[Swyer syndrome with gonadal non-dysgerminoma malignant germ cell tumors: a report of 15 cases in a national medical center].

Objective: To evaluate the incidence, treatment, and survival outcomes of Swyer syndrome with gonadal non-dysgerminoma malignant germ cell tumor (MGCT-NDG). Methods: A retrospective study was performed on Swyer syndrome patients with MGCT-NDG between January 2011 and December 2022 in Peking Union Medical College Hospital to investigate their characteristics and outcomes. Results: A total of 15 patients (4.9%, 15/307) with Swyer syndrome were identified in 307 MGCT-NDG patients. The average age at diagnosis of MGCT-NDG and Swyer syndrome were (16.8±6.7) and (16.7±6.6) years, respectively. Six cases were preoperatively diagnosed as Swyer syndrome, of which 4 cases received bilateral gonadectomy with or without hysterectomy, while the other 2 cases underwent removal of gonadal tumor and unilateral gonadectomy with hysterectomy, respectively. Of the 9 patients postoperatively diagnosed as Swyer syndrome, unilateral gonadectomy, removal of gonadal tumor, and unilateral gonadectomy with hysterectomy were performed in 6 patients, 2 patients, and 1 patient, respectively. Mixed malignant germ cell tumor (MGCT;10 cases), yolk sac tumor (4 cases), and immature teratoma (1 case) were the pathological subtypes, in the descending order. There were International Federation of Gynecology and Obstetrics (FIGO) stage Ⅰ in 6 cases, stage Ⅱ in 3 cases, stage Ⅲ in 5 cases, and stage Ⅳ in 1 case, respectively. Eleven patients received reoperation for residual gonadectomy after a average delay of (7.9±6.2) months, including 8 MGCT-NDG patients and 1 gonadoblastoma patient, no tumor involved was seen in the remaining gonads in the other 2 cases. Ten patients experienced at least one recurrence, with a median event free survival of 9 months (5, 30 months), of which 2 patients received surgery only at the time of initial treatment. All patients with recurrence received surgery and combined with postoperative chemotherapy. After a median follow-up of 25 months (15, 42 months), 10 patients were disease-free, 3 patients died of the tumor, 1 died of side effects of leukemia chemotherapy, and 1 survived with disease. Conclusion: The incidence rate of Swyer syndrome in patients with MGCT-NDG is about 4.9%; timely diagnosis and bilateral gonadectomy should be emphasized to reduce the risk of reoperation and second carcinogenesis in this population.

Acute Lymphoblastic Leukemia Developing in a Patient with 46, XY Pure Gonadal Dysgenesis (Swyer Syndrome) with Malignant Gonadal Germ Cell Tumor: A Case Report and Literature Review.

A female phenotype with strip-like gonads, 46, XY pure gonadal dysgenesis (PGD) has a high tendency to develop into gonadal germ cell tumors. We described one patient with 46, XY PGD, who had a gonadal mixed germ cell tumor (GCT) and acute lymphoblastic leukemia (ALL). This is a unique case because two malignancies developed and relapsed in one person with chromosome abnormality, and the patient is the youngest reported so far. There is an association between her GCT and ALL, as the two malignancies may share a common clonal origin and the NRAS mutation likely plays a role in tumor genesis. We organized MDT to formulate a suitable plan of treatment. We completed the surgery and full cycles of chemotherapy for GCT and controlled ALL by chemotherapy and bone marrow transplantation. However, unfortunately, the young life finally ended following a rare transplant rejection. We concluded that ALL likely shares common clonal origin with GCT and that gene mutations may play a role in neoplasia, which requires further exploration. In the face of such complex conditions, we need to balance the treatment of both diseases to prolong survival and improve the patients' quality of life.

Non-obvious diagnosis and breast development in pure gonadal dysgenesis.

Pure gonadal dysgenesis is a situation when the karyotype is 46, XY, but for various reasons there is a disorder of differentiation of Wolffian and Mullerian structures and in consequence the phenotype is female. It is known that abdominal gonads and the presence of Y chromosome allow to qualify this condition as a high risk of tumor. In most cases breast development is limited because of lack or low level of estrogen. A 27-year-old patient with differences of sexual development (DSD), was admitted to the Department of Endocrinological Gynecology for a control examination. In the history: dysgerminoma, primary amenorrhea and ambiguous karyotype. The patient has not taken hormonal replacement therapy. The breast development is Tanner stage V.

Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review.

Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases. Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals. 46,XX carriers appear to have normal fertility and no developmental abnormalities. Pathogenic variants occur almost exclusively within known domains of the MAP3K1 protein, facilitating annotation when identified. Where studied, these variants have been modeled to alter the local MAP3K1 folding and surface domains and have been shown to alter interactions with known binding partners. The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination.

Broad-spectrum XX and XY gonadal dysgenesis in patients with a homozygous L193S variant in PPP2R3C.

CONTEXT: Homozygous and heterozygous variants in PPP2R3C are associated with syndromic 46,XY complete gonadal dysgenesis (Myo-Ectodermo-Gonadal Dysgenesis (MEGD) syndrome), and impaired spermatogenesis, respectively. This study expands the role of PPP2R3C in the aetiology of gonadal dysgenesis (GD). METHOD: We sequenced the PPP2R3C gene in four new patients from three unrelated families. The clinical, laboratory, and molecular characteristics were investigated. We have also determined the requirement for Ppp2r3c in mice (C57BL6/N) using CRISPR/Cas9 genome editing. RESULTS: A homozygous c.578T>C (p.L193S) PPP2R3C variant was identified in one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. The patients with complete GD had low gonadal and adrenal androgens, low anti-Müllerian hormone, and high follicle-stimulating hormone and luteinizing hormone concentrations. All patients manifested characteristic features of MEGD syndrome. Heterozygous Ppp2r3c knockout mice appeared overtly normal and fertile. Inspection of homozygous embryos at 14.5, 9.5, and 8.5 days post coitum(dpc) revealed evidence of dead embryos. We conclude that loss of function of Ppp2r3c is not compatible with viability in mice and results in embryonic death from 7.5 dpc or earlier. CONCLUSION: Our data indicate the essential roles for PPP2R3C in mouse and human development. Germline homozygous variants in human PPP2R3C are associated with distinctive syndromic GD of varying severity in both 46,XY and 46,XX individuals.

Demetylation of the sex-determining region Y gene promoter and incidence of disorder of sex development in cloned dog males.

Canine cloning is occasionally accompanied by abnormal sexual development. Some male donor cells produce cloned pups with female external genitalia and complete male gonadal dysgenesis, which is classified as an XY disorder of sex development (XY DSD). In this study, we examine the potential of 5-aza-2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, to reduce the phenotypic abnormality XY DSD in somatic cell nuclear transfer (SCNT)- derived pups. We used a 9-year-old normal male German Shepherd dog as a cell donor. Donor cells were treated with 10 nM 5-aza-dC for 4 days before being used for SCNT. At the same stage of cell development, significantly lower levels of DNA methylation of the sex-determining region Y (SRY) promoter was observed in the treated donor cells compared to that in the untreated cells (95.2% versus 53.3% on day 4 for the control and treated groups, respectively). No significant differences were observed in the control or treatment groups concerning fusion rate, pregnancy rate (30 days or entire period), the number of pups, or the incidence of XY DSD. However, more XY DSD dogs were observed in the control group (31.25%) than in the treatment group (14.29%). Hypermethylation of the SRY promoter was observed in the XY DSD cloned pups in both the treatment (84.8%) and control groups (91.1 ± 1.4%) compared to the methylation level in the phenotypically normal male pups of the treatment (23.2 ± 20.9%) and control groups (39.1 ± 20.1%). These results suggest that 5-aza-dC treatment of donor cells can reduce the methylation level of the SRY promoter in donor cells, and thus, 5-aza-dC is advantageous for reducing the incidence of XY DSD in canine cloning.

A novel missense heterozygous mutation in MAP3K1 gene causes 46, XY disorder of sex development: case report and literature review.

BACKGROUND: Disorders of sex development (DSD) can result from congenital defect in sex determining pathway. Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is one of the commonest genes that has been identified to cause 46, XY DSD. It can present as complete or partial gonadal dysgenesis even within the same kindred. Few mutations in this gene have previously been identified in a high proportion of individuals with 46, XY gonadal dysgenesis. METHODS AND RESULTS: We report three siblings with same novel variant in MAP3K1 gene presenting with variable degrees of partial gonadal dysgenesis. Clinical and genetic assessments were performed for the three siblings, while endocrine evaluation was done for two of them. The identified mutation (p.Thr657Arg) was previously classified as a pathogenic variant, although apparently there are no reported humans with this mutation. CONCLUSION: This report adds to the genotype-phenotype correlation, highlighting the clinical importance of considering MAP3K1 gene defects as part of the differential diagnosis for complete or partial gonadal dysgenesis especially with multiple affected family members.

46, XY complete gonadal dysgenesis with pubertal virilisation due to dysgerminoma/gonadoblastoma.

Complete gonadal dysgenesis (CGD) or Swyer syndrome is characterised by sexual infantilism in a phenotypic female with 46, XY karyotype. Patients with gonadal dysgenesis and Y-chromosome material are at a high risk of developing gonadoblastoma and dysgerminoma. A 16-year-old girl presented with progressive virilisation, poor breast development and primary amenorrhea. On evaluation, she was found to have male-range serum testosterone, large abdominopelvic mass lesion, elevated germ cell tumour markers and 46, XY karyotype. She underwent surgical excision of left gonadal mass and right streak gonad, histopathology of which revealed dysgerminoma and gonadoblastoma, respectively. A diagnosis of virilising germ cell tumour arising in the setting of 46, XY CGD was, therefore, made. This case highlights a rare presentation of 46, XY CGD and the need to consider early prophylactic gonadectomy in patients affected with this rare condition. The presence of dysgerminoma/gonadoblastoma should be suspected if a hitherto phenotypic female with CGD undergoes virilisation.

Monochorionic diamniotic twins of discordant external genitalia with 45,X/46,XY mosaicism.

BACKGROUND: Monozygotic twins with 45,X/46,XY mosaicism, discordant for phenotypic sex, are extremely rare. METHODS: This report describes the clinical findings of a rare case of 45,X/46,XY mosaicism in monozygotic twins with different external genitalia. Single nucleotide polymorphism (SNP) array analysis, performed by collecting DNA from each umbilical cord, showed identical SNPs in the autosomal chromosomes of both fetuses. RESULTS: Chorionic villus sampling of a 37-year-old primigravida carrying monozygotic twins revealed a 45,X/46,XY karyotype. Autopsy of the aborted fetuses revealed a penis and testes on one fetus and a vagina, uterus, and ovaries in the other fetus--which also had severe cystic hygroma. Cell counting using fluorescence in situ hybridization with XY probes (XY-FISH) showed 20% and 80% abundance of 45,X cells in the internal genitalia, liver, heart, lung, adrenal gland, bone marrow, and spine of the male and female fetuses, respectively. CONCLUSION: These results indicated that the fetuses were genetically monozygotic twins and their different degrees of mosaicism may have resulted in different genital phenotypes.

Variation of Gonadal Dysgenesis and Tumor Risk in Patients With 45,X/46,XY Mosaicism.

OBJECTIVE: To describe the gonadal features of patients with 45,X/46,XY mosaicism, and to evaluate the prevalence of gonadal tumor in different phenotypes. MATERIALS AND METHODS: The medical records of consecutive patients with 45,X/46,XY karyotype or its variants who had undergone gonadal biopsy or gonadectomy at a single institute between 1996 and 2017 were retrospectively reviewed. RESULTS: Of 34 patients with 45,X/46,XY mosaicism, a unilateral dysgenetic testis and a contralateral streak gonad was detected in 20 patients (59%), bilateral streak gonads in 9 (26%), and bilateral dysgenetic testes in 5 (15%). A gonad composed of both streak and dysgenetic testicular portions was observed in 7 gonads of 6 patients. All streak gonads were removed, and bilateral gonadectomy was performed in 15 patients raised as girls. Pathologic examination revealed gonadal tumors in 6 of the 34 (18%) patients, including a gonadoblastoma in 7 gonads among 5 patients and an association of dysgerminoma with gonadoblastoma in 1 gonad. All 6 patients who developed gonadal tumor had female genitalia. Postoperative course was uneventful except 1 boy. A seminoma was developed in his soritaly scrotal testis at the age of 16 years. CONCLUSION: The prevalence of gonadal tumor in patients with 45,X/46,XY mosaicism may vary according to the phenotype, and high in patients with female phenotype. Considering the increased risk of gonadal tumors in such patients, early investigation and individual management, including prophylactic gonadectomy, are recommended. In male patients, a close follow-up of the preserved testes is mandatory until adulthood.

Clinical Findings and Follow-Up of 46,XY and 45,X/46,XY Testicular Dysgenesis.

Historically, the terms partial (PGD) and mixed gonadal dysgenesis (MGD) have been used to describe incomplete testicular differentiation in individuals with 46,XY or 45,X/46,XY karyotypes, respectively. However, it is currently unclear to what extent clinical features actually differ between these individuals. The aim of this study was to compare clinical, laboratory, and histological findings in these 2 groups. Patients with testicular dysgenesis seen in our service between 1989 and 2013 were selected. Sixty-one patients met the inclusion criteria. Individuals with 46,XY and 45,X/46,XY karyotypes were compared regarding genital features, gonadal histology and function, growth, and associated conditions. Twenty-five had mosaicism with a 45,X cell line (MGD), while a 46,XY karyotype (PGD) was found in 36 cases belonging to 32 families. Mutations in NR5A1, WT1, and SRY genes associated with testicular dysgenesis were found in 12 families. There were no significant differences regarding parental consanguinity, degree of external androgenization, gonadal location, histology, and function, and associated conditions. However, in the MGD group, the presence of a uterus, lower birth weight and length, and short stature were more often observed. Therefore, the use of histological features to classify PDG and MGD should be abandoned and replaced by classification based on karyotype.

Novel pathogenic mutations in disorders of sex development associated genes cause 46,XY complete gonadal dysgenesis.

Disorders of sex development (DSDs) are congenital conditions in which chromosomal, gonadal and sex is atypical. It is difficult to diagnose and manage patients with DSD in clinical practice, and the molecular etiology of DSD is still not completely understood. Here, we identified two novel pathogenic mutations from three unrelated Chinese patients with 46,XY complete gonadal dysgenesis (CGD) that is a clinical subgroup of DSD by whole exome sequencing. A novel mutation in the SRY gene (c.161delG) was identified in the first patient, and the second patient carried a novel missense mutation in the MAP3K1 gene (c.2117T>G). Bioinformatics analysis found that the deletion of SRY (c.161delG) led to a premature stop codon at amino acid 59 in the SRY protein, which resulted in lacking the DNA binding domain of SRY protein. Functional studies found that the missense mutation in the MAP3K1 gene (c.2117T>G) could interfere with the gene function through increasing the phosphorylation of the downstream targets of MAP3K1, ERK1/2 and p38, which resulted in reducing testis-determining factor SOX9 expression and increasing ovary-promoting factor ß-catenin activity. According to the American college of medical genetics and genomics (ACMG) standards and guidelines, these mutations were categorized as "pathogenic" mutations. Thus, our findings provide two novel pathogenic mutations associated with 46,XY CGD that can improve the etiological diagnosis for 46,XY CGD. ABBREVIATIONS.

Atypical Presentation of Swyer Syndrome.

BACKGROUND: Swyer syndrome is a rare type of disorder of sex development and typically presents with delayed puberty and primary amenorrhea. We describe an unusual presentation of this condition. CASE: A 17-year-old female patient with typical thelarche and adrenarche presented with primary amenorrhea. Pelvic ultrasound showed normally developed uterus and bilateral ovoid hypoechoic structures suggestive of gonads. Laboratory investigations revealed highly elevated gonadotrophins with estradiol level within a range typical for a female of reproductive age and chromosome analysis showed a 46,XY karyotype. Histopathological examination of the gonadectomy specimens revealed gonadoblastoma and dysgerminoma with no functional ovarian or testicular tissue. SUMMARY AND CONCLUSION: This report reminds us the possibility of diagnosis of Swyer syndrome in the presence of normal pubertal development and normal sex steroid levels considered to be produced by gonadoblastoma.

PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans.

Context Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B″gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results We have identified three different homozygous PPP2R3C variants, c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.

Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein.

Missense mutations in the gene, MAP3K1, are a common cause of 46,XY gonadal dysgenesis, accounting for 15-20% of cases [Ostrer, 2014, Disorders of sex development (DSDs): an update. J. Clin. Endocrinol. Metab., 99, 1503-1509]. Functional studies demonstrated that all of these mutations cause a protein gain-of-function that alters co-factor binding and increases phosphorylation of the downstream MAP kinase pathway targets, MAPK11, MAP3K and MAPK1. This dysregulation of the MAP kinase pathway results in increased CTNNB1, increased expression of WNT4 and FOXL2 and decreased expression of SRY and SOX9. Unique and recurrent pathogenic mutations cluster in three semi-contiguous domains outside the kinase region of the protein, a newly identified N-terminal domain that shares homology with the Guanine Exchange Factor (residues Met164 to Glu231), a Plant HomeoDomain (residues Met442 to Trp495) and an ARMadillo repeat domain (residues Met566 to Glu862). Despite the presence of the mutation clusters and clinical data, there exists a dearth of mechanistic insights behind the development imbalance. In this paper, we use structural modeling and functional data of these mutations to understand alterations of the MAP3K1 protein and the effects on protein folding, binding and downstream target phosphorylation. We show that these mutations have differential effects on protein binding depending on the domains in which they occur. These mutations increase the binding of the RHOA, MAP3K4 and FRAT1 proteins and generally decrease the binding of RAC1. Thus, pathologies in MAP3K1 disrupt the balance between the pro-kinase activities of the RHOA and MAP3K4 binding partners and the inhibitory activity of RAC1.

'Size does matter': Prophylactic gonadectomy in a case of Swyer syndrome.

Swyer syndrome also known as pure or complete gonadal dysgenesis is a very rare disorder of sex development wherein the individuals are phenotypically females with 46, XY genotype and preserved mullerian structures. These individuals characteristically have dysgenetic streak gonads which carry an increased risk of malignant transformation. Prophylactic gonadectomy is highly recommended as soon as a clinical diagnosis is established to diminish the chances of tumor development. We present a case of complete gonadal dysgenesis with bilateral small gonads with a dysgerminoma arising in a background of gonadoblastoma in one gonad and immature teratoma in the other. The present case, besides adding a rare case to the literature, highlights the importance of detailed pre-operative assessment of gonadal size and prompt prophylactic gonadectomy in cases with gonadal dysgenesis.

Is interstitial 8p23 microdeletion responsible of 46,XY gonadal dysgenesis? One case report from birth to puberty.

BACKGROUND: Chromosome 8p deletions are associated with a variety of conditions, including cardiac abnormalities, mental, behavioral problems with variable morphotype and genitourinary anomalies in boys. METHODS: We describe the follow-up over almost 15 years of a boy who initially presented with perineal hypospadias with a micropenis and cryptorchidism with 46,XY DSD. RESULTS: Imaging, pathology, and hormonal exploration suggested gonadal dysgenesis. Further genetic studies were deemed necessary during follow-up. The child's further development recommended further genetic analyses. High-resolution analysis showed an interstitial deletion on the short arm of a chromosome 8: 46,XY,del(8)(p23.1p23.1). We reviewed the literature and found 102 cases including 54 boys: 62.7% had mental problems, 50.9% a dysmorphic disorder, 55.9% cardiac anomalies, and 46.3% of the boys had genitourinary anomalies. Our patient's genital abnormalities can be explained by the haploinsufficiency of the genes, such as GATA4 (OMIM 600576) that are included in the deleted area. CONCLUSION: This case of severe 46,XY DSD raises the question of the role played by 8p23 microdeletion in gonadal dysgenesis. Clinicians are encouraged to look for this anomaly on chromosome 8 in cases of unexplained gonadal dysgenesis even when few signs suggestive of this anomaly are present.

45,X/46,XY Mosaicism Presenting With Isolated Unilateral Cryptorchidism and a Normal Blood Karyotype.

Context: 45,X/46,XY mosaicism is a disorder of sex development leading to abnormal gonadal development and to unpredictable genital phenotype, growth, and pubertal development. Case Description: A 2-year-old male presented with a right impalpable testis. Blood karyotype was 46,XY. A laparoscopy performed for right orchidopexy revealed a right streak gonad with Mullerian structures, whereas on the left side, a normal descended testis was present. The karyotype of the removed gonad was 45,X/46,XY. The child grew along the second centile, within the midparental height (MPH) range, until the time of puberty, when linear growth worsened due to a lack of a pubertal growth spurt, and growth hormone (GH) therapy was initiated. He developed spontaneous puberty (13 years of age) and showed normal pubertal progression. However, from the age of 15 years, he had low normal testosterone, raised follicle-stimulating hormone, and reduction of inhibin B, possibly suggestive of declining testicular function. His final height was -2.24 standard deviation score (SDS) (-2.4 SDS at GH start; MPH -1.6 SDS). Conclusions: Our case describes a mild male phenotype associated with 45,X/46,XY mosaicism characterized by unilateral cryptorchidism, spontaneous onset of puberty, and normal blood karyotype. The case illustrates the difficulties inherent in making a diagnosis of 45,X/46,XY mosaicism when there is no genital ambiguity and makes the point that growth and testicular impairment may occur, mostly manifesting during adolescence. An early diagnosis is crucial to initiate careful monitoring for growth and pubertal disorders, increased tumor risk, and fertility issues commonly seen in these children.

Presence of viable germ cells in testicular regression syndrome remnants: Is routine excision indicated? A systematic review.

There is no consensus in the literature about the necessity for excision of testicular remnants in the context of surgery for an impalpable testis and testicular regression syndrome (TRS). The incidence of germ cells (GCs) within these nubbins varies between 0 and 16% in previously published series. There is a hypothetical potential future malignancy risk, although there has been only one previously described isolated report of intratubular germ-cell neoplasia. Our aim was to ascertain an accurate incidence of GCs and seminiferous tubules (SNTs) within excised nubbins and hence guide evidence-based practice. The systematic review protocol was designed according to the PRISMA guidelines, and subsequently published by the PROSPERO database after review (CRD42013006034). The primary outcome measure was the incidence of GCs and the secondary outcome was the incidence of SNTs. The comprehensive systematic review included articles published between 1980 and 2016 in all the relevant databases using specific search parameters and terms. Strict inclusion and exclusion criteria were ultilised to identify articles relevant to the review questions. Twenty-nine paediatric studies with a total of 1455 specimens were included in the systematic review. The mean age of the patients undergoing nubbin resection was 33 months and the TRS specimen was more commonly excised from the left (68%). The incidence of SNTs was 10.7% (156/1455) and the incidence of GCs, 5.3% (77/1455). Histological analysis excluding the presence of either SNTs or GCs was consistent with TRS, fibrosis, calcification or haemosiderin deposits. There is limited evidence on subset analysis that GCs and SNTs may persist with increasing patient age. This systematic review has identified that 1 in 20 of resected testicular remnants has viable GCs and 1 in 10 has SNTs present. There is insufficiently strong evidence for the persistence of GCs and SNTs with time or future malignant potential. Intra-abdominal TRS specimens may contain more elements and, therefore, require excision, although this is based on limited evidence. However, there is no available strong evidence to determine that a TRS specimen requires routine excision in an inguinal or scrotal position.

Cellular and molecular responses of adult testis to changes in nutrition: novel insights from the sheep model.

This review explores the cellular and molecular mechanisms that regulate spermatogenesis in the post-pubertal testis that is regressing in response to mild undernutrition, using the sexually mature male sheep as a model. Testis regression leads to reductions in daily sperm production and in the quality of ejaculated spermatozoa (poorer movement, DNA damage). There is also a reduction in spermatogenic efficiency that appears to be caused, at least partially, by increases in germ cell apoptosis. Sertoli cell number does not change with testis regression, although about 1% of Sertoli cells do appear to retain proliferative ability after puberty. On the other hand, Sertoli cell function is disrupted during testis regression, as evidenced by a disorganization of tight junctions and indications that cell differentiation and maturation are reversed. Disrupted Sertoli cell function can explain, at least partially, the increase in germ cell apoptosis and any decrease in the rate of spermatogenesis, the two major contributors to spermatogenic efficiency. These outcomes seem to be mediated by changes in two RNA-based processes: (i) the expression of small non-coding RNAs that are involved in the regulation of Sertoli cell function, spermatogenesis and germ cell apoptosis and (ii) alternative pre-mRNA splicing that affects the regulation of spermatogenesis but does not appear to affect germ cell apoptosis, at least during testis progression induced by undernutrition in the male sheep. These research outcomes can be extended to other animal models and are relevant to issues in human male fertility.