Unilateral Cryptorchidism Research Articles

Proteomic profiles of unilateral cryptorchidism in pigs at different ages using MALDI-TOF mass spectrometry and in-gel digestion coupled with mass spectrometry (GeLC-MS/MS) approaches

BackgroundCryptorchidism is a condition that occurs when one or both testes fail to descend into the scrotum. It is a common congenital disorder, causing economic loss in pig production. However, there have been only limited studies of differential protein expression profiles in undescended testes (UDTs) in the abdomen and descended testes (DTs) in cryptorchid pigs, especially at the peptidome and proteome levels. The present study aimed to analyze the peptidome of UDTs and DTs in unilateral cryptorchid pigs aged 1–2, 6, 15 and 20 weeks and in normal testes of healthy pigs aged 1–2 and 12 weeks, using peptide mass fingerprinting and three-dimensional principal component analysis (3D-PCA) with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and to identify potential protein candidates, using in-gel digestion coupled with mass spectrometry (GeLC-MS/MS). Western blot analysis was used to verify protein expression. Protein sequence was affirmed by liquid chromatography–tandem mass spectrometry.ResultsA PCA plot showed a discrete cluster for each sample group. Peptide mass fingerprints (PMFs) demonstrated unique peptide fragments in UDTs at different ages. A number of markedly expressed proteins from GeLC-MS/MS were identified, including the multifunctional tumor necrosis factor receptor superfamily member 18 (TNFRSF18), in DTs at 1–2 and 6 weeks and in UDTs at 15 and 20 weeks of age. Using western blot analysis, high expression of TNFRSF18 was observed in the UDTs at 15 weeks. Using the STITCH database, this protein was found to be related to apoptosis, corresponding to the previous report in the UDTs at the same age.ConclusionsThe present study revealed the specific PMFs and clusters for porcine cryptorchidism, and a novel protein, TNFRSF18, associated with the disease mechanism. These results could provide further insights into the pathogenesis of the disease.

Primary Testicular Failure with Unilateral Cryptorchidism

Background: Primary Testicular Failure (PTF) in men with unilateral cryptorchidism is a rare case, which might be the first time reported. Case: A 34-year-old man came with infertility and azoospermia. Signs of secondary sex found. FSH levels: 60.68 mIU / ml, LH levels: 15.96 mIU / ml, T levels: 336.14 ng / dl, E2 levels: 27.81 ng / dl. Ultrasound showed the left testis in the left inguinal +/- 2,4x1,1x3,6 cm in size, with decrease vascularization; +/- 4.1 cm from the base of the penis. The right testis size +/- 2,8x1,1x2,2 cm in the right scrotum accompanied by spermatocele. The patient was referred to the Urology department for orchidopexy of the left testis in the inguinal. Discussion: Primary testicular failure, in this case, may occur due to idiopathic but does not rule out the mosaic type of Klinefelter syndrome. The patient has unilateral cryptorchidism for 20 years, there will be a risk of testicular cancer. Management of cryptorchidism must be performed orchidopexy the first year after birth. After orchidopexy, monitoring is needed every year until at least 5 years. Conclusion: PTF occurs when the parenchymal tissue contained in the testes is no longer able to produce sperm or testosterone. PTF diagnosis is only possible through pathology and testicular cytology, but the combination of FSH and Inhibin B examination remains the best recommendation as a biomarker for patients with PTF.

The incidence of epididymal anomalies in the bilateral and unilateral cryptorchidism cases: A comparative study

Our study was planned based on the hypothesis that epididymal anomalies may be more incidental and more severe in cases with bilateral undescended testicles compared to unilateral undescended cases. We also aimed to review the classifications of epididymal anomalies in the literature and to establish a simpler and clinically applicable classification in the present study. In this study, we retrospectively reviewed 197 pediatric patients who had been operated for undescended testis between January 2014 and January 2018. In the collective analysis of bilateral undescended testes cases, if the present anomaly were present in any testis, the anomaly was considered to be present for these cases and subjected to statistical analysis. The study included a total of 241 testicles of 197 patients. The incidence of epididymal anomalies was found to be significantly higher in cases with bilateral undescended testicles compared to unilateral cases (68.2%, 43.1%, respectively; p=0.003). It was observed that the incidence of epididymal anomaly and the severity of the anomaly statistically significantly decreased as the localization of the undescended testicle changed between the intraabdominal position and the external inguinal ring (p=0.0001). The effects of the undescended testicles on fertilization have been subject to evaluation in a limited number of studies and it has been reported that the rate of fertility is lower in patients with bilateral undescended testicles, whereas the fertility rate is close to that of healthy males in patients with unilateral undescended testicles. The incidence of epididymal anomalies was found to be higher in cases with bilateral undescended testicle, as shown in our study. However, based on these data, it is not possible to make a comment about whether this condition leads to infertility or not. Furthermore, accurate documentation of epididymal anomalies and standardization of the classifications of epididymal anomalies may be guiding in the prevention of complications for the surgeons in the treatment of patients who will undergo orchiopexy. We concluded that the incidence of epididymal anomalies was significantly higher in cases with bilateral undescended testicles compared to unilateral cases. In our study, based on a comprehensive high-quality surgical image archive, we believe that the differentiation of epididymal anomalies according to the classification we have proposed will make it possible to create a database that is easier to use clinically in a more objective way.

Analysis of transcript and methylation levels of INSL3 and RXFP2 in undescended and descended dog testes suggested promising biomarkers associated with cryptorchidism

Cryptorchidism is the most common disorder of sex development (DSD) in dogs. This malformation is associated with reduced fertility and with a higher risk of gonadal cancer. Testicular descent is a complex process, and the functions of many environmental and genetic factors are crucial for the proper migration of fetal gonads into the scrotum. Among these, the hormone INSL3 (insulin-like peptide 3) and its receptor RXFP2 (relaxin family peptide receptor 2) play crucial roles in the transabdominal migration of the testes. The genetic background of canine cryptorchidism is poorly elucidated. The aim of this study was to compare the transcript and methylation levels of INSL3 and RXFP2 genes in undescended and descended testes of isolated unilateral cryptorchids, and in gonads of control male dogs with scrotal testes. Next, we searched for polymorphic variants in the 5′-regulatory regions of both genes associated with predispositions to cryptorchidism. The INSL3 transcript level was significantly higher in the undescended testes than in the descended testes of both the affected and control dogs. On the other hand, the mRNA level of RXFP2 was significantly lower in the retained gonads of cryptorchids than in the scrotal testes. The methylation level of a single CpG site located 15 bp upstream of the translation start codon in INSL3 was significantly higher in the testes of the control dogs than in both gonads of cryptorchids. The methylation level of 14 CpG sites in the coding region of INSL3 was significantly higher in undescended testes than in the scrotal testes, which may be associated with the higher mRNA levels of INSL3 observed in these samples. The methylation pattern of two CpG sites in the 5′-flanking region of RXFP2 was similar in both descended and undescended testes. We detected three and seven single nucleotide polymorphisms (SNPs) in the 5′-regulatory regions of INSL3 and RXFP2, respectively. Among these, the frequency of A > C substitution (ss7093349755) located 495 bp upstream of the transcription start site of RXFP2 differed significantly between cryptorchids and control dogs. Our study showed two possible genetic biomarkers associated with canine cryptorchidism: a hypomethylation of a single CpG site in the 5′-flanking region of INSL3, and the ss7093349755 SNP in the 5′-flanking region of RXFP2.

Altered expression of CYP17A1 and CYP19A1 in undescended testes of dogs with unilateral cryptorchidism.

Cryptorchidism is the most common disorder of sex development in dogs and testosterone plays a crucial role in the inguinal phase of the testes descending into the scrotum. The molecular background of impaired testosterone synthesis in the testes of cryptorchid dogs is poorly elucidated. In this study, we analyzed the expression of four genes involved in testicular steroidogenesis (CYP17A1, CYP19A1, HSD3B2 and HSD17B3) in undescended and contralateral scrotal testes from inguinal unilateral cryptorchid dogs (n=13) and from the scrotal gonads of normal males (n=15). We found that transcript level of CYP17A1 was significantly increased in inguinal gonads, while the level of CYP19A1 was decreased. For these two genes, we analyzed the methylation level of single CpG sites in the promoter region localized within putative target sites for testicular transcription factors (NUR77, CREB, CAR and HSF2). A correlation between decreased methylation in the promoter of CYP17A1 and its increased transcript level in undescended gonads was observed, but the change in protein level was not significant. We also resequenced the 5'-flanking region of both genes and two known polymorphic sites, SNP in CYP17A1 and an indel in CYP19A1, were found. However, the distribution of the variants in affected (n=80) and control (n=75) dogs was not associated with cryptorchidism. We tentatively conclude that the altered expression of CYP17A1 and CYP19A1 in undescended testes could be caused by their exposure to increased temperature in the body. Furthermore, we showed that the identified polymorphisms cannot be considered markers associated with a predisposition to cryptorchidism.

Testicular volume in non-obstructive azoospermia with a history of bilateral cryptorchidism may predict successful sperm retrieval by testicular sperm extraction.

PurposeCryptorchidism is one of the most common causes of non‐obstructive azoospermia (NOA) in adulthood. Even if early orchidopexy is performed to preserve fertility potential, some patients still suffer from azoospermia. Fertility potential is significantly lower in bilateral than unilateral cryptorchidism. The aims of this study were to identify clinical parameters that predict the likely success of sperm recovery by microscopic testicular sperm extraction (micro‐TESE) and also the likely outcome of intracytoplasmic sperm injection using sperm from NOA patients who submitted to bilateral orchidopexy.MethodsFifty‐two NOA patients with a history of bilateral cryptorchidism underwent micro‐TESE. The following clinical parameters were evaluated as predictive factors for successful sperm recovery: age at micro‐TESE; age at orchidopexy; period from orchidopexy to micro‐TESE; luteinizing hormone (LH); follicle‐stimulating hormone (FSH); testosterone; average testicular volume; and body mass index.ResultsIn the successful sperm retrieval group, average testicular volume was significantly greater, while serum LH and FSH, and body mass index were significantly lower. In a multivariate analysis, average testicular volume was positively correlated with successful sperm recovery.ConclusionOur results indicate that testicular volume in NOA patients with bilateral cryptorchidism is a predictor for successful sperm recovery.

Renal dysplasia, ectopic ureter, septic ureterectasia and cryptorchidism in an 11‐month‐old Cob colt presenting with ascending pyoureter and pyocystis

SummaryAn 11‐month‐old entire male Cob colt was presented for unilateral cryptorchid castration and intermittent purulent urethral discharge. Cystoscopy, trans‐cutaneous and trans‐rectal abdominal ultrasonography and contrast enhanced computed tomography examinations confirmed unilateral cryptorchidism, ipsilateral renal dysplasia and pyoureter with dilatation and ectopia. While nephrectomy may be a viable treatment approach for some cases of unilateral renal dysplasia, surgical intervention was not attempted in this case owing to financial constraints and the yearling was subjected to euthanasia. To the authors’ knowledge, this is the first report of a case of complex congenital urogenital malformation including ipsilateral renal dysplasia, pyoureter with dilatation and ectopia and cryptorchidism, a finding which has been reported more commonly in human males.

Does Excision of Mullerian Structures Jeopardize Testicular Growth and Function in Persistent Mullerian Duct Syndrome (PMDS): a Single Center Experience

Persistent Mullerian duct syndrome (PMDS) is a rare form of Disorders of Sexual Development (DSD) characterized by persistence of mullerian structures in a phenotypically and genotypically normal male. The most frequent clinical presentation is that of unilateral or bilateral cryptorchidism. Contrasting opinions exist among clinicians regarding the most suitable surgical intervention in this condition and the potential of fertility later. This study revisits PMDS in terms of varied modes of presentation and the optimum surgical approach to such patients. It, thus, attempts to throw light on the pattern of testicular growth and function within a reasonable follow-up time post-removal of mullerian structures and orchidopexy. The study was conducted in a tertiary health care center in North India. It was a retrospective study carried out by retrieving details of ten patients who had undergone treatment over a span of 9 years (January 2010 to January 2019). The clinical features, family history, surgery undertaken, and follow-up are hereby highlighted along with review of literature. Cryptorchidism was the most common presentation. Orchidopexy with excision of mullerian structures could be done in all except one. Testicular position, volume and vascularity, penile growth, and erection were assessed during subsequent visits at 3, 6, 12, and 24 months. All testes were descended with preserved and normal vascularity. Volumes were in normal range and all experienced good erection. Inference regarding fertility was not possible until conclusion of the study due to ongoing follow-up. Cryptorchidism is the most common presenting feature of PMDS. Familial involvement should be kept in mind. Orchidopexy should be the target surgery. Mullerian structures should be removed ensuring testicular viability. This, when performed carefully, ensures normal testicular maturation. However, long follow-ups will be required for conclusive evidence on fertility.

Evaluation of Human Chorionic Gonadotropin (HCG) Therapeutic Results in Patients With Unilateral cryptorchidism (Undescended Testis)

Background: Cryptorchidism or undescended testis is an evolutionary defect where one or both testes fail to descend into the scrotum. HCG causes the testes to fail, possibly due to weight gain, an increase in testicular vasculature, and stimulating the testosterone and di-hydro-testosterone. The present study has been conducted to evaluate the therapeutic effects of HCG on patients with unilateral cryptorchidism. Methods: In a prospective descriptive study, 211 patients of 8 months to 7 years old with unilateral cryptorchidism whose parents refused surgery received HCG therapy. The patients were followed up 1 month, 3months, and 12 months after the first injection. They were examined in terms of the location of testes, possible relapses, sides of undescended testes, treatment complications, and HCG therapeutic results. Results: Four weeks after the first injection, 160 patients (75.12%) out of 211 cases had the descent of testes into the inguinal canal and the scrotum. 69.5% of non-palpable abdominal testes descended into the inguinal canal, 69.7% of patients with inguinal testes, 78% of patients with supra inguinal testes and 100% of patients with retractile testis experienced the descent of testes into the scrotum. Conclusion: The therapeutic response to HCG was successful in more than 50% of the cases in all the groups. Therefore, the need for performing surgical procedures on children with unilateral cryptorchidism would be decreased and they can be treated by a cost-effective and less invasive method. Moreover, at least one-year follow-up of the patients is required to ensure outcomes of the treatment.

Serum concentrations and testicular expressions of insulin-like peptide 3 and Anti-Müllerian hormone in normal and cryptorchid male horses

Insulin-like peptide 3 (INSL3) is an important hormone for testicular descent during embryonic development and a factor for assessing functional status of Leydig cells of testes, but there is limited number of equine studies. Anti-Müllerian hormone (AMH) is a useful diagnostic marker for cryptorchidism in horses. This study aimed to compare serum concentrations and testicular expression intensity of INSL3 and AMH in intact and cryptorchid male horses. Serum INSL3 concentrations in intact (n = 9; mean ± SEM, 19.9 ± 5.9 ng/mL) and noncastrated unilateral cryptorchid (UC) male horses (n = 16; mean ± SEM, 16.8 ± 4.1 ng/mL) were higher compared with hemicastrated unilateral cryptorchid (HCUC) male horses (n = 9; mean ± SEM, 3.8 ± 0.7 ng/mL) (P < 0.05). And serum INSL3 in bilateral cryptorchid (BC) male horses (n = 4; 1.9 ± 0.4; mean ± SEM, ng/mL) were lower compared with intact male horses (P < 0.05). Serum AMH concentrations in BC male horses (n = 3; mean ± SEM, 30.6 ± 4.8 ng/mL) were higher compared with intact male horses (n = 5; mean ± SEM, 12.2 ± 3.9 ng/mL) (P < 0.05). Immunostaining of scrotal and cryptorchid testis showed that Sertoli cells were positive for AMH, and Leydig cells were positive for INSL3. Staining intensity of AMH was higher in cryptorchid testis than in scrotal testis (P < 0.05). Furthermore, AMH expression intensity was higher in abdominal testis than in inguinal testis (P < 0.05). Immunostaining intensity of INSL3 in the testis was positively correlated with serum INSL3 (r, 0.7; P < 0.01), seminiferous tubule area (r, 0.727; P < 0.01), and Johnsen score for spermatogenesis (r, 0.604; P < 0.05), whereas immunostaining intensity of AMH in the testis was negatively correlated with seminiferous tubule area (r, −0.814; P < 0.01) and Johnsen score for spermatogenesis (r, −0.807; P < 0.01). Our findings suggested that AMH is a good biomarker for diagnosing cryptorchidism in male horses, in addition to INSL3 values to assess the testis of intact and cryptorchid male horses.

The relationship between vascular endothelial growth factor and spermatogenesis disturbance in an experimentally-induced unilateral cryptorchidism murine model

This study is to explore the relationship between vascular endothelial growth factor (VEGF) and pathological changes in cryptorchidism by using murine model of intraperitoneal cryptorchidism with surgical operation. To investigate the relationship between the changes of VEGF expression and heat stress inducing germ cell damage in testicular tissue. Six-week-old ICR male mice were operated to make unilateral cryptorchidism mouse model. Here in our study, a remarkable damaged of germ cells are seen in murine model of unilateral cryptorchidism. And the expression of VEGF was significantly changed in a time dependent way and consistent with the pathological changes of testis, this leading us to conclude that there was a negative correlation between VEGF levels and germ cell damage in unilateral cryptorchidism mouse model. We propose that there is a time dependent decrease of VEGF expression in cryptorchidism and confirm that VEGF is essential in spermatogenesis disorder caused by cryptorchidism and non-obstructive azoospermia.

New insights into the expression of androgen and estrogen receptors of the appendix testis in congenital cryptorchidism.

Background The appendix testis (AT) is the most common vestigial remnant of the human testis. Variations in the presence and expression of AT androgen receptor (AR) and estrogen receptor (ER) have been reported in cryptorchidism. We studied the possible association of AR and ER expression of the AT with cryptorchidism. Methods ATs were resected from 40 boys who underwent inguinoscrotal surgery, (20 patients with congenital unilateral cryptorchidism [UC] and 20 controls with orthotopic testes and hydrocele). AR and ER expression was evaluated with immunohistochemistry, and the percentage and intensity of AR and ER expression were evaluated by the Allred scoring method. AT length was compared between the two groups. Correlation of AR and ER expression was evaluated independently in patients and controls. Results The Allred score for AR trended toward lower values in UC compared to controls (p = 0.193), while ER scores presented statistically significant lower values in UC compared to controls (p = 0.017). No significant difference or trend was found in the expression of both receptors between high and low cryptorchidism (p = 0.981 for AR, p = 0.824 for ER) and for the appendiceal length between UC and controls (p = 0.369). Conclusions The findings of a trend for lower AR expression and a statistically significant lower expression of ER in UC may suggest an association of AR and ER with cryptorchidism and may provide an insight into the process of testicular descent.

Disorganization of claudin-11 and dysfunction of the blood-testis barrier during puberty in a cryptorchid rat model.

Cryptorchidism is known to impair spermatogenesis. The blood-testis barrier (BTB) becomes defined in seminiferous tubules around puberty and provides a suitable environment for germ cells. Little is known about the BTB in undescended testes (UDT). To determine the role of BTB during puberty in UDT using a non-surgical cryptorchid rat model. Unilateral cryptorchid male rats were intraperitoneally injected with non-steroidal antiandrogen during intrauterine development; the testes were harvested at 4, 5, and 6weeks after birth. Testicular histology, expression levels of the BTB proteins (claudin-11, occludin, zonula occludens-1), and apoptotic cells were evaluated by immunohistochemistry, Western blotting, and TUNEL assay. The functionality of the BTB was investigated by electron microscopy using the lanthanum tracer method. The testicular histology of undescended testes 6weeks after birth showed maturation arrest at the spermatocyte level. The BTB protein distributions were altered in the UDT, with a noticeable difference in claudin-11(CLDN11) localization from 4 to 5weeks after birth between control and UDT samples. BTB protein levels were similar. More apoptotic germ cells were detected in the adluminal compartment of tubules in the UDT than in the control testes. Electron microscopy showed that the lanthanum tracer was limited to the BTB of control testes, whereas it penetrated the BTB of UDT. Here, loss of normal BTB function and impaired spermatogenesis were observed in UDT during puberty. CLDN11 is a pivotal tight junction protein belonging to the BTB. Tight junctions are considered as essential for normal spermatogenesis, and abnormal CLDN11 organization may cause UDT-associated male infertility. CLDN11 disorganization within the BTB may cause spermatogenic impairment, possibly by limiting the BTB function.

Laparoscopic orchiopexy of palpable undescended testes_ experience of a single tertiary institution with over 773 cases

BackgroundDiscuss the superiority of laparoscopic orchiopexy in the treatment of inguinal palpable undescended testes.MethodsInclusion criteria: Preoperative examination and color Doppler ultrasound examination confirmed that the testes were located in the inguinal canal and could not be pulled into the scrotum, except for retractive and ectopic testes. The surgical steps were depicted as follow. The retroperitoneal wall was carved by ultrasonic scalpels, separates the spermatic vessels closed to the inferior pole of the kidney if necessary, dissects the peritoneum of vas deferens, cuts the testicular gubernaculum, and pulls back the testicle into the abdominal cavity. Besides, protect the vas deferens, and descend the testes to the scrotum and fix them without tension.ResultsThere were 773 patients with 869 inguinal undescended palpable testes, 218 cases on the left side, 459 cases on the right side and 96 cases with bilateral undescended testes, whose age ranged from 6 months to 8 years, with an average of 20 months. All testes were successfully operated, no converted to open surgery. The average operation time was (34.8 ± 5.4) min. There were 692 testes have an ipsilateral patent processus vaginalis (89.5%); In 677 cases of unilateral cryptorchidism, 233 cases (34.4%) have a contralateral patent processus vaginalis, and laparoscopic percutaneous extraperitoneal closure the hernia sac carry out during the surgery. There was no subcutaneous emphysema during the operation, no vomiting, no abdominal distension, no wound bleeding and obvious pain after surgery, especially wound infection is rarely. Doppler ultrasound was evaluated regularly after surgery. The patients were followed up for 6 to 18 months. All the testes were located in the scrotum without testicular retraction and atrophy. No inguinal hernia or hydrocele was found in follow-up examination.ConclusionLaparoscopic orchiopexy manage inguinal palpable cryptorchidism is safe and effective, and there are obvious minimally invasive advantages. Furthermore, It could discover a contralateral patent processus vaginalis, and treat at the same time, which avoid the occurrence of metachronous inguinal hernia.

Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations

BackgroundNoonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype–phenotype correlation.MethodsIndividuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced.ResultsThirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%).ConclusionThe clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.

'Testis-epididymis dissociation' in cryptorchidism and hydrocele: the tip of the iceberg of a persistent genital mesentery.

To investigate whether testis-epididymis dissociation encountered in boys with cryptorchidism/hydrocele is related with an abnormal persistence of the fetal mesentery of testis and associated ducts. We examined the morphology of peritoneal folds of the testis, epididymis, and vas deferens in 25 boys operated for unilateral cryptorchidism [inguinal (n = 20), intrabdominal (n = 5)] and 20 boys operated for unilateral communicating hydrocele. Findings were compared with the normally persisting genital mesentery of rats (n = 30, both sides), a known animal model of the genital mesentery of human fetuses, as well as with the normal mature pattern of genital peritoneal folds in adult male cadavers (n = 12, both sides). Rats before testis descent [aged 18days (n = 15)] served for comparison with boys with cryptorchidism, while rats after testis descent [aged 50 (n = 15)] known to retain patent processi vaginales for comparison with boys with hydrocele. A well-developed genital mesentery, identical to the fetal-type genital mesentery in the rat, was documented in cryptorchidism and hydrocele. The peritoneum enveloped the testis, epididymis, and vas deferens, and formed wide ligaments between testis-epididymis, epididymis-vas deferens, and vas-posterior wall; processus vaginalis was patent in all cases. The testis-epididymis ligament was related with testis-epididymis distancing, the so-called testis-epididymis dissociation. On the contrary, genital mesentery had involuted in the adult male cadavers, except for a small portion of testis-epididymis ligament corresponding to the so-called sinus epididymis. The testis-epididymis dissociation encountered in cryptorchidism/hydrocele is part of an anomalously persisting fetal-type genital mesentery.

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome

Background: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. Results: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. Conclusion: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

Plasma level of laminin 5 and collagen IV in cryptorchidism

PurposeLaminin 5 and collagen IV are the main compounds of the extracellular matrix of the germinal epithelium. The purpose of this study was to evaluate the concentration of these two markers of fibrosis in the plasma of boys with congenital unilateral cryptorchidism. Materials and methodsThe study group comprised 43 boys aged 1–3 years with congenital unilateral cryptorchidism. The control group included 54 healthy, age matched boys, admitted for planned hernioplasty. To assess laminin 5 and collagen IV in the plasma of boys with unilateral cryptorchidism, we used a new biosensor with Surface Plasmon Resonance Imaging technique detection. ResultsThe median concentration of laminin 5 and collagen IV in the serum of boys with congenital, unilateral cryptorchidism was higher than in boys with normal scrotal testis. The difference was statistically significant (p < 0.0001). We did not notice a correlation between a higher position of the testicles in the inguinal and/or their condition and levels of laminin 5 and collagen IV in the plasma. ConclusionLaminin 5 and collagen IV concentrations in the plasma were higher in patients with congenital unilateral cryptorchidism. We believe that in the future, our results could be compared with fertility level in adulthood.

The effects of tobacco consumption on paternity rates of adults with a history of cryptorchidism.

To determine the effect of tobacco consumption on paternity rates in men with a history of cryptorchidism. To compare the paternity rates between formerly unilateral, bilateral cryptorchid smokers, and nonsmokers. A retrospective cohort study of 153 men who had undergone orchiopexy between 1961 and 1985 at the Miguel Servet University Hospital (116 unilateral and 37 bilateral) and a control group of 100 men were evaluated by review of medical records and a questionnaire. A total of 197 men filled the questionnaire (76.7%). There was no difference in paternity rates between smokers compared to nonsmokers (P = 0.21). In the unilateral cryptorchid men (ULC) group, there is no difference in paternity rates when compared with the controls (P = 0.079) or when comparing ULC smokers to ULC nonsmokers (P = 0.35). In the bilateral cryptorchid men (BLC) group, there is no difference in paternity rates when compared to controls (P = 0.075) or when comparing BLC smokers to BLC nonsmokers (P = 0.36). When comparing according to consumption, there is no difference between mild, moderate or heavy smoker cases and controls. There is no difference in paternity rates between men with a history of cryptorchidism that consume tobacco compared to nonsmokers or controls. More studies are needed to determine the impact of tobacco consumption in formerly cryptorchid men.

A case series of infants with increased VAMP7 gene dosage at birth and virilization defects

Genitourinary disorders are the most frequent congenital defects in newborns; however, little is known about their etiology. Several studies have been carried out to find genetic risk factors in the development of these malformations. The expression of VAMP7 is found in testes, epididymis, seminal vesicles, prostatic tissues, penis, and urethra. Alterations in gene dose of VAMP7 were recently reported in a subset of male patients initially identified clinically by the presence of congenital genitourinary disorders. In 2016, the authors developed a diagnostic algorithm for early detection of sex chromosome aneuploidies by quantifying the SHOX, VAMP7, and SRY gene dose in newborns by qPCR using dried blood spot (DBS) samples. Correlate the increased gene dose of VAMP7, obtained by qPCR using DBS, with genitourinary congenital defects attributable to disorders in virilization and verify the increased gene dose by microarrays. Samples that only presented increased VAMP7 gene dosage were selected from a previously analyzed group of 5088 males in which the early detection of sex chromosomes aneuploidies was performed. Eight males were found with an increased gene dose of VAMP7 (relative quantitation>1.3) and were called in for a complete clinical evaluation aimed at the identification of genitourinary anomalies, qPCR and microarrays. Eight males from 5088 samples were identified with increased VAMP7 gene dosage of which six patients were clinically evaluated, of which 50% were identified with alterations in genital development (bilateral cryptorchidism, unilateral cryptorchidism, and glandular hypospadias) and speech delay, while the rest presented different types of atopy. Tannour-Louet etal. postulated on 2014 that the duplication of the Xq28 region, specifically of VAMP7, plays a role in the human masculinization disorders of the urogenital tract. The study was based on array comparative genomic hybridization (aCGH) results performed to 116 males with disorders of sexual differentiation. In the present study, the patients were initially selected due to an increased gene dose of VAMP7 detected by qPCR, then the clinical evaluation and the aCGH were performed, inverse to what was reported previously but with similar percentages between both studies. In this work, the authors report cases of cryptorchidism, hypospadias, language delay and atopy in male preschoolers initially identified because they have an increased gene dose of VAMP7.