Men With Chronic Orchialgia Exhibit Differential Neuroinflammatory Gene Expression Relative to Asymptomatic Controls.

OBJECTIVE: To identify differences in neuroinflammatory gene expression in individuals with chronic orchialgia (CO) compared to asymptomatic controls. METHODS: Vas deferens, spermatic cord fascia, blood, and urine were collected from 9 men with CO at time of microscopic spermatic cord denervation and 7 asymptomatic controls at time of vasectomy. RNA was isolated and analyzed with the NanoString Human Neuroinflammation panel. Data were normalized, gene expression fold changes and enriched pathways relative to asymptomatic controls were determined. Gene expression was considered significantly different if there was a >2-fold change and P-value <.05 relative to controls. RESULTS: Mean patient age was 51 years and median symptom duration 12 months. There were 26 genes with significantly differential expression in vas deferens. cFos, a marker of nociceptive pain, had the greatest difference (30.2-fold change, P <.000001). Enriched pathways in vas deferens included nerve function, matrix remodeling, and innate immune responses. In fascia, cFos also had the greatest differential expression (38-fold, P = .000002), followed by S100A12 (11-fold, inducer of innate immune response). Enriched pathways in fascia included nerve function and inflammation. In blood, there were no differentially expressed genes, and in urine there were 95 differentially expressed genes. CONCLUSION: Men with CO have a diverse set of neuroinflammatory genes with differential expression in tissue and urine relative to healthy controls. These findings confirm pathologic changes in tissue targeted by denervation surgery, and suggest molecular changes in neuropathic pain that could lead to biomarker identification and novel treatment.

The importance of genetic research in cases of severe male factor infertility: A case of 46,XX testicular disorder of sex development.

46,XX testicular disorder of sex development is a rare syndrome characterized by an inconsistency between genotype and phenotype. Affected individuals present variant genitalia between male and ambiguous, non-functional testicles, non-obstructive azoospermia, generally accompanied by hypergonadotropic hypogonadism, a condition known for high levels of gonadotrophic hormones. In some cases, disorders of sexual development are diagnosed during puberty. However, a significant number of individuals show physical characteristics common to males that are not clinically suspicious. As a result, patients with the condition may remain undiagnosed. Many individuals with the condition are diagnosed as adults, due to infertility. The present study discusses the case of an individual who underwent karyotyping for sterility and was found to be a 46,XX male. Despite having a female karyotype, the presence of the sex-determining region Y gene explains the manifestation of masculine secondary sex characteristics. This report highlights the importance of genetic evaluation, considering that carriers may present significant complications resulting from the disorder. Based on correct diagnosis, it is possible to improve a carrier's quality of life through multidisciplinary approaches and help them achieve pregnancy through assisted reproductive technology treatments.

Depletion of high-mobility group box 2 causes seminiferous tubule atrophy via aberrant expression of androgen and estrogen receptors in mouse testis†.

High-mobility group box 2, a chromatin-associated protein that interacts with deoxyribonucleic acid, is implicated in multiple biological processes, including gene transcription, replication, and repair. High-mobility group box 2 is expressed in several tissues, including the testis; however, its functional role is largely unknown. Here, we elucidated the role of high-mobility group box 2 in spermatogenesis. Paraffin-embedded testicular tissues were obtained from 8-week-old and 1-year-old wild-type and knock-out mice. Testis weight and number of seminiferous tubules were decreased, whereas atrophic tubules were increased in high-mobility group box 2-depleted mice. Immunohistochemistry revealed that atrophic tubules contained Sertoli cells, but not germ cells. Moreover, decreased cell proliferation and increased apoptosis were demonstrated in high-mobility group box 2-depleted mouse testis. To elucidate the cause of tubule atrophy, we examined the expression of androgen and estrogen receptors, and the results indicated aberrant expression of androgen receptor and estrogen receptor alpha in Sertoli and Leydig cells. Southwestern histochemistry detected decreased estrogen response element-binding sites in high-mobility group box 2-depleted mouse testis. High-mobility group box 1, which has highly similar structure and function as high-mobility group box 2, was examined by immunohistochemistry and western blotting, which indicated increased expression in testis. These findings indicate a compensatory increase in high-mobility group box 1 expression in high-mobility group box 2 knock-out mouse testis. In summary, depletion of high-mobility group box 2 induced aberrant expression of androgen receptor and estrogen receptor alpha, leading to decreased germ cell proliferation and increased apoptosis which resulted in focal seminiferous tubule atrophy.

A rare case of 46, XX (SRY positive) testicular disorder of sex development with growth hormone deficiency: Case report.

RATIONALE: Chromosome karyotype analysis and SRY (sex determined region of Y chromosome) gene detection are routines for the diagnosis of growth hormone deficiency (GHD), but further whole exome gene sequencing occasionally leads to subversive results and unexpected conclusions. PATIENT CONCERNS: We report a single case of a 7-year-old Chinese boy who had stunted growth since he was 1 year old. He was short in height (height Standard Deviation Score (SDS) was less than 2.9), bilateral scrotal dysplasia and delayed bone age. DIAGNOSIS: His growth hormone (GH) stimulation tests showed GHD. His karyotype analysis and polymerase chain reaction (PCR) analyses indicated a 46, XX disorder of sex development (DSD) without the presence of the SRY gene. Nevertheless, considering that female gonad was not observed in the chest and abdominal magnetic resonance imaging, the whole exome gene sequencing was performed. Sequencing data confirmed the presence of SRY gene sequence and two copies of chromosome X. Later, using different primer sequences for PCR, it showed that the SRY gene was positive. The final diagnosis was a rare case of "46, XX (SRY positive) testicular DSD with GHD". INTERVENTIONS: The boy's parents agreed to use recombinant human growth hormone (rhGH) for GHD treatment, the starting dose was 0.035 mg / kg / day. But they disagreed with molecular diagnostics and genomic analysis of the Y chromosome. OUTCOMES: The boy was treated with rhGH for 3 months and his height increased by 2.2 cm. The patient will be followed-up until the end of his puberty. LESSONS: In summary, whole exome gene sequencing overturned the preliminary diagnosis results of karyotype analysis and SRY gene detection, and found that there may be a certain correlation between testicular DSD and GHD.

Fermented Maillard reaction products attenuate stress-induced testicular dysfunction in mice.

Chronic stress can cause psychological diseases and affect male fertility and the reproductive system. Maillard reaction of milk proteins improves their functional and nutritional properties through modification of proteins. Previously, we determined that Maillard reaction product (MRP) from milk casein and MRP fermented (FMRP) with Lactobacillus rhamnosus 4B15 (4B15) had anti-anxiolytic effects in mice under chronic stress. Therefore, we aimed to investigate the effects of MRP and FMRP on chronic stress-induced testicular dysfunction in mice through quantitative real-time PCR (qRT-PCR) and in situ hybridization analysis. Mice were pretreated with MRP and FMRP for 10 wk; simultaneously, from the third week of the experimental period, they were exposed to unpredictable chronic mild stress (UCMS) for 7 wk. The expression levels of the luteinizing hormone subunit ß (Lhb) and follicle-stimulating hormone subunit ß (Fshb) were remarkably reduced after exposure to UCMS. However, treatment with MRP and FMRP inhibited the UCMS-induced reduction, with FMRP showing especially significant inhibition. Moreover, the expression of steroidogenesis-related genes [luteinizing hormone receptor (Lhr), follicle-stimulating hormone (Fshr), 3-ß hydroxysteroid dehydrogenase 2 (Hsd3b2), and steroidogenic acute regulatory protein (StAR)] were significantly reduced in response to UCMS. In contrast, the transcript levels of these genes were highest in the MRP-treated mice. Mice pretreated with FMRP also exhibited higher levels of gene expression compared with the nonstressed mice. Moreover, UCMS significantly downregulated the expression of genes associated with testicular function [i.e., a disintegrin and metallopeptidase domain 5 (Adam5), Adam29, bone morphogenetic protein 2 (Bmp2), tektin 3 (Tekt3), and sperm adhesion molecule 1 (Spam1)]. However, the administration of MRP and FMRP prevented the UCMS-induced reduction in the expressions of above genes. The localization of Lhr, Srd5a2, Adam29, and Spam1 was confirmed by in situ hybridization analysis and the results were consistent with those of qRT-PCR. Consequently, these results indicated that MRP and FMRP, manufactured by the heat treatment of milk casein and fermentation with probiotic 4B15, have the potential to prevent chronic stress-induced testicular dysfunction.

Generating adverse outcome pathway (AOP) of inorganic arsenic-induced adult male reproductive impairment via integration of phenotypic analysis in comparative toxicogenomics database (CTD) and AOP wiki.

BACKGROUND: Inorganic arsenic (iAs) is a worldwide environmental pollutant which exerts complicated and various toxic effects in organisms. Increasingly epidemic studies have revealed the association between iAs exposure and adult male reproductive impairment. Consistent with the proposal for toxicity testing in the 21st century (TT21C), the adverse outcome pathway (AOP) framework may help unravel the iAs-caused molecular and functional changes leading to male reproductive impairment. METHOD: Combining CTD's phenotype-disease inference data, iAs-phenotypes were anchored to five male reproductive diseases induced by iAs, and local network topological algorithm was applied in prioritizing their interference significance. Through integrating analysis in AOP Wiki knowledge base, filtered phenotypes were linked to key events consisting of AOPs and assembled together based on evidentially upstream and downstream relationships. RESULTS: A subset of 655 phenotypes were filtered from CTD as potential key events and showed a significant coherence in five reproductive diseases wherein 39 significant phenotypes showed a good clustering features involving cell cycle, ROS and mitochondria function. Two AOP subnetworks were enriched in AOP Wiki where testosterone reduction and apoptosis of sperm served as focus events respectively. Besides, a candidates list of molecular initialing events was provided of which glucocorticoid receptor activation was overall assessed as an example. CONCLUSION: This study applied computational and bioinformatics methods in generating AOPs for arsenic reproductive toxicity, which identified the imperative roles of testosterone reduction, response to ROS, spermatogenesis and provided a global view about their internal association. Furthermore, this study helped address the existing knowledge gaps for future experimental verification.

Cold-induced RNA-binding protein (CIRBP) regulates the expression of Src-associated during mitosis of 68 kDa (Sam68) and extracellular signal-regulated kinases (ERK) during heat stress-induced testicular injury.

In this study, the ability of cold-induced RNA-binding protein (CIRBP) to regulate the expression of Src-associated during mitosis of 68 kDa (Sam68) and extracellular signal-regulated kinases (ERK) in the mouse testis and mouse primary spermatocytes (GC-2spd cell line) before and after heat stress was examined to explore the molecular mechanism by which CIRBP decreases testicular injury. A mouse testicular hyperthermia model, a mouse primary spermatocyte hyperthermia model and a low CIRBP gene-expression cell model were constructed and their relevant parameters were analysed. The mRNA and protein levels of CIRBP and Sam68 were significantly decreased in the 3-h and 12-h testicular heat-stress groups, extracellular signal-regulated kinase 1/2 (ERK1/2) protein expression was not significantly affected but phospho-ERK1/2 protein levels were significantly decreased. GC-2spd cellular heat-stress results showed that the mRNA and protein concentrations of CIRBP and Sam68 were reduced 48h after heat stress. In the low CIRBP gene-expression cell model, CIRBP protein expression was significantly decreased. Sam68 mRNA expression was significantly decreased only at the maximum transfection concentration of 50nM and Sam68 protein expression was not significantly affected. These findings suggest that CIRBP may regulate the expression of Sam68 at the transcriptional level and the expression of phospho-ERK1/2 protein, both of which protect against heat-stress-induced testicular injury in mice.

Testicular Involvement is a Hallmark of Apo A-I Leu75Pro Mutation Amyloidosis.

CONTEXT: Apo A-I Leu75Pro is a rare hereditary form of amyloidosis that mainly involves the kidney, the liver, and the testis. OBJECTIVE: To define the characteristics of organ damage and testis impairment in the largest cohort collected to date of men with Apo A-I Leu75Pro amyloidosis. DESIGN, SETTING, AND PATIENTS: Retrospective study from a prospectively collected database of 129 male subjects >18 years with Apo A-I Leu75Pro amyloidosis from a reference center at the University Hospital of Brescia, Italy. MAIN OUTCOME MEASURES: We evaluated liver and renal function, scrotal ultrasound, reproductive hormone levels, testis biopsy, hypogonadal symptoms, and fertility. RESULTS: Progressive involvement of testis, kidney, and liver was observed in 96/129 (74.4%) cases. Testis impairment was found in 88/129 patients (68.2%), liver in 59 (45.7%) and renal in 50 (38.8%). Testis damage was often the first manifestation of the disease and the only dysfunction in 30% of younger patients (<38 years). Testicular involvement was characterized mainly by primary (73/88 patients, 83.0%) and subclinical (8/88, 9.1%) hypogonadism. Almost all (85/88, 96.6%) also had high follicle-stimulating hormone, suggesting a primary global damage of endocrine and spermatogenic functions, and 30% of them did not conceive. Macroorchidism was found in 53/88 (60.2%) patients, especially in men <54 years (30/33, 90.9%). Apo A-I amyloid deposits were found in Sertoli cells, germinal epithelium, and vessel walls. CONCLUSION: In men with Apo A-I Leu75Pro amyloidosis, testicular involvement is the hallmark of the disease, characterized by global primary testicular dysfunction and macroorchidism due to amyloid deposits.

Isolated 17, 20 Lyase Deficiency Secondary to a Novel CYB5A Variant: Comparison of Steroid Metabolomic Findings with Published Cases Provides Diagnostic Guidelines and Greater Insight into Its Biological Role.

OBJECTIVE: The objective of this study was to report CYB5A deficiency, to discuss the contribution of steroid metabolomics to diagnosis and interpretation, and to highlight the presence of testicular microlithiasis. METHODS: Two siblings with ambiguous genitalia at birth were later found to carry novel CYB5A variants, with resulting isolated 17, 20 lyase deficiency. We compared urine steroid data obtained between birth and adulthood with that from other cases. RESULTS: Neonatal urine steroid profiles show a relative increase of 16-hydroxylated pregnenolone metabolites. Thereafter, there are no distinguishing features until puberty, when sex steroid deficiency drives gonadotrophin production, resulting in marked increases of 17-hydroxyprogesterone metabolites derived from the gonads. This excess may be revealed pre-pubertally by gonadotrophin stimulation testing. Novel findings are first, a considerable capacity for DHEA synthesis in the neonatal period compared to childhood and adulthood, suggesting that DHEAS production is much less dependent on CYB5A at birth; second, no consistent change in "backdoor pathway" intermediates; third, side chain cleavage of cortisol is largely unaffected, supporting the existence of a different lyase not dependent on CYB5A; fourth, increased 17-hydroxyprogesterone metabolites and very low androgen metabolites are diagnostic post-pubertally. CONCLUSION: This is the fourth disease-causing variant in CYB5A in isolated 17, 20 lyase deficiency and the first associated with testicular microlithiasis. Establishing a biochemical diagnosis pre-pubertally should now be possible using urine steroid profiling, supported by synacthen and gonadotrophin stimulation testing. We recommend liquid chromatography-mass spectrometry/mass spectrometry rather than immunoassay for serum steroid analysis, early methaemoglobin measurement and surveillance should testicular microlithiasis be detected.

Unbalanced Y;7 Translocation between Two Low-Similarity Sequences Leading to SRY-Positive 45,X Testicular Disorders of Sex Development.

Unbalanced translocations of Y-chromosomal fragments harboring the sex-determining region Y gene (SRY) to the X chromosome or an autosome result in 46,XX and 45,X testicular disorders of sex development (DSD), respectively. Of these, Y;autosome translocation is an extremely rare condition. Here, we identified a 20-year-old man with a 45,X,t(Y;7)(q11.21;q35) karyotype, who exhibited unilateral cryptorchidism, small testis, intellectual disability, and various congenital anomalies. The fusion junction of the translocation was blunt, and the breakpoint-flanking regions shared only 50% similarity. These results indicate that Y;autosome translocations can occur between 2 low-similarity sequences, probably via nonhomologous end joining. Furthermore, translocations of a Ypterq11.21 fragment to 7q35 likely result in normal or only mildly impaired male-type sexual development, along with various clinical features of 7q deletion syndrome, although their effects on adult testicular function remain to be studied.

Los ARNs no codificantes largos y su vinculación con las patologías testiculares / Long non-coding RNAs and their involvement in testicular pathologies / RNAs longos não-codificantes e sua ligação com patologias testiculares

Si bien la porción del genoma destinada a la síntesis de proteínas es muy pequeña, actualmente se sabe que casi todo el genoma se expresa bajo forma de ARNs no codificantes. Entre dichos ARNs se encuentran los ARNs no codificantes largos (lncRNAs). Aunque los lncRNAs han sido muy poco estudiados, recientemente han comenzado a centrar la atención de los investigadores, al descubrirse que los mismos pueden desempeñar diversas funciones en la regulación de la expresión génica. Además, su vinculación con patologías ha comenzado a ser puesta de manifiesto. Curiosamente, la cantidad de lncRNAs presentes en el testículo es abrumadoramente mayor que en cualquier otro órgano o tejido estudiado. Los perfiles de expresión de estos lncRNAs varían significativamente a lo largo de la espermatogénesis, y algunas evidencias sugieren que al menos algunos de ellos podrían participar en el proceso de formación de células germinales masculinas. No obstante, el conocimiento sobre el tema es aún muy escaso. En este trabajo revisamos la información disponible sobre la expresión de lncRNAs en el testículo y sus posibles funciones. Asimismo, analizamos algunos ejemplos que ilustran la participación de lncRNAs en el desarrollo de patologías como la infertilidad y el cáncer testicular.

Although the portion of the genome devoted to protein synthesis is very small, it is now known that almost the entire genome is expressed as non-coding RNAs. Among them, there are long noncoding RNAs (lncRNAs). Despite that lncRNAs have been very poorly studied, they have recently started to focus the attention of researchers, as it has been found out that lncRNAs can perform diverse functions in the regulation of gene expression. Besides, their involvement in pathologies is being revealed. Intriguingly, the amount of lncRNAs in the testis is overwhelmingly higher than in any other analyzed organ or tissue. LncRNA expression profiles significantly vary along spermatogenesis, and some evidence suggests that at least some of them could participate in the formation of male germ cells. However, knowledge on the subject is still very scarce. In this work we review the available information on the expression of lncRNAs in testis and their possible roles. We also analyze some examples that illustrate the participation of lncRNAs in the development of pathologies such as infertility and testicular cancer.

Embora a porção do genoma usada para a síntese proteica seja muito pequena, sabe-se agora que quase todo o genoma é expresso na forma de RNAs não-codificantes. Entre esses RNAs estão os longos RNAs não codificantes (lncRNAs). Embora os lncRNAs tenham sido pouco estudados, eles recentemente começaram a focar a atenção dos pesquisadores, ao descobrirem que podem desempenhar diversas funções na regulação da expressão gênica. Além disso, sua ligação com as patologias começou a ser revelada. Curiosamente, a quantidade de lncRNAs presentes nos testículos é esmagadoramente maior do que em qualquer outro órgão ou tecido estudado. Os perfis de expressão destes lncRNAs variam significativamente ao longo da espermatogênese, e algumas evidências sugerem que pelo menos alguns deles poderiam participar no processo de formação de células germinativas masculinas. No entanto, o conhecimento sobre o assunto ainda é muito escasso. Neste trabalho, revisamos as informações disponíveis sobre a expressão de lncRNAs no testículo e suas possíveis funções. Também analisamos alguns exemplos que ilustram a participação dos lncRNAs no desenvolvimento de patologias como infertilidade e câncer testicular.

Hyaline Arteriolosclerosis in 30 Strains of Aged Inbred Mice.

During a screen for vascular phenotypes in aged laboratory mice, a unique discrete phenotype of hyaline arteriolosclerosis of the intertubular arteries and arterioles of the testes was identified in several inbred strains. Lesions were limited to the testes and did not occur as part of any renal, systemic, or pulmonary arteriopathy or vasculitis phenotype. There was no evidence of systemic or pulmonary hypertension, and lesions did not occur in ovaries of females. Frequency was highest in males of the SM/J (27/30, 90%) and WSB/EiJ (19/26, 73%) strains, aged 383 to 847 days. Lesions were sporadically present in males from several other inbred strains at a much lower (<20%) frequency. The risk of testicular hyaline arteriolosclerosis is at least partially underpinned by a genetic predisposition that is not associated with other vascular lesions (including vasculitis), separating out the etiology of this form and site of arteriolosclerosis from other related conditions that often co-occur in other strains of mice and in humans. Because of their genetic uniformity and controlled dietary and environmental conditions, mice are an excellent model to dissect the pathogenesis of human disease conditions. In this study, a discrete genetically driven phenotype of testicular hyaline arteriolosclerosis in aging mice was identified. These observations open the possibility of identifying the underlying genetic variant(s) associated with the predisposition and therefore allowing future interrogation of the pathogenesis of this condition.

Genetic and genomic analyses of testicular hypoplasia in Nellore cattle.

Reproductive performance is a key indicator of the long-term sustainability of any livestock production system. Testicular hypoplasia (TH) is a morphological and functional reproductive disorder that affects bulls around the world and consequently causes major economic losses due to reduced fertility rates. Despite the improvements in management practices to enhance performance of affected animals, the use of hypoplastic animals for reproduction might contribute to expand the prevalence of this disorder. The aim of this study was to identify genomic regions that are associated with TH in Nellore cattle by performing a genome-wide association study (GWAS) and functional analyses. Phenotypic and pedigree data from 47,563 animals and genotypes (500,689 Single Nucleotide Polymorphism, SNPs) from 265 sires were used in this study. TH was evaluated as a binary trait measured at 18 months of age. The estimated breeding values (EBVs) were calculated by fitting a single-trait threshold animal model using a Bayesian approach. The SNP effects were estimated using the Bayes C method and de-regressed EBVs for TH as the response variable (pseudo-phenotype). The top-15 ranking windows (5-adjacent SNPs) that explained the highest proportion of variance were identified for further functional and biological network analyses. The posterior mean (95% highest posterior density) of the heritability for TH was 0.16 (0.08; 0.23). The most important genomic windows were located on BTA1, BTA3, BTA4, BTA5, BTA9, BTA22, BTA23, and BTA25. These windows explained together 22.69% of the total additive genetic variance for TH. Strong candidate genes associated with metabolism and synthesis of steroids, cell survival, spermatogenesis process and sperm motility were identified, which might play an important role in the expression of TH. Our findings contribute to a better biological understanding of TH and future characterization of causal variants might enable improved genomic prediction of this trait in beef cattle.

A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant.

Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.

Genes associated with testicular germ cell tumors and testicular dysgenesis in patients with testicular microlithiasis.

Testicular microlithiasis (TM) is one of the symptoms of testicular dysgenesis syndrome (TDS). TM is particularly interesting as an informative marker of testicular germ cell tumors (TGCTs). KIT ligand gene (KITLG), BCL2 antagonist/killer 1 (BAK1), and sprouty RTK signaling antagonist 4 (SPRY4) genes are associated with a high risk of TGCTs, whereas bone morphogenetic protein 7 gene (BMP7), transforming growth factor beta receptor 3 gene (TGFBR3), and homeobox D cluster genes (HOXD) are related to TDS. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, we investigated allele and genotype frequencies for KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876), BAK1 (rs210138), BMP7 (rs388286), TGFBR3 (rs12082710), and HOXD (rs17198432) in 142 TGCT patients, 137 TM patients, and 153 fertile men (control group). We found significant differences in the KITLG GG_rs995030 genotype in TM (P = 0.01) and TGCT patients (P = 0.0005) compared with the control. We also revealed strong associations between KITLG_rs1508595 and TM (G allele, P = 0.003; GG genotype, P = 0.01) and between KITLG_rs1508595 and TGCTs (G allele, P = 0.0001; GG genotype, P = 0.0007). Moreover, there was a significant difference in BMP7_rs388286 between the TGCT group and the control (T allele, P = 0.00004; TT genotype, P = 0.00006) and between the TM group and the control (T allele, P = 0.04). HOXD also demonstrated a strong association with TGCTs (rs17198432 A allele, P = 0.0001; AA genotype, P = 0.001). Furthermore, significant differences were found between the TGCT group and the control in the BAK1_rs210138 G allele (P = 0.03) and the GG genotype (P = 0.01). KITLG and BMP7 genes, associated with the development of TGCTs, may also be related to TM. In summary, the KITLG GG_rs995030, GG_rs1508595, BMP7 TT_rs388286, HOXD AA_rs17198432, and BAK1 GG_rs210138 genotypes were associated with a high risk of TGCT development.

Novel RSPO1 mutation causing 46,XX testicular disorder of sex development with palmoplantar keratoderma: A review of literature and expansion of clinical phenotype.

Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal (MIM # 610644) is a clinically distinctive form of SRY-negative 46,XX disorder of sex development. It is a rare autosomal recessive disorder caused due to biallelic loss of function mutations in RSPO1 gene. RSPO1 acts by activating the canonical ß-catenin pathway and is one of the most important genes controlling female gonadal differentiation. RSPO1-associated disorders of sex development have been described only in three instances in the past. We report fourth such case with additional findings and perform a comparative review of previous phenotypic descriptions, thereby expanding the clinical phenotype of this syndrome.

[Clinical report of testicular hypoplasia combined with 21-hydroxylase deficiency].

OBJECTIVE To investigate the correlation of 21-hydroxylase deficiency (21-OHD) with male testicular dysplasia. METHODS Clinical data of 8 infertile males with congenital adrenal hyperplasia due to 21-OHD was retrospectively analyzed. In addition, potential mutations of the CYP21A2 gene was detected. RESULTS All patients were referred because of azoospermia or severe oligospermia and had small testis with averaged testicular volume of 6.1 mL. Three patients had testicular adrenal rest tumors. Endocrinologic examinations revealed low levels of leutinizing hormone and follicular stimulating hormone, normal or elevated testosterone, elevated progesterone, elevated or normal adrenocoticotropic hormone, and low or normal cortisol. All patients had adrenal cortical hyperplasia, 5 with adrenal adenoma, 1 case associated with bilateral adrenal myelolipoma. All patients were given glucocorticoid replacement therapy for 3 to 6 months, which successfully improved the seminal status of 6 patient and resulted pregnancies in 5 couples. Seven pathogenic mutations of the CYP21A2 gene among the 8 patients. CONCLUSION 21-OHD can cause testicular hypoplasia and spermatogenic failure. Glucocorticoids and operations can obtain good result and improve spermatogenesis. Our results have shown a good genotype/phenotype correlation in these cases. All patients have carried the p.Ile172Asn mutation, which is associated with simple virilizing form.

Is testicular dysgenesis syndrome a genetic, endocrine, or environmental disease, or an unexplained reproductive disorder?

Progressive increases in the incidence of male reproductive disorders inclusive of hypospadias, cryptorchidism, poor semen quality, and testicular germ cell cancer (TGCC) have been observed in recent times. The central hypothesis of this study asserted that these disorders may all collectively signify testicular dysgenesis syndrome (TDS). This review aimed to provide evidence verifying the reality of TDS based on four key aspects: environmental endocrine-disrupting chemicals (EDCs), genetic factors, intrauterine growth disorders and lifestyle factors. Although TDS might result from genetic polymorphisms or aberration, recent evidence has highlighted links indicating the conditions associations to both environmental and lifestyle factors due to the rapid temporal changes in the clinical symptoms observed over recent decades. Based on our review of genetic and environmental factors, a key observation of our study suggested that there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. At present, current research has yet to elucidate the mechanisms of TDS, in addition to the lack of genuine consideration of a variety of potentially key factors and TDS mechanisms. In conclusion, our study revealed that environmental exposures owing to modern lifestyles are primary factors involved in the associated trends of the syndrome, which are capable of affecting the adult endocrine system via direct means or through epigenetic mechanisms.

A case of Riley Ruvalcaba syndrome with a novel PTEN mutation accompanied by diffuse testicular microlithiasis and precocious puberty.

BACKGROUND: Bannayan Riley Ruvalcaba syndrome (BRRS) is exceedingly rare, with only about 50 reported cases to date. CASE PRESENTATION: We report a patient with hypoglycemia, precocious puberty and diffuse testicular microlithiasis accompanying BRRS, and think that this case is important in the light of a newly identified mutation in the PTEN gene. CONCLUSIONS: Close attention must be paid in terms of PTEN mutations in cases of macrocephaly and accompanying neurological and dermatological findings.

A duplication in a patient with 46,XX ovo-testicular disorder of sex development refines the SOX9 testis-specific regulatory region to 24 kb.

A custom CGH microarray that covers the SOX9 regulatory region. Log2 ratio scatterplot showing individual data points. Blue box highlights copy number gain with 3' breakpoint region magnified.