Proximal Hypospadias and a Novel WT1 Variant: When Should Genetic Testing Be Considered?

We present a case of an infant with proximal hypospadias, penoscrotal transposition, and bilaterally descended testes found to have a clinically significant WT1 gene alteration on a customized disorder of sex development genetic panel in which 62 genes associated with 46, XY disorders of sex development were evaluated. This diagnosis led to early screening for and diagnosis and treatment of Wilms tumor. Patients with proximal hypospadias are not routinely evaluated by genetic testing, and when initial hormonal analyses are within normal ranges for a typical male patient, the genital atypia is usually attributed to an isolated anatomic abnormality. There is no consensus among urologists, endocrinologists, or geneticists regarding when genetic testing is warranted in these patients or the extent of genetic testing that should be pursued. However, given advances in genetic testing and the discovery of more genetic variants, the genetic evaluation of infants with proximal hypospadias should be considered on an individual patient basis. Only with continued evaluation and the identification of further genetic variants can we establish future parameters for genetic evaluation in patients with proximal hypospadias and more appropriately counsel patients and their families regarding the implications of these variants.

Urethral Reconstruction with Small Intestinal Submucosa Seeded with Oral Keratinocytes and TIMP-1 siRNA Transfected Fibroblasts in a Rabbit Model.

BACKGROUND: To evaluate the effect of tissue inhibitor of metalloproteinase-1 small interfering RNA (TIMP-1 siRNA) transfected fibroblasts (FB) for urethral reconstruction. MATERIALS AND METHODS: A ventral urethral mucosal defect was created. Substitution urethroplasty was performed with small intestinal submucosa (SIS) alone (8 rabbits, group 1), autogenic oral keratinocytes (OK)-seeded SIS (8 rabbits, group 2) or autogenic OK and TIMP-1 siRNA transfected FB-seeded SIS (8 rabbits, group 3). At 1 and 6 months after surgery (4 rabbits at each time point), retrograde urethrogram and histologic analysis were performed to evaluate the outcomes of urethroplasty. RESULTS: TIMP-1 siRNA transfected FB decreased the secretion of type I collagen. Under retrograde urethrography, 5 rabbits in group 1, 6 in group 2 and 7 in group 3 maintained a wide urethral caliber. Histologically, inflammation and fibrosis were observed at 6 months in group 1. The speed of urothelium, smooth muscle and vessel regeneration in group 3 was faster than that in group 2. Comparison of smooth muscle-to-collagen ratio, epithelial layers, smooth muscle content and microvessel density among three groups revealed a significant increase (p < 0.05). CONCLUSIONS: TIMP-1 siRNA transfected FB could be used as a source of seed cell for urethral tissue engineering and could prevent the proliferation of urethral scar tissue.

A case report of urethral prolapse in a 38 year old female with 46XY karyotype.

A 38-year old female presented with the acute onset of a vulval mass associated with pain and vaginal bleeding. She is female phenotype but has 46XY karyotype and Complete Androgen Insensitivity Syndrome (CAIS). At 15 years old she had a laparotomy and bilateral orchidectomy. Following admission, an examination under anaesthesia and cystoscopy was performed. A diagnosis of strangulated complete urethral prolapse was made. The lesion was excised with diathermy and the meatal skin was reanastomosed to the urethra. At follow-up, the urethra was well healed. The patient now attends Menopause Clinic for oestrogen-replacement therapy. We hope this case raises awareness of the possibility of urethral prolapse in younger women who are oestrogen deficient. It provides further incentive for compliance with hormone replacement therapy for patients with CAIS following gonadectomy, or other women with premature menopause.

Effect of nucleic acid amplification testing on detection of extragenital gonorrhea and chlamydial infections in men who have sex with men sexually transmitted disease clinic patients.

BACKGROUND: In 2010, the Centers for Disease and Control and Prevention recommended using nucleic acid amplification tests (NAATs) for extragenital gonorrhea (GC) and chlamydia (CT) testing because of NAATs' improved sensitivity compared with culture. METHODS: In 2011, the Public Health-Seattle & King County Sexually Transmitted Disease Clinic introduced NAAT-based testing for extragenital GC and CT infection in men who have sex with men (MSM) using AptimaCombo2. We compared extragenital GC and CT test positivity and infection detection yields in the last year of culture-based testing (2010) to the first year of NAAT testing (2011). RESULTS: Test positivity of GC increased by 8% for rectal infections (9.0%-9.7%) and 12% for pharyngeal infections (5.8%-6.5%) from 2010 to 2011; CT test positivity increased 61% for rectal infections (7.4%-11.9%). Pharyngeal CT was identified in 2.3% of tested persons in 2011 (not tested in 2010). We calculated the ratio of extragenital cases per 100 urethral infections to adjust for a possible decline in GC/CT incidence in 2011; the GC rectal and pharyngeal ratios increased 77% and 66%, respectively, and the CT rectal ratio increased 127%. The proportion of infected persons with isolated extragenital infections (i.e., extragenital infections without urethral infection) increased from 43% in 2010 to 57% in 2011. CONCLUSIONS: Extragenital testing with NAAT substantially increases the number of infected MSM identified with GC or CT infection and should continue to be promoted.

A patient with a unique frameshift mutation in GPC3, causing Simpson-Golabi-Behmel syndrome, presenting with craniosynostosis, penoscrotal hypospadias, and a large prostatic utricle.

We present a Hispanic male with the clinical and molecular diagnosis of Simpson-Golabi-Behmel syndrome (SGBS). The patient was born with multiple anomalies not entirely typical of SGBS patients, including penoscrotal hypospadias, a large prostatic utricle, and left coronal craniosynostosis. In addition, he demonstrated endocrine anomalies including a low random cortisol level suspicious for adrenal insufficiency and low testosterone level. To our knowledge, this is the first report of a prostatic utricle in SGBS and the second report of craniosynostosis. The unique disease-causing mutation likely arose de novo in the mother. It is a deletion-insertion that leads to a frameshift at the p.p. S359 [corrected] residue of GPC3 and a premature stop codon after five more amino acids. p. S359 [corrected] is the same residue that is normally cleaved by the Furin convertase, although the significance of this novel mutation with respect to the patient's multiple anomalies is unknown. We present this case as the perinatal course of a patient with unique features of SGBS and a confirmed molecular diagnosis.

Angiotensin type 2 receptor is important in the normal development of the ureter.

In humans, the actions of angiotensin II are transduced through the AT1 and AT2 receptors which have recently been implicated in renal organogenesis. Polymorphisms in the human angiotensin II receptor genes have been linked to cardiovascular and nephrological disorders. In this study we evaluated 35 patients with either primary obstructive megaureter or posterior urethral valves. Each was genotyped for the A1166 AT1 polymorphism and the recently described A-1332G AT2 transition. The incidence of these genetic variants was also evaluated in normal controls without any ultrasonographic urological abnormalities. Similar to our previous findings in congenital urological abnormalities, the AT1 receptor genotype distribution did not differ between patients with either primary obstructive megaureter or posterior urethral valves versus controls. In contrast, compared with normal controls, there was a dramatic increase in the occurrence of the AT2 A-1332G transition in patients with primary obstructive megaureter (75.0% vs. 41.9% in controls, P<0.025). In patients with posterior urethral valves, there was no difference in the occurrence of the transition versus controls (36.9%, P=NS). Thus, there is no correlation between the AT1 receptor gene polymorphism and urological abnormalities. However there is an increased incidence in the AT2 genetic variant in patients with primary obstructive megaureter.

Detection of human papillomavirus DNA by PCR in semen from patients with and without penile warts.

OBJECTIVES: To determine the prevalence of urethral HPV infection, as indicated by the presence of HPV DNA in semen, in males with and without penile warts. DESIGN: Prevalence study of HPV types 6/11 and 16 DNA using PCR and Southern blot hybridisation analysis of semen. SETTING: Department of Genitourinary Medicine, Blundell Street Clinic, Leeds General Infirmary and the Assisted Conception Unit (ACU) Kings' College, London. SUBJECTS: Patients attending the Genitourinary Clinic for treatment of sexually transmitted diseases including penile warts and males attending Kings' ACU for investigations of infertility. MAIN OUTCOME MEASURES: HPV DNA detected by polymerase chain reaction (PCR) and/or Southern blot hybridisation in semen. RESULTS: HPV DNA was detected by PCR in 23 of 27 (85%) specimens from patients attending the GUM clinic for treatment of genital warts and in one of two specimens from patients attending the clinic for other conditions. By Southern blot, nine (33%) of the 29 specimens from GUM clinic patients were HPV DNA-positive. HPV DNA was detected by PCR in 43 of 104 (41%) of specimens from males attending the ACU, whilst 70 of these tested by Southern blot hybridisation were all negative for HPV DNA. CONCLUSIONS: The data suggest that urethral HPV infections, as indicated by the presence of HPV DNA in semen, are prevalent in males with and without genital warts.

Incidence of struvite urinary calculi in two ancestral lines of beagles.

In the last 17 years, 55 of 2,125 (2.6%) purebred beagles maintained in a closed colony had urolithiasis. Males comprised 72.7% of the affected animals. All the uroliths except one set in the kidneys were in the urinary bladder, the urethra, or both. All uroliths were nearly pure magnesium ammonium phosphate hexahydrate. Partially inbred beagles had a 10.7% incidence of urolithiasis, compared to a 2.0% incidence in an outbred line.