Male Genital Anomalies Research Articles

22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan–McDermid syndrome

Phelan-McDermid syndrome is a developmental disability syndrome with varying deletions of 22q13 and varying clinical severity. We tested the hypothesis that, in addition to loss of the telomeric gene SHANK3, specific genomic regions within 22q13 are associated with important clinical features. We used a customized oligo array comparative genomic hybridization of 22q12.3-terminus to obtain deletion breakpoints in a cohort of 70 patients with terminal 22q13 deletions. We used association and receiver operating characteristic statistical methods in a novel manner and also incorporated protein interaction networks to identify 22q13 genomic locations and genes associated with clinical features. Specific genomic regions and candidate genes within 22q13.2q13.32 were associated with severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes. We also found regions suggestive of a negative association with autism spectrum disorders. This work advances the field of research beyond the observation of a correlation between deletion size and phenotype and identifies candidate 22q13 loci, and in some cases specific genes, associated with singular clinical features observed in Phelan-McDermid syndrome. Our statistical approach may be useful in genotype-phenotype analyses for other microdeletion or microduplication syndromes.

Penile length and genital anomalies in Egyptian male newborns: epidemiology and influence of endocrine disruptors

This is an attempt to establish the normal stretched penile length and prevalence of male genital anomalies in full-term neonates and whether they are influenced by prenatal parental exposure to endocrine-disrupting chemicals. A thousand newborns were included; their mothers were subjected to the following questionnaire: parents' age, residence, occupation, contact with insecticides and pesticides, antenatal exposure to cigarette smoke or drugs, family history of genital anomalies, phytoestrogens intake and history of in vitro fertilization or infertility. Free testosterone was measured in 150 neonates in the first day of life. Mean penile length was 3.4±0.37 cm. A penile length <2.5 cm was considered micropenis. Prevalence of genital anomalies was 1.8% (hypospadias 83.33%). There was a higher rate of anomalies in those exposed to endocrine disruptors (EDs; 7.4%) than in the non-exposed (1.2%; p<0.0001; odds ratio 6, 95% confidence interval 2-16). Mean penile length showed a linear relationship with free testosterone and was lower in neonates exposed to EDs.

New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies

We report a new mutation in the human DNAJC19 gene that causes early onset dilated cardiomyopathy syndrome (DCMA). Two brothers of Finnish origin presented with an unusual combination of early onset dilated cardiomyopathy syndrome, a disease which was associated with cardiac noncompaction, microcytic anemia, ataxia, male genital anomalies and methylglutaconic aciduria type V. Suspicion of a DCMA syndrome prompted sequencing of the human DNAJC19 gene. Sequencing of the human DNAJC19 gene showed a homozygous single nucleotide (A) deletion in alanine 63 coding triplet in exon 6, which does not immediately cause amino acid change but leads 11 amino acids later to a stop codon and to premature termination of the peptide. This DNAJC19 protein is located in the inner mitochondrial membrane and has been shown to function as a mitochondrial chaperone. This is the first clinical report of DCMA syndrome, a human DNAJC19 deficiency, that is related to cases of severe dilated cardiomyopathy diagnosed in Europe. DNAJC19 deficiency causes a relatively specific finding in urinary organic acid analysis (methylglutaconic aciduria type V), which together with the clinical features of the ensuing cardiac disease, allows for effective screening before undertaking molecular genetic analysis.

Maternal Urinary Phthalates and Phenols and Male Genital Anomalies

Maternal Urinary Phthalates and Phenols and Male Genital Anomalies

Association between deletion size and important phenotypes expands the genomic region of interest in Phelan–McDermid syndrome (22q13 deletion syndrome)

BackgroundThe clinical features of Phelan–McDermid syndrome (also known as 22q13 deletion syndrome) are highly variable and include hypotonia, speech and other developmental delays, autistic traits and mildly dysmorphic features. Patient...

Prevalence and patterns of male genital anomalies in upper egypt: a cross-sectional community-based study of 1134 infants

Prevalence and patterns of male genital anomalies in upper egypt: a cross-sectional community-based study of 1134 infants

No association between maternal pre-pregnancy obesity and risk of hypospadias or cryptorchidism in male newborns

Hypospadias and cryptorchidism, two relatively common male genital anomalies, may be caused by altered maternal hormone levels, blood glucose levels, or nutritional deficiencies. Maternal obesity, which increases risk of diabetes and could influence hormone levels, may, therefore, be associated with risk of hypospadias and cryptorchidism. The purpose of this study was to assess the association between pre-pregnancy maternal obesity and hypospadias and cryptorchidism. We conducted a case-control study of hypospadias and cryptorchidism in male singleton newborns using Washington State birth records from 1992 to 2008 linked to birth-hospitalization discharge records. Maternal pre-pregnancy body mass index (BMI) was calculated from pre-pregnancy weight and height. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for hypospadias or cryptorchidism were estimated by fitting multivariable logistic regression models adjusted for year of birth, and maternal age, education, parity, race, and cigarette smoking during pregnancy. The complete-case analysis included 2219 hypospadias cases, 2563 cryptorchidism cases, and 32,734 controls. Maternal obesity (BMI ≥30 kg/m(2) ) was not associated with risk of hypospadias or cryptorchidism in male offspring: hypospadias (aOR, 1.07; 95% CI, 0.95-1.21); cryptorchidism (aOR, 0.99; 95% CI, 0.89-1.11), and no trend in risk with increasing maternal BMI was found. There was little indication of risk associated with BMI among any subgroup of mothers examined, including women with pre-existing diabetes or hypertension, women who developed preeclampsia, non-Hispanic white women, first-time mothers, or mothers aged ≥30 years. The results of this study do not support the hypothesis that pre-pregnancy maternal obesity is a cause of hypospadias or cryptorchidism in male infants.

Cystic dysplasia of the epididymis: a disorder of mesonephric differentiation associated with renal maldevelopment

The occurrence of congenital epididymal malformations with a cystic component has not been fully characterized. Most epididymal cysts occur later in life and are likely acquired. In addition, congenital malformations of the male excretory system are extremely uncommon in fetuses and neonates, and epididymal dysplastic changes have not been reported in these cases. In this study, we report 20 cases (including 19 fetal/neonatal autopsies and one surgical specimen from an older child) showing the same spectrum of histological findings in the epididymis, characterized by cystic ductal dilation with dysplastic ducts of variable diameters and irregular shapes, with ill-defined walls. Efferent ductules also showed dysplastic features. In addition, 18 cases had either renal and/or urinary tract anomalies, including renal dysplasia (eight), pelvicaliceal dilation (eight), renal agenesis (four) and hypoplasia (one), ureteral agenesis (two) and hypoplasia (one), urethra and bladder agenesis (two), prostate agenesis (two), and autosomal recessive polycystic renal disease (two). Our observations led to the recognition of a peculiar, not previously described congenital lesion of the epididymis, and we propose the term cystic dysplasia of the epididymis for this anomaly. Similar to what is observed in other male genital system anomalies (including malformations of the rete testis, vas deferens, and seminal vesicles), most lesions occurred in association with renal and/or urinary tract malformations, suggesting a spectrum of congenital malformations. The shared embryological origin of these structures may explain their simultaneous occurrence, possibly related to disrupted mesonephric duct development.

The incidence of external male genital defects in Enugu State of Nigeria: an estimate based on the prevalence among secondary school students

Background : Enugu State typifies a Third World environment where most deliveries occur outside the hospital setting. In such circumstances, therefore, hospital-based data about congenital defects are unreliable and call for special methods of approach. Objective : To assess the place of school prevalence survey results in estimating the population incidence of anomalies of the male external genitalia. Method : From February 2, 2002 to August 1, 2004 a sample of male students aged 10 years and above seen in randomly selected secondary schools in Enugu State of Southeast Nigeria were guided through a protocol involving; self-administered questionnaires, physical examinations for evidence and types of anomalies present in their external genitalia and personal interviews. The participant schools were selected by stratified random sampling; first by Local Government Area (LGA) and then by school. Consents for the study were obtained from Local Government authorities, Heads of the schools, and Parents' Teachers Associations, (P T A) Executives. Results : Altogether, four urban and thirteen rural schools were studied over the 18 month-period of the investigation and a total of 6226 male students participated. Overall, 416 (6.8%) were identified with various types of external genital anomalies, with the prevalence rates observed being within the ranges of population prevalence reported in the literature. The commonest types of anomalies encountered were crypto-orchidism with / or without scrotal hypoplasia 268 (4.30%), inguino-(scrotal) hernias 56 (0.90%), and hydrocoeles 52 (0.83%), in descending order. As many as 183 (44%) of those with congenital genital defects were not aware they had them. When compared with urban schools, rural schools were characterized by a higher frequency [8.4% vs. 2.8% respectively; x 2 = 58.35; P Conclusion : School prevalence surveys may provide close approximations of population prevalence with respect to external male genital anomalies. There is, however, a need for further studies in this direction. Orient Journal of Medicine Vol. 18(1&2) 2006: 43-49

Prenatal Phthalate Exposure and Anogenital Distance in Male Infants

In our article “Decrease in Anogenital Distance among Male Infants with Prenatal Phthalate Exposure” (Swan et al. 2005), we reported results of our recent study on the relationship between anogenital distance (AGD) in boys and their mother’s urinary concentration of phthalate metabolites (Swan et al. 2005). The primary question we addressed was the relationship between the concentration of phthalate metabolites in maternal prenatal urine and the AGD, or the more appropriate derived measure anogenital index (AGI = AGD/weight), in human male offspring. We designed our study to focus on this specific measurement because of highly reliable results in the animal literature showing that certain phthalates reduce AGD (and AGI) in rodents and because, as continuous variables, AGD and AGI would not require a large sample size to demonstrate this relationship, if it existed. Changes in the frequency of a dichotomous and relatively rare end point such as frank cryptorchidism, also caused in animals by prenatal phthalate exposure, require far larger sample sizes. Secondarily, we looked at AGI in relation to other genital measurements (penile volume, testicular descent, and scrotal size), examining these interrelationships in several ways. In our article (Swan et al. 2005), we reported that urinary concentrations of four phthalate metabolites [mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), monoethyl phthalate (MEP), and mono-isobutyl phthalate (MiBP)] were inversely and significantly related to AGI. We also examined three metabolites of diethylhexyl phthalate (DEHP). Although the associations between AGD and the secondary DEHP metabolites [mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP)] were suggestive, they were not statistically significant, and the metabolite MEHP appeared to be unrelated to AGI. We examined the relationship between AGI and testicular descent in several ways, varying whether each of these variables was entered into the analysis untransformed (e.g., as they were recorded in the examination) or as dichotomous variables. AGD was measured by the examiner using a Vernier calipers. Both AGD and AGI are continuous, and approximately normally distributed, variables. The degree of descent of each testicle was categorized as follows: 0 = normal, 1 = normal retractile, 2 = high scrotal, 3 = suprascrotal, 4 = inguinal, and 5 = nonpalpable or ectopic. The testicular placement score (TPS) is the sum of the recorded value for the left and right testicle. Therefore, the lower the TPS, the more complete the testicular descent. We first examined the relationship between AGI and testicular descent by calculating the correlation coefficient between AGI and TPS (an ordinal variable). In the complete data set, including 134 boys with genital examination, AGI is significantly and inversely related to TPS (correlation coefficient −0.201, p-value 0.021). That is, shorter AGI was significantly associated with less complete testicular descent. This analysis assumes that TPS is an interval variable; for example, the difference between a score of 0 (both testicles “normal”) and 1 (one testicle “normal” and one “normal retractile”) is equal to that between 1 and 2 (either both “normal retractile,” or one “normal” and one “high scrotal”). We also examined TPS as a dichotomous variable, which does not require this assumption. For this purpose, testicular descent was coded as 0 and called “complete” if both testicles were rated as either normal or normal retractile; otherwise, it was coded as 1 and called “incomplete.” This dichotomous variable was also significantly correlated with AGI (correlation coefficient −0.192, p-value 0.027). Since results by these two methods were similar, we did not include this latter analysis in our article (Swan et al. 2005). As is common practice in epidemiologic analyses, we also dichotomized AGI to create two groups to serve as cases and controls. For this purpose, we classified boys into “short” AGI (< 25% of expected for age) or “not short.” We looked at the proportion of boys with incomplete testicular descent in these groups. We incorrectly stated the p-value for not short (0.136) in our article (Swan et al. 2005) to be statistically significant. That this analysis was not statistically significant, while the analysis of the AGI as continuous variable was, is not surprising; dichotomizing a continuous variable results in a loss of power, and thus a larger sample size is needed to achieve a similar level of statistical significance (Ragland 2002). In conclusion, in all analyses boys with shorter AGI had less complete testicular descent, and significantly so for the two analyses in which AGI was treated as a continuous variable. The miscalculation of statistical significance for one analysis, while unfortunate, in no way alters any of our conclusions. Also, this error does not weaken this article’s (Swan et al. 2005) support for the importance of examining patterns of subtle changes in humans, as suggested by toxicology, when assessing the effects of environmental exposures.

Organochlorine Pesticides and Male Genital Anomalies in the Child Health and Development Studies

Increasing rates of cryptorchidism and hypospadias in human populations may be caused by exogenous environmental agents. We conducted a case–control study of serum levels of p,p′-dichlorodiphenyltrichloroethane (DDT) and its major metabolite, p,p′-dichlorodiphenyldichloroethylene (DDE), and cryptorchidism and hypospadias in the Child Health and Development Study, a longitudinal cohort of pregnancies that occurred between 1959 and 1967, a period when DDT was produced and used in the United States. Serum was available from the mothers of 75 male children born with cryptorchidism, 66 with hypospadias, and 4 with both conditions. We randomly selected 283 controls from the cohort of women whose male babies were born without either of these conditions. Overall, we observed no statistically significant relationships or trends between outcomes and serum measures. After adjusting for maternal race, triglyceride level, and cholesterol level, compared with boys whose mothers had serum DDE levels < 27.0 ng/mL, boys whose mothers had serum DDE levels ≥61.0 ng/mL had odds ratios of 1.34 [95% confidence interval (CI), 0.51–3.48] for cryptorchidism and 1.18 (95% CI, 0.46–3.02) for hypospadias. For DDT, compared with boys whose mothers had serum DDT levels < 10.0 ng/mL, boys whose mothers had serum DDT levels ≥20.0 ng/mL had adjusted odds ratios of 1.01 (95% CI, 0.44–2.28) for cryptorchidism and 0.79 (95% CI, 0.33–1.89) for hypospadias. This study does not support an association of DDT or DDE and hypospadias or cryptorchidism.

MEASURING THE EFFECTS OF DDT AND DDE ON PRETERM DELIVERY, SMALL-FOR-GESTATIONAL AGE BIRTH AND LOW BIRTHWEIGHT BIRTH

ISEE-473 Objective: Though banned in the United States since 1972, the pesticide 1,1,1-trichloro-2,2’-bis(p-chlorophenyl)ethane (DDT) is used elsewhere for mosquito control. Its human health costs and benefits thus remain a current concern. DDT, and its persistent metabolite DDE, have been associated with negative reproductive outcomes in birds, rabbits and sea lions. However, there are inconsistencies regarding exposure to DDT and effects on human health. This study was designed to evaluate the effects of serum levels of DDT and its major metabolite DDE on three adverse human birth outcomes - preterm delivery, small-for-gestational-age birth and low birthweight. Methods: Nested case-control study. We studied a sample of male live births from a longitudinal cohort study of 20,754 pregnancies that occurred between 1959 and 1967 (a period of high domestic DDT usage in the United States). The 283 male subjects included in this analysis were randomly selected controls from another study of the effects of organochlorine pesticides on male genital anomalies. Birth outcome data and maternal demographic/behavioral data were collected through maternal interviews and abstracted medical records. Maternal serum samples were taken during pregnancy and post-partum. Serum DDT and DDE were determined by gas chromatography/electron capture detection (GC/ECD). Data were analyzed using multivariate logistic regression for preterm delivery and small-for-gestational age birth and linear regression for birthweight. Results: Mean serum levels for DDT and DDE were 1.6 and 5.9 μg/g lipid, respectively. Variables identified as significant in bivariate analysis against each outcome variable were included as covariates in multivariate analysis. Preliminary findings indicate that maternal DDT and DDE levels, controlling for a range of demographic and behavioral variables associated with birth outcomes (i.e., age, race, education, marital status, income, occupation, place of birth, parity, BMI, and smoking and alcohol use) do not predict preterm delivery (n=23); small-for-gestational age birth (n=28), or low birthweight (n=13). Final results of regression analyses, including odds ratios and confidence intervals, will be presented. Discussion: The effect of DDT and DDE on human birth outcomes in this study appears null. However, we were limited by the small size of the study and the fact that we were only able to examine live births. Considering the persistence of DDT in the environment and its role in malaria control, further studies using more robust data should continue to assess this relationship.

P154: Second trimester ultrasound detection of cloaca exstrophy associated with unusual male genital anomalies

P154: Second trimester ultrasound detection of cloaca exstrophy associated with unusual male genital anomalies

Endocrine disruptors and congenital anomalies

The specialized literature was reviewed concerning the suspected increasing secular trends in the frequency of female births, male genital congenital anomalies, abnormal sperm counts, and testicular cancer. Although no risk factors could be identified yet, the observed sex ratio decline during the last decades has been considered to be an effect of certain pollutants on normal hormone activity, and human reproductive development. Reported increasing trends in the frequencies of hypospadias and cryptorchidism are very difficult to be interpreted due to the large variability in the registered frequency of these malformations due to operational as well as biological reasons.

Monozygotic twin girls with diploid/triploid chromosome mosaicism and cutaneous pigmentary dysplasia

Diploid/triploid mosaicism is an uncommon clinical syndrome with a subtle but distinctive phenotype. Characteristic features include prenatal and postnatal asymmetric growth deficiency, triangular and/or asymmetric facies, micrognathia, finger and/or toe syndactyly, clinodactyly, single transverse palmar creases, male genital anomalies, hypotonia and psychomotor retardation. This disorder is underdiagnosed because in 70% of cases the triploid cell line is only seen in fibroblasts. In cases in which a triploid cell line is found in lymphocytes, it usually occurs in less than 5% of cells. While some reports of diploid/triploid mosaicism have mentioned unusual skin pigmentary patterns, including hypomelanosis of Ito, it was only recently recognized that this is a helpful diagnostic clue in mosaic chromosome disorders. We report monozygotic twin girls with diploid/triploid mosaicism whose cutaneous pigmentary dysplasia led to their diagnosis.