The valine allele of the V89L polymorphism in the 5-alpha-reductase gene confers a reduced risk for hypospadias

CONTEXT: Hypospadias is one of the most common malformations in man, with an incidence of 1:300 in newborn boys. No gene has been identified that causes isolated hypospadias, but the androgenic influence is important during male genital development. OBJECTIVE: A key enzyme for the androgenic function is steroid 5-alpha-reductase (SRD5A2). The V89L polymorphism in the SRD5A2 gene has been studied and found to be of functional importance. The leucine version of the enzyme is 30% less efficient than the valine variant. DESIGN, SETTING, PATIENTS, AND RESULTS: We have genotyped 158 hypospadias cases and 96 unaffected controls for this polymorphism and found a significant negative association for the V89 allele in hypospadias (odds ratio, 0.24; 95% confidence interval, 0.14-0.41 for homozygous individuals). This indicates that a fully functional 5-alpha-reductase enzyme (homozygous for V89) protects the male urethral development. This association is shown regardless of heredity, ethnicity, and severity of phenotype. We have also sequenced a selected material of 37 sporadic cases of more severe hypospadias for mutations in the androgen receptor AR, SRD5A2, and 17beta-hydroxysteroid dehydrogenase HSD17B3 genes and found only two previously described mutations, one in the AR and one in the SRD5A2 gene. CONCLUSION: This finding is in accordance with the assumption that functional polymorphisms may play an important role in complex disorders such as hypospadias when several genes as well as environmental factors contribute to the etiology.     

Degree of abnormality is associated with rate of change in measures of beta-amyloid,glucose metabolism and cognition in an autopsy-verified Alzheimer’s disease case

The degree of abnormality and rate of change in cognitive functions, positron emission tomography Pittsburg compound B (PET PIB), and fluorodeoxyglucose (FDG) measures were studied for 8 years in an autopsy-confirmed Alzheimer’s disease (AD) patient, who died 61 years old (Mini-Mental State Examination (MMSE) score 7). At first encounter with medical care, the patient was very mildly demented (MMSE score 27). She had four cognitive assessments and two examinations with PET PIB and FDG in 23 bilateral brain regions. The onset of cognitive decline was retrospectively estimated to have started in the early forties. The degree of impairment was inversely related to the rate of decline. A similar relationship was seen between the rate of change and the level of abnormality in both PIB and FDG. To conclude, rate of change in cognition, PIB, and FDG was associated with the degree of abnormality.     

Laparoscopic-assisted pull-through for Hirschsprung's disease,a prospective repeated evaluation of functional outcome

Aim of the study

To evaluate the functional outcome of laparoscopic-assisted endorectal pull-through (LAP) for Hirschsprung's disease (HSCR) over time.

Methods

Thirty-five children with HSCR underwent laparoscopic-assisted pull-through at our institution between 1998 and 2009. The diagnosis was histologically confirmed in all cases. Clinical data was extracted from the case records. A prospective assessment of the functional outcome was performed in 2009 and 2012. Exclusion criteria were a follow-up of less than 6 months after treatment (1 case) and total colonic aganglionosis (1 case). An independent examiner, not involved in the clinical care of the patients, performed interviews using a semi-structured questionnaire. Four patients could not be traced for the first interview. Two cases were lost for the second interview. Altogether twenty-seven patients completed the study. Data from the two interviews were compared. The regional ethical review board approved the study.

Main Results

The median patient age was 4 years old (range 2–16) at the time of the first interview and 7 years old (range 5–19) at the time of the second interview . There were 23 males and 4 females in the study group. The median age at laparoscopic-assisted pull-through was 104 days old (range 29 days–8 years). In the first interview 11 patients reported constipation, 18 patients reported soiling more frequently than once per week when they had loose stools and 16 patients when they had solid stools. Laxatives or irrigations were used by 13 of the patients. In the second interview 4 patients reported constipation, 16 patients reported soiling when they had loose stools and 15 patients reported soiling when they had solid stools. Eight patients used laxatives or irrigations. The decrease in constipation was statistically significant (p = 0,023).

Conclusions

Our study shows a statistically significant reduction of constipation over time. There is a high risk of incontinence after laparoscopic-assisted pull-through, with few signs of short-term improvement.