Malignant thyroid teratoma: an integrated analysis of case series/case reports.

Malignant thyroid teratoma (MTT) is a very rare thyroid malignancy. These neoplasms have been reported only in case reports and small-sized case series so far. In this study, we searched for MTTs in the Surveillance, Epidemiology, and End Result (SEER) program during 1975-2016. Subsequently, we incorporated the SEER data with published MTT cases in the literature to analyze the characteristics and prognostic factors of MTTs. Integrated data were analyzed using chi-square or Fisher's exact test for categorical covariates, and t-test or Mann-Whitney test for continuous variables. We included 28 studies with 36 MTT cases and found additional 8 cases from the SEER program for final analyses. Our results showed that MTT is typically seen in adult females. These neoplasms were associated with an aggressive clinical course with high rates of extrathyroidal extension (80%) and nodal involvement (62%). During follow-up, the development of recurrence and metastases were common (42% and 46%, respectively), and one-third of patients died at the last follow-up. Large tumor size (P = 0.022) and the presence of metastases during follow-up (P = 0.008) were associated with a higher mortality rate. In conclusion, our study demonstrated the characteristic features of MTT patients and outlined some parameters associated with a negative outcome which could help clinicians better predict the clinical course of these neoplasms.

Acceptability and feasibility of sexually transmissible infection screening among pregnant women in Hanoi, Vietnam.

Background Vietnam currently has no antenatal screening program for curable sexually transmissible infections (STIs). The aim of this study was to determine the prevalence of curable STIs, correlates of infections and assess the acceptability and feasibility of antenatal STI screening in Hanoi, Vietnam. METHODS: A study involving 800 pregnant women visiting Ha Dong Hospital in Hanoi, Vietnam from June 2016 to July 2017, was conducted. Participants provided either a self-collected vaginal swab or urine sample to be screened for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV). RESULTS: The prevalence of CT, NG and TV was 6.0% (95%CI: 4.5-7.9%), 0.13 (95%CI: 0.003-0.7%) and 0.8% (95%CI: 0.16-2.2%) respectively. CT infection was significantly associated with being <25 years and not being married to last sex partners at the multivariable level. Acceptability and feasibility were high, with 99.5% of eligible women consenting to testing, and 96% of infected women getting treatment. Most women considered STI screening during pregnancy to be important and were willing to notify their sex partners if they were infected. CONCLUSIONS: CT was the most common curable STI among pregnant women in Hanoi, Vietnam. Antenatal screening of curable STIs was highly acceptable and feasible in this population.

Self-perceptions and actual employment patterns amongst recent Australian dental graduates.

INTRODUCTION: With nine dental schools across Australia graduating over 500 dental students each year, in addition to nearly 200 overseas-qualified dentists entering the workforce, dental students are anecdotally advised that they are joining a profession ubiquitous with workforce oversupply. The aim of this study was to shed light on the employment patterns of recent dental graduates from Australian universities and their self-perceptions of the job market. MATERIALS AND METHODS: This cross-sectional pilot study involved an online survey conducted in 2017 on recent dental graduates from all Australian dental schools. Graduates' demographics, their perception of the dental employment prospects, their employment-related behaviours and employment outcomes, and the relationships between these variables were explored. RESULTS: Data on seventy-one survey respondents (approximately 12% of the total sampling frame) were analysed. They suggested that recent Australian dental graduates are seeking work (73.2%) and undertaking work experience (54.9%) prior to graduation, successfully finding employment within the first-year post-graduation (97%), yet not always in their perceived ideal workplace environment (42.2%). Relationships between age, perception of market competitiveness and job searching patterns were revealed. Graduates expressed a desire for more workplace mentorship. The small sample size of this study limits the generalisability of the results, indicating that further research is required. CONCLUSIONS: The dental employment landscape appears to have adequate employment opportunities for recent dental graduates, yet not always in their perceived ideal workplace environment. Graduates are seeking more mentorship in the workplace.

Clinical significance of RET and RAS mutations in sporadic medullary thyroid carcinoma: a meta-analysis.

There are ongoing debates with respect to the prognostic roles of molecular biomarkers in sporadic medullary thyroid carcinoma (MTC). In this study, we aimed at investigating the prognostic value of RET and RAS mutations - the two most common mutations in sporadic MTCs. A search was conducted in four electronic databases. Relevant data were extracted and pooled into odds ratios (OR), mean differences (MD) and corresponding 95% confidence intervals (CI) using the random-effect model. We used Egger's regression test and visual of funnel plots to assess the publication bias. From 2581 studies, we included 23 studies with 964 MTCs for meta-analysis. Overall, the presence of RET mutation was associated with an elevated risk for lymph node metastasis (OR = 3.61; 95% CI = 2.33-5.60), distant metastasis (OR = 2.85; 95% CI = 1.64-4.94), advanced tumor stage (OR = 3.25; 95% CI = 2.02-5.25), tumor recurrence (OR = 3.01; 95% CI = 1.65-5.48) and patient mortality (OR = 2.43; 95% CI = 1.06-5.57). RAS mutation had no significant prognostic value in predicting tumor aggressiveness. To summarize, our results affirmed that RET mutation is a reliable molecular biomarker to identify a group of highly aggressive sporadic MTCs. It can help clinicians better assess patient prognosis and select appropriate treatment decisions.

BRAF Mutation is Associated with an Improved Survival in Glioma-a Systematic Review and Meta-analysis.

Newly emerged molecular markers in gliomas provide prognostic values beyond the capabilities of histologic classification. BRAF mutation, especially BRAF V600E, is common in a subset of gliomas and may represent a potential prognostic marker. The aim of our study is to investigate the potential use of BRAF mutations on prognosis of glioma patients. Four electronic databases were searched for potential articles, including PubMed, Scopus, ISI Web of Science, and Virtual Health Library (VHL). Data of hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) were directly obtained from original papers or indirectly estimated from Kaplan Meier curve (KMC). A random effect model weighted by inverse variance method was used to calculate the pooled HR. From 705 articles, we finally included 11 articles with 1308 glioma patients for the final analysis. The overall estimates showed that BRAF V600E was associated with an improved overall survival (OS) in glioma patients (HR = 0.60; 95% CI = 0.44-0.80). Results for progression-free survival (PFS), however, were not statistically significant (HR = 1.39; 95% CI = 0.82-2.34). In subgroup analyses, BRAF V600E showed its effect in improving survival in pediatric and young adult gliomas (under 35 years) but did not have prognostic value in old adult. Additionally, BRAF V600E was only associated with a favorable prognosis in lower grade glioma. Our meta-analysis provides evidence that BRAF mutation has a favorable prognostic impact in gliomas and its prognostic value might be dependent on patient age and tumor grade. This mutation can be used as a prognostic factor in glioma but additional studies are required to clarify its prognostic value taking into account other confounding factors.

TERT promoter mutation and its interaction with IDH mutations in glioma: Combined TERT promoter and IDH mutations stratifies lower-grade glioma into distinct survival subgroups-A meta-analysis of aggregate data.

The clinical significance of telomerase reverse transcriptase (TERT) promoter mutation in glioma remains unclear. The aim of our meta-analysis is to investigate the prognostic impact TERT promoter mutation in glioma patients and its interaction with other molecular markers, particularly Isocitrate Dehydrogenase (IDH) mutation from aggregate level data. Relevant articles were searched in four electronic databases including PubMed, Scopus, Web of Science and Virtual Health Library. Pooled HRs were calculated using random effect model weighted by inverse variance method. From 1010 studies, we finally included 28 studies with 11519 patients for meta-analyses. TERT mutation is significantly associated with compromised overall survival (OS) (HR=1.38; 95% CI=1.15-1.67) and progression-free survival (PFS) (HR=1.31; 95% CI=1.06-1.63) in glioma patients. In studying its reaction with IDH, TERT promoter mutation was associated with reduced OS in both IDH-mutant (IDH-mut) and IDH-wild type (IDH-wt) glioblastomas but shown to have inverse effects on IDH-mut and IDH-wt grade II/III tumors. Our analysis categorized WHO grade II/III glioma patients into four distinct survival subgroups with descending survival as follow: TERT-mut/IDH-mut≫TERT-wt/IDH-mut≫TERT-wt/IDH-wt≫TERT-mut/IDH-wt. Prognostic value of TERT promoter mutations in gliomas is dependent on tumor grade and the IDH mutational status. With the same tumor grade in WHO grade II and III tumors and the same IDH mutation status, TERT-mut is a prognostic factor.

A meta-analysis of prognostic roles of molecular markers in papillary thyroid carcinoma.

The prognostic role of molecular markers in papillary thyroid carcinoma (PTC) is a matter of ongoing debate. The aim of our study is to investigate the impact of RAS, BRAF, TERT promoter mutations and RET/PTC rearrangements on the prognosis of PTC patients. We performed a search in four electronic databases: PubMed, Scopus, Web of Science and Virtual Health Library (VHL). Data of hazard ratio (HR) and its 95% confidence interval (CI) for disease-specific survival (DSS) and disease-free survival (DFS) were directly obtained from original papers or indirectly estimated from Kaplan-Meier curve (KMC). Pooled HRs were calculated using random-effect model weighted by inverse variance method. Publication bias was assessed by using Egger's regression test and visual inspection of funnel plots. From 2630 studies, we finally included 35 studies with 17,732 patients for meta-analyses. TERT promoter mutation was significantly associated with unfavorable DSS (HR = 7.64; 95% CI = 4.00-14.61) and DFS (HR = 2.98; 95% CI = 2.27-3.92). BRAF mutations significantly increased the risk for recurrence (HR = 1.63; 95% CI = 1.27-2.10) but not for cancer mortality (HR = 1.41; 95% CI = 0.90-2.23). In subgroup analyses, BRAF mutation only showed its prognostic value in short-/medium-term follow-up. Data regarding RAS mutations and RET/PTC fusions were insufficient for meta-analyses. TERT promoter mutation can be used as an independent and reliable marker for risk stratification and predicting patient's outcomes. The use of BRAF mutation to assess patient prognosis should be carefully considered.

Fine mapping analysis confirms and strengthens linkage of four chromosomal regions in familial hypospadias.

Hypospadias is a common male genital malformation and is regarded as a complex disease affected by multiple genetic as well as environmental factors. In a previous genome-wide scan for familial hypospadias, we reported suggestive linkage in nine chromosomal regions. We have extended this analysis by including new families and additional markers using non-parametric linkage. The fine mapping analysis displayed an increased LOD score on chromosome 8q24.1 and 10p15 in altogether 82 families. On chromosome 10p15, with the highest LOD score, we further studied AKR1C2, AKR1C3 and AKR1C4 involved in steroid metabolism, as well as KLF6 expressed in preputial tissue from hypospadias patients. Mutation analysis of the AKR1C3 gene showed a new mutation, c.643G>A (p.(Ala215Thr)), in a boy with penile hypospadias. This mutation is predicted to have an impact on protein function and structure and was not found in controls. Altogether, we homed in on four chromosomal regions likely to harbor genes for hypospadias. Future studies will aim for studying regulatory sequence variants in these regions.

Hospital psychiatric comorbidity and its role in heroin dependence treatment outcomes using naltrexone implant or methadone maintenance.

Our objectives were to (i) estimate lifetime prevalence of psychiatric comorbidity in heroin users and (ii) evaluate psychiatric comorbidity as a predictor of drug-related hospitalization following either (a) methadone maintenance or (b) naltrexone implant treatment. Our method consisted of retrospective, longitudinal follow-up using prospectively collected, state-wide hospital data on two cohorts of heroin-dependent persons (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), first time treated with naltrexone implant (n = 317) or methadone (n = 521) between January 2001 and December 2002. Outcome measures were: (i) prevalence of comorbidity and (ii) changes in risk for drug-related hospitalization - categorized as 'opioid drugs', 'non-opioid drugs', and 'any drug' - to 3.5 years post-treatment. Nearly 32% had psychiatric comorbidity. In both cohorts, comorbid patients generally had significantly greater odds of drug-related hospitalization pre-treatment compared with non-comorbid counterparts. These differences generally reduced in magnitude post-treatment. Comorbid naltrexone-treated patients had less 'opioid' and 'any drug' related hospitalizations post-treatment. Similarly, comorbid methadone-treated patients had reduced hospitalization risk for 'non-opioid' and 'any drug' related hospitalization post-treatment. Treatment of persons without depression, anxiety, or personality disorder with naltrexone implant was associated with increased risk of 'non-opioid' drug-related hospitalization, while methadone treatment was associated with increased risk of 'opioid' drug-related hospitalization. Although comorbid heroin users entered treatment with significantly higher risk of drug-related hospitalization than non-comorbid users, substantial reductions in drug-related hospitalization were generally observed post-treatment. This challenges the view that comorbidity predicts poor drug treatment outcomes. Differences in research methodology were noted; recommendation for rigorous analytical methodology in future research on assessing treatment outcomes was accordingly offered.

Risk factors for craving and relapse in heroin users treated with oral or implant naltrexone.

BACKGROUND: Oral naltrexone effectively antagonizes heroin, but patient noncompliance limits its utility; sustained-release preparations may overcome this. Few data are available on optimal blood naltrexone levels for preventing craving and/or return to heroin use. This study assesses various risk factors, including blood naltrexone level, for heroin craving and relapse to illicit opioids. METHODS: Heroin-dependent persons from a randomized controlled trial of oral versus implant naltrexone were followed up for 6 months. Thirty-four participants received 50 mg oral naltrexone daily, plus placebo implant; thirty-five participants received a single dose of 2.3 g naltrexone implant, plus daily oral placebo tablets. RESULTS: Compared to oral naltrexone patients, implant naltrexone patients were significantly less likely to use any opioids and had one-fifth the risk of using heroin > or = weekly. Risk of > or = weekly heroin use increased by 2.5 times at blood naltrexone concentration < .5 ng/mL compared with > or = .5 ng/mL, with 3 ng/mL associated with very low risk of use. Craving remained near "floor" levels for implant patients but rebounded to higher levels among oral patients. Lower craving scores (< or = 20/70) predicted lower relapse risk. Noncompliance with daily oral formula, higher baseline craving, longer history of use, and being younger predicted higher craving at follow-up. CONCLUSIONS: Implant naltrexone was better associated with reduced heroin craving and relapse than oral naltrexone. Effective treatment was achieved at blood naltrexone levels of 1 ng/mL to 3 ng/mL, with higher levels associated with greater efficacy. Craving assessment may be valuable in predicting relapse risk allowing timely intervention.

Mutational study of the MAMLD1-gene in hypospadias.

Hypospadias, when the urethral opening is situated on the ventral side of the penis, is a common genital malformation in boys and is partly caused by genetic factors. Mutations in the Mastermind-like domain containing 1 (MAMLD1 or CXorf6) gene have been reported in hypospadias cases. We have performed direct sequencing of the MAMLD1 gene in 99 sporadic hypospadias cases to further elucidate the role of this gene in hypospadias. Five non-synonymous mutations, one synonymous and one non-coding mutation were found. Of those, p.P286S, p.V432A, p.N589S and p.531ins3Q have previously been reported and are indicated in our study as polymorphisms. One new mutation, p.Q529K, was found in one patient with severe hypospadias and it was predicted to affect the splicing process. In our material we also found a weak association between hypospadias and the p.N589S polymorphism and in a haplotype analysis the rare alleles of p.P286S and p.N589S were more common in cases than in controls.

A new susceptibility locus for hypospadias on chromosome 7q32.2-q36.1.

Hypospadias is a common malformation (1/300 boys) where the urethra opens on the ventral side of the penis. It is considered a complex disorder with both genetic and environmental factors involved in the pathogenesis. To identify the chromosomal loci involved in the pathogenesis of hypospadias, we performed a genome-wide linkage analysis in a three-generational family showing autosomal dominant inheritance of hypospadias. Fifteen individuals, whereof seven affected, were genotyped within a total of 426 microsatellite markers and the genotyping results were analyzed using parametric and non-parametric linkage analyses. The genome-wide linkage analysis and subsequent fine mapping gave a maximum linkage in both parametric (LOD score 2.71) and non-parametric (NPL score 5.01) single-point analyses for marker D7S640. A susceptibility haplotype shared by all affected boys was identified with the centromeric and telomeric boundaries defined by markers D7S2519 and D7S2442, respectively. This suggests a novel hypospadias locus at chromosome 7q32.2-q36.1 that encompasses 18.2 Mb (25 cM) and harbors hundreds of genes. Mutation analysis of two genes within the region, the AKR1D1 (aldo-keto reductase family 1, member D1) gene involved in the androgen pathway and the PTN gene coding for pleiotrophin, an embryonic differentiation and growth factor, was performed but without putative findings.

Frequencies of PRNP gene polymorphisms in Vietnamese dairy cattle for potential association with BSE.

Summary Since 2004, significant associations between bovine spongiform encephalopathy (BSE) susceptibility in cattle and frequencies of insertion/deletion (ins/del; indel) polymorphisms within the bovine prion protein gene (PRNP) have been reported. In this study, we investigated the frequencies of indel polymorphisms within two variable sites, a 23-bp indel polymorphism in the promoter region (23indel) and a 12-bp indel polymorphism in intron 1 region (12indel), in the PRNP in 206 Vietnamese dairy cattle and seven Japanese BSE-affected cattle. In Vietnamese dairy cattle, the frequency distributions of del allele and del/del genotypic polymorphisms in the 23indel site, which are thought to be associated with BSE susceptibility, were significantly higher, whereas the frequencies of del allelic and del/del genotypic polymorphisms in the 12indel site, which have been reported to confer BSE susceptibility, were significantly lower. We have provided evidence that Vietnamese dairy cattle have a unique genetic background in the PRNP gene in comparison with cattle or sires previously reported in other countries.

Comparing drug-related hospital morbidity following heroin dependence treatment with methadone maintenance or naltrexone implantation.

CONTEXT: Most research on heroin dependence treatments assesses short-term changes in patients' self-reported drug use. To our knowledge, long-term sustainability of changes in patients' drug use and associated hospital morbidity posttreatment have not been studied. OBJECTIVES: To evaluate drug-related hospital morbidity in heroin users at 6 months and 3 1/2 years after receiving naltrexone implant treatment and to compare these results with outcomes from a similar cohort treated with methadone maintenance treatment. DESIGN: Retrospective longitudinal follow-up, using data prospectively collected via a state hospital (public and private) reporting system. SETTING: Perth, Western Australia. Methadone maintenance dosage was generally dispensed daily by registered community pharmacies. Naltrexone implant treatment was performed as a day procedure at a community clinic. PARTICIPANTS: A total of 522 and 314 heroin-dependent persons (according to DSM-IV), first time treated with methadone maintenance or a naltrexone implant, respectively, between January 1, 2001, and December 30, 2002, were identified, using health record linkage. MAIN OUTCOME MEASURES: Planned outcomes included crude hospital admission rates, adjusted changes in risks (odds ratio [OR]), and rates (rate ratio) of "overdose-related" and "non-overdose-related" hospital morbidity associated with opioid vs nonopioid drugs 6 months and 3 1/2 years posttreatment. RESULTS: Following naltrexone implant treatment, opioid-related risk decreased for overdose (OR, 0.23; 95% confidence interval [CI], 0.11-0.48) and nonoverdose (OR, 0.64; 95% CI, 0.46-0.89) conditions at 3 1/2 years. Such reductions were not observed after methadone treatment. Overdose on nonopioid drugs increased in older patients to 6 months: OR of 16.31 (95% CI, 3.07-86.53) for naltrexone and OR of 5.03 (95% CI, 1.18-21.54) for methadone. Nonoverdose (eg, dependence and withdrawal) associated with nonopioid drugs also increased for patients receiving the naltrexone implant: OR of 1.52 (95% CI, 1.04-2.23) at 3 1/2 years. In addition, there were 6 drug-related deaths: 5 after methadone maintenance and 1 after naltrexone implantation. CONCLUSIONS: Naltrexone implants, but not methadone maintenance, has long-term benefits in reducing opioid-related hospital morbidity. However, long-lasting and increased nonopioid drug-related morbidity following naltrexone implantation is particularly concerning. Similar studies are required to confirm these findings.

Biodegradability of naltrexone-poly(DL) lactide implants in vivo assessed under ultrasound in humans.

Ultrasound was used to assess the in vivo biodegradability of a sustained release poly(DL)lactide naltrexone implant in 71 persons previously treated for heroin dependence. We assessed 139 implant sites ranging from 2 to 1808 days post implant. Ultrasound assessment showed that implant tablets were initially well demarcated from each other and from the surrounding tissues. Biodegradation resulted in less demarcated tablets followed by clumping into a single mass-like structure. This mass subsequently dispersed by approximately 1201 days post implant with no implant material visualized by ultrasound. The biodegradation was also assessed by visual clinical examination and palpation of the implant site as well as patient self-report. These measures were generally well correlated with ultrasound results. Clinical assessment of the biodegradation process concluded that the implant changed from 'firm' to 'less firm' and from 'initial square edge' to 'rounded edge' tablets. Collectively, these data provide direct evidence of the in vivo absorption of the Go Medical implant over time, and its biodegradability in humans.

Mental health outcomes following naltrexone implant treatment for heroin-dependence.

BACKGROUND: Oral naltrexone is an approved treatment for opioid dependence. However, the impact of sustained release naltrexone on the mental health of treated opioid users has not been studied. AIMS: To assess if naltrexone via implant treatment was associated with any change in (i) risk, (ii) rate, and (iii) duration for hospital morbidity related to several categories of mental disorders among treated heroin users. METHOD: A cohort of 359 heroin users treated with sustained release naltrexone via implants in Western Australia was retrospectively followed up for mental health related outcomes via a health record linkage system over an average period of 1.78 years post-treatment. RESULTS: Individual patient's risk for hospital mental diagnoses was not altered after naltrexone implant. On a population cohort level, hospital admission rates related to all mental health problems, except mood disorders, declined significantly post-treatment; however, length of hospital stay did not improve. Overall, young, female patients or those with pre-existing mental illness were more likely than other patients to require hospital care for mental health issues following treatment. Longer period of heroin use was associated with poorer mood outcomes. CONCLUSIONS: Naltrexone implants were not associated with an increased risk for hospitalisation due to mental illness, and in most cases, were associated with a decrease in mental related hospital admission rate.

Obesity in adults: an emerging problem in urban areas of Ho Chi Minh City, Vietnam.

OBJECTIVE: To assess the prevalence of overweight, obesity and underweight among Vietnamese adults living in urban areas of Ho Chi Minh City (HCMC), Vietnam. DESIGN: This cross-sectional survey was conducted in the local health stations of 30 randomly selected wards, which represent all 13 urban districts of HCMC, over a period of 2 months from March to April 2004. SUBJECTS: A total of 1488 participants aged 20-60 years completed the interview, physical examination and venous blood collection. MEASUREMENTS: Anthropometric measurements of body weight, height, waist and hip circumference were taken to construct indicators of adiposity including body mass index (BMI), waist circumference, and waist-to-height and waist-to-hip ratios. Both systolic and diastolic blood pressure and biochemical indicators of cardiovascular disease and type II diabetes risk (lipid profile and fasting blood glucose) were also measured. RESULTS: The age and sex standardized prevalence of overweight and obesity using Asian specific BMI cutoffs of 23.0 and 27.5 kg/m2 was 26.2 and 6.4%, respectively. The prevalence of overweight and obesity was slightly higher in females (33.6%) than males (31.6%), and progressively increased with age. The age and sex-standardized prevalence of underweight (BMI <18.5 kg/m2) among Vietnamese adults living in HCMC was 20.4%. The prevalence was slightly higher in males (22.0%) than in females (18.9%), and there was a much higher prevalence in all underweight categories in younger women than in men but this was reversed for older men. CONCLUSION: The adult population in HCMC Vietnam is in an early 'nutrition transition' with approximately equal prevalence of low and high BMI. The prevalence of overweight and obesity of Vietnamese urban adults was lower than that reported for other east and southeast Asian countries.

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.