Male Malformations Research Articles

Urine-derived exosomes and their role in modulating uroepithelial cells to prevent hypospadias

PurposeUrethral hypospadias, a common congenital malformation in males, is closely linked with disruptions in uroepithelial cell (UEC) processes. Evidence exists reporting that urine-derived exosomes (Urine-Exos) enhance UEC proliferation and regeneration, suggesting a potential role in preventing hypospadias. However, the specific influence of Urine-Exos on urethral hypospadias and the molecular mechanisms involved are not fully understood. This study focuses on investigating the capability of Urine-Exos to mitigate urethral hypospadias and aims to uncover the underlying molecular mechanisms. MethodsBioinformatics analysis was performed to identify key gene targets in Urine-Exos potentially involved in hypospadias. Subsequent in vitro and in vivo experiments were conducted to validate the regulatory effects of Urine-Exos on hypospadias. ResultsBioinformatics screening revealed syndecan-1 (SDC1) as a potential pivotal gene for the prevention of hypospadias. In vitro experiments demonstrated that Urine-Exos enhanced the proliferation and migration of UECs by transferring SDC1 and inhibiting cell apoptosis. Notably, Urine-Exos upregulated β-catenin expression through SDC1 transfer, further promoting UEC proliferation and migration. These findings were confirmed in a congenital hypospadias rat model induced by di(2-ethylhexyl) phthalate (DEHP). ConclusionThis study reveals the therapeutic potential of Urine-Exos in hypospadias, mediated by the SDC1/β-catenin axis. Urine-Exos promote UEC proliferation and migration, thereby inhibiting the progression of hypospadias. These findings offer new insights and potential therapeutic targets for the management of congenital malformations.

Management of Hypospadias in Identical Twins at Mali Gavardo Hospital

This is a prospective study of two cases of hypospadias in identical twins with the same location and the same symptomatology at Mali Gavardo Hospital. Hypospadias corresponds to hypoplasia of the tissues forming the ventral surface of the penis responsible for an ectopic abruption of the urethra. Its aetiology is multifactorial, the surgical management is adapted according to the anatomical location.the Mathieu urethroplasty technique was used in both patients, urine drainage was performed with 8fr silicone catheter for 5 days. Post-operative follow-up was marked by a skin fistula in one case on the fourth day with spontaneous closure on day 8. Material Methodology: This was a prospective study of two cases of hypospadias in identical twins at the Mali Gavardo Hospital. The following parameters were studied: age, reasons for consultation, physical examination, complementary examinations, surgical treatment and post-operative follow-up. Conclusion: Hypospadias is a congenital malformation in males, the frequency of which is increasing throughout the world, and should be treated from an early age. In our context, the presence of the same anatomical form and the same location in both twins is still very rare in the literature, hence the need to share our experience with others. The Mathieu technique remains the reference technique for the management of hypospadias.

Expanding the phenotypic spectrum of ARCN1-related syndrome

PurposeThis study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. MethodsPatients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. ResultsIn total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported. ConclusionARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype–phenotype correlations are required.

Profile of hypospadias patients at Dr. Moewardi General Hospital Surakarta period 2015-2020

Background: Hypospadias is the second most common congenital malformation in males and the most common congenital malformation of the penis. This malformation is characterized by the anatomical position of the urinary tract opening on the ventral or anterior part of the penis. The prevalence of hypospadias in western countries around 8 of 1000 live births and is reported to increase every year.Methods: This study is a descriptive study with a retrospective cross-sectional approach. All data were retrieved from RSUD Dr. Moewardi Surakarta using hypospadias patients medical records from January 2015 – December 2020. The hypospadias case were classified into mild, moderate, and severe hypospadia based on location. The age of being diagnosed, concomitant congenital disease, surgery technique, and surgical complication were described.Results: There were 120 cases of hypospadias, consisted of 47.5% severe hypospadias, 34.9% moderate hypospadias and 17.4% mild hypospadias. Patients’ age of being diagnosed was most in the 1-5 years group (35.9%). Seventy-eight (75.7%) cases without concomitant congenital disease, 10.7% with undecensus testiculorum, 4.8% with cyanotic congenital disease, and 3.8% with cloacal. There were 68.9% cases repaired with first-stage surgical technique and 31.1% repaired with two-stage surgical technique. Most surgical complications were meatal stenosis 9%.Conclusions: Majority of hypospadias cases were severe hypospadia. Other profile like age of being diagnosed, concomitant congenital disease, surgery technique, and surgical complication were found in this study.

Expression of Mafb is down-regulated in the foreskin of children with hypospadias

Hypospadias is the second most common congenital malformation in males. Although the aetiology of hypospadias is not clear, it is generally thought to be affected by both genetic and environmental endocrine-disrupting factors that affect the development of the urethra, leading to deformity. To investigate the difference in expression of the transcription factor Mafb in hypospadias and normal penile tissues and to assess whether it is related to the occurrence of hypospadias. Penile tissue was obtained from children with hypospadias who underwent surgical repair at the Children's Hospital of Chongqing Medical University. Patients diagnosed with undescended testicles, intersex status or endocrine abnormalities were excluded from the study. Twenty-five cases with hypospadias (average 3.5 years old) and 15 cases with circumcisions (as control) (average 5 years old) were included in this study. Real-time quantitative polymerase chain reaction, Immunochemistry and Western blot were used to detect the expression of Mafb. Mafb mRNA expressions in the prepuce of cases with hypospadias was significantly reduced compared with that in the controls [(1.179±0.1275), (0.6652±0.07506), p<0.05)]. Hypospadias cases also showed decreased Mafb protein expression in the preputial subcutaneous mesenchymal cell layer. Mafb protein levels were significantly decreased in those with hypospadias compared with controls [(1.932±0.1139), (1.006±0.03312), p<0.05]. However, no such differences were found in Mafb expression between subjects with mild and severe hypospadias. Compared to the normal foreskin, expression of the Mafb gene was down-regulated at both mRNA and protein levels, which was consistent with our RNA-seq sequencing results in Diethylhexyl phthalate (DEHP)-induced hypospadias rats. This study is the first to report abnormal expression of Mafb in the preputial tissue of hypospadias cases. An in-depth study of the relationship between Mafb and cell proliferation, apoptosis, and urethra development may reveal the pathogenesis of hypospadias. Expression of the Mafb gene and protein in the foreskin of children with hypospadias is lower than that in normal foreskin. We postulate that such abnormal expression of the Mafb gene may be related to the occurrence of hypospadias and that this abnormal expression may affect the development of the urethra during the embryonic period.

High and intermediate anorectal malformation in males with perineal fistula: Beware of urethral involvement

Anorectal malformation (ARM) with recto-perineal fistula is considered low-type anomaly and standard management of perineal anoplasty without colostomy is recommended. Unusual variants are scarcely reported and present unique challenges in management. We present two cases of ARM with unusual fistula managed in our hospital. Case 1 A term baby boy status-post colostomy creation at birth in an overseas hospital for ARM presented to us at 4 months of age for definitive surgery. Distal loopogram demonstrated a very fine recto-penile fistulous opening at the peno-scrotal area hence perineal anorectoplasty was planned. Intra-operatively, the bulbar urethra was laid open for complete fistula tract excision due to a 3cm shared common wall between fistula tract and urethra. A double-layered urethral repair was performed and a neoanus created after mobilisation of a high rectal pouch. The baby recovered well post-operatively after 3 weeks of urethral stenting and is currently awaiting stoma closure. Case 2 A term male newborn was noted to have ARM with a recto-scrotal fistula. After initial stabilisation and workup, he was scheduled for perineal anoplasty on day 2 of life. Intra-operatively, we noted a fine, long cutaneous track running in the scrotal raphe close to the bulbar urethra. The bulbar urethra was inadvertently entered during fistula tract excision and needed repair. The rectal pouch located above the levator muscle was mobilised and anorectoplasty was performed. The baby was managed post-operatively with gut rest and total parenteral nutrition, and recovered well. Rare-variant ARM with recto-penile/recto-scrotal fistulae can be associated with high or intermediate type anomalies in contrary to classical recto-perineal fistula. Management of these cases should be planned carefully, with possible need for urethral repair during anorectoplasty.

Evidence for sex differences in morphological abnormalities in type I Chiari malformation.

Relatively little is known about the influence of individual difference variables on the presentation of macro-level brain morphology in type I Chiari malformation (CMI). The goal of the present study is to examine how case-control differences in Chiari are affected by patient sex. Patient-provided magnetic resonance images were acquired through the Chiari 1000 database. Twenty-four morphometric measurements were taken using mid-sagittal images of 104 participants (26 male CMI, 26 female CMI, 26 male controls, and 26 female controls) using internally developed and validated custom software, Morphpro. Case-control comparisons were conducted separately by sex using healthy controls matched by age and body mass index. Probability-based t-tests, effect sizes (Cohen's d), and confidence intervals were used to compare case-control differences separately by sex. Male and female case-control comparisons yielded largely the same trends of CMI-related morphometric abnormalities. Both groups yielded reductions in posterior cranial fossa (PCF) structure heights. However, there was evidence for greater PCF structure height reductions in male CMI patients as measured by Cohen's d. Case-control differences indicated strong consistency in the morphometric abnormalities of CMI malformation in males and females. However, despite the higher prevalence rates of CMI in females, the results from the present study suggest that male morphometric abnormalities may be greater in magnitude. These findings also provide insight into the inconsistent findings from previous morphometric studies of CMI and emphasize the importance of controlling for individual differences when conducting case-control comparisons in CMI.

Paracetamol during pregnancy: how safe is it?

Acetaminophen (paracetamol) is the most commonly used analgesic and antipyretic during pregnancy. Research suggests that acetaminophen use in pregnancy is associated with abnormal fetal neurodevelopment (an increased risk for neurodevelopmental impairment − ADHD, autism and hyperactivity symptoms). Paracetamol causes language delay (less than 50 words at 30 months of age). Other recent studies describe the association of urogenital male malformations after prenatal paracetamol exposure.

Steroid 5-alpha-reductase type 2 (SRD5A2) gene V89L polymorphism and hypospadias risk: A meta-analysis

Hypospadias is a common congenital malformation in males, in which the urethral orifice is found on the ventral side of the penis as a result of incomplete fusion of urethral folds. The etiology of hypospadias is poorly understood, and may be multifactorial, including genetic, endocrine and environmental factors. The steroid 5-alpha-reductase type 2 (SRD5A2) gene, which is mainly expressed in the ventral side of the urethra in the process of male genital development, plays an important role in urethral shaping. To investigate, with database searches of related published papers, whether SRD5A2 gene V89L polymorphism has an association with hypospadias risk. The following databases were searched for relevant papers, and all published case-control studies of hypospadias were used to perform a meta-analysis: PubMed, Embase, Springer Link, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu. A quality assessment was performed using the Newcastle-Ottawa scale of a case-control study. To assess the strength of the association under various genetic models, odds ratio (OR) and its 95% confidence interval (CI) were calculated using fixed-effect or random-effects model according to the heterogeneity. Overall and stratified subgroup analyses, including ethnicity, source of controls, sample for DNA extraction, and hypospadias classification, were performed. All data were analyzed using Review Manager 5.3. This analysis included six eligible case-control studies with 1130 cases and 1279 controls. Overall, there was a statistically significant association between hypospadias risk and V89L polymorphism for allele contrast (C vs G: OR 1.91, 95% CI 1.13-3.23), P=0.02), codominant model (CC vs GG: OR 2.97, 95% CI 1.25-7.04, P=0.01; GC vs GG: OR 2.36, 95% CI 1.35-4.13, P=0.003), dominant model (GC+CC vs GG: OR 2.46, 95% CI 1.28-4.72, P=0.007), and recessive model (CC vs GC+GG: OR 1.91, 95% CI 1.00-3.66, P=0.05). Moreover, there was also a statistically significant association in some subgroups. The positive results are shown in the Summary Table. This meta-analysis suggested that the V89L polymorphism definitely increases the risk of hypospadias, and the C allele is a genetic risk factor for hypospadias occurrence.

Anorectal Malformations in Males: Pros and Cons of Neonatal versus Staged Reconstruction for High and Intermediate Varieties.

Background:High and intermediate types of anorectal malformations (ARMs) in male neonates may be managed either by primary neonatal reconstruction without colostomy cover or by traditional policy of staged reconstruction after neonatal colostomy. Posterior sagittal anorectoplasty (PSARP) is the current widely practiced reconstructive technique with varied results.Aim:To assess our functional results of PSARP without colostomy in male neonates with high and intermediate ARMs compared to 3-stage (neonatal colostomy – PSARP – colostomy closure) methodology in a high volume tertiary care institution of a developing country.Patients and Methods:The number of colostomies performed for male high/intermediate anomalies and the number of babies who completed 3-stage reconstruction during a 10-year period is analyzed. The outcome of primary neonatal PSARPs during the same period was analyzed. Eighty primary PSARPs were compared to 81 staged reconstructions for outcome analysis, using Kelly score.Results:A total of 453 colostomies were performed, but only 253 of them completed all stages of reconstruction (52%). Good continence was achieved in 45% of cases of primary PSARP versus 26% in 3-staged surgery.Conclusions:Primary PSARP in neonatal period without colostomy is a good option for high and intermediate ARMs in males if the treating surgeon is reasonably skilled in neonatal surgery and PSARP procedures.

Incidence and distribution of congenital malformations in newborns: a hospital based study

Background: It is considered that the congenital disorders are not a public health problem among the developing countries, however, over the recent years, they are actually experiencing a transition in the epidemiology like significant reduction in infant mortality rates, decline in infections and malnutrition and also a relative rise in morbidity as well as mortality due to the congenital malformations. Present study describes the incidence and distribution of congenital malformations in newborns during the study period at Government Medical College and Hospital, Aurangabad, Maharashtra, India. Methods: This study was a hospital based cross sectional study. Seven thousand and twelve (7012) babies born over a period extending from 1 st March 1994 to 31 st April 1995 at Government Medical College and Hospital, Aurangabad, Maharashtra were studied for congenital malformations diagnosed clinically within 3 days of life. Both major and minor malformations were recorded. Minor variations such as capillary haemangioma, mongolian spots, superficial sacral dimples, small umbilical hernias, saddle nose, mild bowing of tibia and hydrocele of the testis were not considered as malformation. Results: Out of 7012 subjects, 66 newborns (0.94%) were found to be affected with congenital malformations. There was no statistically significant difference between the incidence of congenital malformations in males and females with a male: female ratio of 0.97:1. Central nervous system malformations were the most common and found in 51.66% cases. There was statistically significant higher rate of congenital malformations among stillborn babies (8.54%) as compared to live born babies (0.62%) with a p value less than 0.05. Out of 66 newborns with congenital malformations, 19 newborns had other birth defects apart from the congenital malformation. Conclusions: Congenital malformations were noted in 0.94% of the newborns at the tertiary care hospital and central nervous system malformations were the most common.

Questions and dilemmas in the management of hypospadias

Hypospadias is the second most common congenital malformation in males. Etiology remains unknown in about 70% of the cases. Distal hypospadias is considered not only developmental abnormality of the urethra in males, but it may also constitute a mild form of sexual development disorder in 46,XY males. Most urologists and endocrinologists consider that it is necessary to perform a detailed investigation of children presenting with proximal hypospadias associated with a small phallus or poorly developed scrotum and undescended testes. Currently, there is no generally accepted recommendation for the preoperative evaluation of hypospadias and, therefore, masculinizing surgery without preoperative evaluation is performed in these children. The authors summarize the international literature data and their own experience for the assessment and management of hypospadias concerning questions and problems related to preoperative investigation, masculinizing surgery and additional surgery. A detailed algorithm is presented for preoperative evaluation of both proximal and distal hypospadias.

Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability.

Many factors affect the risks for neurodevelopmental maladies such as autism spectrum disorders (ASD) and intellectual disability (ID). To compare environmental, phenotypic, socioeconomic and state-policy factors in a unified geospatial framework, we analyzed the spatial incidence patterns of ASD and ID using an insurance claims dataset covering nearly one third of the US population. Following epidemiologic evidence, we used the rate of congenital malformations of the reproductive system as a surrogate for environmental exposure of parents to unmeasured developmental risk factors, including toxins. Adjusted for gender, ethnic, socioeconomic, and geopolitical factors, the ASD incidence rates were strongly linked to population-normalized rates of congenital malformations of the reproductive system in males (an increase in ASD incidence by 283% for every percent increase in incidence of malformations, 95% CI: [91%, 576%], p<6×10−5). Such congenital malformations were barely significant for ID (94% increase, 95% CI: [1%, 250%], p = 0.0384). Other congenital malformations in males (excluding those affecting the reproductive system) appeared to significantly affect both phenotypes: 31.8% ASD rate increase (CI: [12%, 52%], p<6×10−5), and 43% ID rate increase (CI: [23%, 67%], p<6×10−5). Furthermore, the state-mandated rigor of diagnosis of ASD by a pediatrician or clinician for consideration in the special education system was predictive of a considerable decrease in ASD and ID incidence rates (98.6%, CI: [28%, 99.99%], p = 0.02475 and 99% CI: [68%, 99.99%], p = 0.00637 respectively). Thus, the observed spatial variability of both ID and ASD rates is associated with environmental and state-level regulatory factors; the magnitude of influence of compound environmental predictors was approximately three times greater than that of state-level incentives. The estimated county-level random effects exhibited marked spatial clustering, strongly indicating existence of as yet unidentified localized factors driving apparent disease incidence. Finally, we found that the rates of ASD and ID at the county level were weakly but significantly correlated (Pearson product-moment correlation 0.0589, p = 0.00101), while for females the correlation was much stronger (0.197, p<2.26×10−16).

Phenotypic and molecular characterization of 19q12q13.1 deletions: A report of five patients

A syndrome associated with 19q13.11 microdeletions has been proposed based on seven previous cases that displayed developmental delay, intellectual disability, speech disturbances, pre- and post-natal growth retardation, microcephaly, ectodermal dysplasia, and genital malformations in males. A 324-kb critical region was previously identified as the smallest region of overlap (SRO) for this syndrome. To further characterize this microdeletion syndrome, we present five patients with deletions within 19q12q13.12 identified using a whole-genome oligonucleotide microarray. Patients 1 and 2 possess deletions overlapping the SRO, and Patients 3-5 have deletions proximal to the SRO. Patients 1 and 2 share significant phenotypic overlap with previously reported cases, providing further definition of the 19q13.11 microdeletion syndrome phenotype, including the first presentation of ectrodactyly in the syndrome. Patients 3-5, whose features include developmental delay, growth retardation, and feeding problems, support the presence of dosage-sensitive genes outside the SRO that may contribute to the abnormal phenotypes observed in this syndrome. Multiple genotype-phenotype correlations outside the SRO are explored, including further validation of the deletion of WTIP as a candidate for male hypospadias observed in this syndrome. We postulate that unique patient-specific deletions within 19q12q13.1 may explain the phenotypic variability observed in this emerging contiguous gene deletion syndrome.

19q13.11 cryptic deletion: description of two new cases and indication for a role of WTIP haploinsufficiency in hypospadias

Developmental delay/intellectual disabilities, speech disturbance, pre- and postnatal growth retardation, microcephaly, signs of ectodermal dysplasia, and genital malformations in males (hypospadias) represent the phenotypic core of the recent emerging 19q13.11 deletion syndrome. Using array-CGH for genome-wide screening we detected an interstitial deletion of chromosome band 19q13.11 in two patients exhibiting the recognizable pattern of malformations as described in other instances of this submicroscopic genomic imbalance. The deletion detected in our patients has been compared with previously reported cases leading to the refinement of the minimal overlapping region (MOR) for this microdeletion syndrome to 324 kb. This region encompasses five genes: four zinc finger (ZNF) genes belonging to the KRAB-ZNF subfamily (ZNF302, ZNF181, ZNF599, and ZNF30) and LOC400685. On the basis of our male patient 1 and on further six male cases of the literature, we also highlighted that larger 19q13.11 deletions including the Wilms tumor interacting protein (WTIP) gene, proximal to the MOR, results in hypospadias making this gene a possible candidate for this genital abnormality due to its well-known interaction with WT1. Although the mechanism underlying the phenotypic effects of copy number alterations involving KRAB-ZNF genes at 19q13.11 has not clearly been established, we suggest their haploinsufficiency as the most likely candidate for the phenotypic core of the 19q13.11 deletion syndrome. In addition, we hypothesized WTIP gene haploinsufficiency as responsible for hypospadias.

Myelodysplastic syndrome in a child with 15q24 deletion syndrome

15q24 deletion syndrome is a recently-described chromosomal disorder, characterized by developmental delay, growth deficiency, distinct facial features, digital abnormalities, loose connective tissue, and genital malformations in males. To date, 19 patients have been reported. We report on a 13-year-old boy with this syndrome manifesting childhood myelodysplastic syndrome (MDS). He had characteristic facial features, hypospadias, and mild developmental delay. He showed neutropenia and thrombocytopenia for several years. At age 13 years, bone marrow examination was performed, which showed a sign suggestive of childhood MDS: mild dysplasia in the myeloid, erythroid, and megakaryocytic cell lineages. Array comparative genomic hybridization (array CGH) revealed a de novo 3.4 Mb 15q24.1q24.3 deletion. Although MDS has not been described in patients with the syndrome, a boy was reported to have acute lymphoblastic leukemia (ALL). The development of MDS and hematological malignancy in the syndrome might be caused by the haploinsufficiency of deleted 15q24 segment either alone or in combination with other genetic abnormalities in hematopoietic cells. Further hematological investigation is recommended to be beneficial if physical and hematological examination results are suggestive of hematopoietic disturbance in patients with the syndrome.

Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy: a multigenerational national cohort study

Prenatal diethylstilbestrol (DES)-exposed mice have raised the suspicion of a transgenerational effect in the occurrence of genital malformation in males. This nationwide cohort study in collaboration with a French association of DES-exposed women studied 529 families and showed that a significant proportion of boys born to DES daughters exhibited hypospadias with no other molecular defects identified.

McKusick‐Kaufman syndrome: The difficulty of establishing a prenatal diagnosis of an uncommon disorder

Prenatal evaluation of abdominal cystic masses can be complex and challenging. We report the case of a fetus with a large cystic abdominal mass and discuss how the differential diagnosis was narrowed to include McKusick-Kaufman syndrome (MKS). MKS is characterized by the triad of postaxial polydactyly, congenital heart disease, hydrometrocolpos, and genital malformations in males. Rare conditions such as MKS are difficult to diagnose prenatally and require postnatal phenotyping and molecular studies before a definitive diagnosis can be established.

Imposex level and penis malformation in Hexaplex trunculus from the Tunisian coast

Hexaplex trunculus (Linnaeus, 1758) is a gonochoric marine gastropod. Previous studies demonstrated that the biocide TBT (tributyltin) induced a sexual abnormality known as imposex (superimposition of male sexual characters onto females) in this whelk. Our study showed imposex in 19 stations out of 20 along the Tunisian coast. The frequency of imposex ranged from 0 to 100%. Among the 19 sites where the condition was found, 8 were considered as highly affected by imposex (VDSI > 3.7), 6 were moderately affected (VDSI > 1.3), and 4 were slightly affected (VDSI > 0). The most affected population was observed in the Bizerta Channel where the highest boating traffic was recorded; no imposex features were found in the Sea of Zarat where boating traffic was very low. Significant differences in imposex levels were obtained among sites with low, moderate, and high boating traffic. All the imposex indices values (I%, RPSI, RPLI, VDSI, FPL, and VDL) were significantly more elevated at sites with high boating traffic compared with sites with low and moderate boating traffic. Malformations of the penis were observed only in five stations and in very low rates, but where imposex rates were high. The incidence of penis malformation in males was significantly related to the boating traffic, I%, and VDSI. However, in females, a correlation was obtained only for the RPLI. The present study provides data on imposex level and penis malformations in H. trunculus from the Tunisian Coast that could be used as a starting point for future monitoring programs and for temporal trend surveillance related to TBT pollution in Tunisia where the use of TBT is not yet banned.

Chromosome deletions in 13q33–34: Report of four patients and review of the literature

Deletions of chromosome bands 13q33-34 are rare. Patients with such deletions have mental retardation, microcephaly, and distinct facial features. Male patients frequently also have genital malformations. We report on four patients with three overlapping deletions of 13q33-34 that have been characterized by tiling-path array-CGH. Patient 1 had mental retardation and microcephaly with an interstitial 4.7 Mb deletion and a translocation t(12;13)(q13.3;q32.3). His mother (Patient 2), who also had mental retardation and microcephaly, carried the identical chromosome aberration. Patient 3 was a girl with a de novo insertion ins(7;13)(p15.1;q22q31) and interstitial 4.5 Mb deletion in 13q33-34. She had mental retardation and microcephaly. Patient 4 was a newborn boy with severe genital malformation (penoscrotal transposition and hypospadias) and microcephaly. He had a de novo ring chromosome 13 lacking the terminal 9.3 Mb of 13q. Karyotype-phenotype comparisons of these and eight previously published del13q33-34 patients suggest EFNB2 as a candidate gene for genital malformations in males. Molecular cytogenetic definition of a common deleted region in all patients suggests ARHGEF7 as a candidate gene for mental retardation and microcephaly.