounting for less than 1% of all prostatic cancers. We report on 2 patients with primary squamous cell carcinoma of the prostate: 1 with organ-confined disease and 1 with metastatic disease. Both patients presented with urinary obstructive symptoms and carcinoma was not suspected on digital rectal examination. Serum acid phosphatase and prostate specific antigen levels were normal. From a review of the literature and our 2 cases it is apparent that squamous cell carcinoma of the prostate is biologically more aggressive than adenocarcinoma.

Renal Ultrasound Changes After Pyeloplasty in Children With Ureteropelvic Junction Obstruction: Long-term Outcome in 47 Renal Units

PURPOSE We evaluated the use of renal ultrasound for monitoring pyelocaliectasis after pyeloplasty in children. MATERIALS AND METHODS Changes in pyelocaliceal dilatation following pyeloplasty were assessed by serial ultrasound. Of 104 children 0 to 12 years old who underwent pyeloplasty between 1982 and 1992, 44 (47 renal units) were monitored with serial ultrasound for at least 2 years (range 2 to 9, mean 3.8). Patient ages at pyeloplasty were 0 to 3 months (17), 4 to 12 months (8), 1 to 6 years (13) and 7 to 12 years (6). Preoperative and postoperative ultrasound was reviewed by a single pediatric radiologist blinded to the date of surgery. The degree of pyelocaliectasis was graded as 0 to 4 according to the classification of the Society for Fetal Urology. RESULTS Preoperative ultrasound revealed grade 4 pyelocaliectasis in 26 kidneys (55%) and grade 3 disease in 21 (45%). Grade was the same or worse 1 month after pyeloplasty in the majority of kidneys (92%) studied at this interval. Of the 47 renal units assessed 43 (91%) showed improvement in pyelocaliectasis during postoperative followup. Only 38% of the kidneys improved during the first 6 months of followup, while 81% were improved 2 years postoperatively. Improvement to grade 0 or 1 dilatation occurred in only 9 kidneys (19%). The rate of resolution of pyelocaliectasis was not related to preoperative grade or patient age at pyeloplasty. CONCLUSIONS Improvement on renal ultrasound after pyeloplasty appears to be gradual. Less than half of the patients had improvement in the initial 6 months after pyeloplasty and pyelocaliectasis rarely resolved completely. While renal ultrasound can provide an accurate and cost-effective means of monitoring children on a long-term basis after pyeloplasty, sonographic evaluation in the early postoperative period commonly shows increased or unchanged pyelocaliectasis.