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Introduction The bell-clapper deformity (BCD) predisposes to intravaginal torsion (IVT) and is classically bilateral. The precise pathological definition of what constitutes a BCD is not clear. The current study aims to clarify the specific anatomic details of this anomaly. Methods A systematic review was performed utilizing the PRISMA principles. Studies are presented chronologically based on their level of evidence. They are further divided into study types: autopsy and operative studies of acute torsion, intermittent torsion and studies of the contralateral testis in vanishing testis. Results The bell-clapper deformity is best defined by complete investment of the testis, epididymis and a length of the spermatic cord by the tunica vaginalis. Based on autopsy studies the rate of BCD in scrotal testis varied from 4.9% to 16%; with bilaterality in 66%–100%. In cases of acute IVT bilaterality was noted in 54%–100%. The most disparate results were in cases of testicular regression syndrome where contralateral BCD was noted in 0%–87% of cases. Conclusion We suggest future studies employ the strict anatomical definition above. As there is evidence of age-dependent investment of the testes, it will be important to develop age-standardized measurements of intravaginal length of spermatic cord. This critical morphometric measurement will allow a better understanding of the risk of IVT. Level of evidence Systematic review of diagnostic studies: lowest level of evidence of included manuscripts Level IV (case–control studies with a poor reference standard).

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.

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.

Objective To determine the prevalence of etiologic causes of primary amenorrhea in Indian population. Materials and methods A retrospective study was performed using 102 complete medical records of women with primary amenorrhea who attended the Gynaecologic Endocrinology Clinic, Department of Obstetrics and Gynaecology, AIIMS, New Delhi from September 2012 to September 2015. Cases were analysed according to clinical profile, development of secondary sexual characteristics, physical examination, pelvic and rectal examination, X-ray of chest and lumbo-sacral spine, hormone profile, pelvic USG, MRI, and cytogenetic study including karyotype. Results The three most common causes of primary amenorrhea were Mullerian anomalies (47%), gonadal dysgenesis (20.5%), and hypogonadotropic hypogonadism (14.7%) in the present study. There were 3 cases of Turner syndrome (45,XO), 5 cases of Swyer's syndrome (46,XY) and 2 cases of Androgen insensitivity syndrome (46,XY). One case had pituitary macroadenoma and eight cases (7.8%) were of genital tuberculosis. Conclusions The present study has currently been the largest case series of primary amenorrhea from North India. Mullerian anomaly is the most prevalent etiological factor leading to amenorrhoea followed by gonadal dysgenesis in our study. Racial, genetic and environmental factors could play role in the cause of primary amenorrhea.

17α-hydroxylase/17, 20-lyase deficiency (17OHD) is caused by mutations in the cytochrome P450 17A1 (CYP17A1) gene. To better understand 17OHD, a rare disease, we described the clinical features and performed CYP17A1 gene analysis in 8 affected Chinese patients.Patients with complete (7/8) or partial (1/8) 17OHD were derived from 6 families. The diagnosis was established according to their clinical, biochemical, hormonal, and radiological characteristics. Long-term follow-up of some patients was also designed.Patients with 17OHD suffered from varying degrees of hypokalemia and hypertension. Symptoms in female patients with partial 17OHD manifested as secondary amenorrhea, recurrent ovarian cysts, elevated estradiol level, and lower follicle-stimulating hormone and luteinizing hormone levels; primary amenorrhea was typical in patients with complete 17OHD. Adrenal masses and decreased bone mineral density (BMD) were discovered in 2 patients, respectively. During long-term follow-up, 4 patients developed low BMD, while 3 individuals underwent respiratory infections and recurrent urinary tract infections. CYP17A1 gene analysis revealed 7 different kinds of mutation, including 1 novel mutation, L266V.The clinical characteristics of partial 17OHD were different from those of complete 17OHD. Low BMD and infections were common in patients with 17OHD on long-term steroid treatment. Seven mutations were identified in the CYP17A1 gene, and 1 was novel.ACTH = adrenocorticotropic hormone BMD = bone mineral density CAH = congenital adrenal hyperplasia CT = computed tomography DEXA = dual-energy X-ray absorptiometry DEX = dexamethasone 17OHD = 17α-hydroxylase/17, 20-lyase deficiency.

Made available in DSpace on 2021-06-25T10:24:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-04-01 Responsible for post-testicular maturation, concentration, protection and sperm storage, the epididymis is an organ that can be easily subdivided into three segments: caput, corpus and cauda. Each epididymal region displays different morphology and functions within the sperm maturation process. Despite the great importance of this organ, studies on its morphology and hormonal control in bats remain scarce. Thus, the aim of this study was to morphologically analyze the epididymis of the bat Molossus molossus (Chiroptera: Molossidae), in order to evaluate its morphological and morphometric variations, as well as some aspects of its hormonal control during the annual reproductive cycle. For this purpose, 60 sexually adult males were used in this study, comprising five specimens collected monthly for one year to form 12 sample groups. The epididymis was subjected to morphological, morphometric and immunohistochemical analyses. The results demonstrated that the processes of total testicular regression and posterior recrudescence suffered by M. molossus also impacts the physiology of the epididymis, however, a delay in the epididymal response is seen due to the storage of sperm. Similar to other mammals, the epididymis of M. molossus has a large predominance of principal and basal cells. The epididymal seasonal variations appear to be directly correlated to rainfall and photoperiod, but not to temperature. Meanwhile, epididymal physiology appears to be regulated, at least partially, by the expression of the androgen receptor in epithelial cells, which has agonist effects on cell proliferation. Center of Biological and Health Science UFOB - Universidade Federal do Oeste da Bahia Department of Zoology and Botany UNESP – Univ. Estadual Paulista Department of Biology UNESP – Univ. Estadual Paulista Department of Zoology and Botany UNESP – Univ. Estadual Paulista Department of Biology UNESP – Univ. Estadual Paulista

Some seasonally-breeding animals are more aggressive during the short, “winter-like” days (SD) of the non-breeding season, despite gonadal regression and reduced circulating androgen levels. While the mechanisms underlying SD increases in aggression are not well understood, previous work from our lab suggests that pineal melatonin (MEL) and the adrenal androgen dehydroepiandrosterone (DHEA) are important in facilitating non-breeding aggression in Siberian hamsters (Phodopus sungorus). To characterize the role of MEL in modulating seasonal transitions in aggressive behavior, we housed male hamsters in long days (LD) or SD, treated them with timed MEL (M) or saline injections, and measured aggression after 3, 6, and 9 weeks. Furthermore, to assess whether MEL mediates seasonal shifts in gonadal and adrenal androgen synthesis, serum testosterone (T) and DHEA concentrations were quantified 36 h before and immediately following an aggressive encounter. LD-M and SD males exhibited similar physiological and behavioral responses to treatment. Specifically, both LD-M and SD males displayed higher levels of aggression than LD males and reduced circulating DHEA and T in response to an aggressive encounter, whereas LD males elevated circulating androgens. Interestingly, LD and SD males exhibited distinct relationships between circulating androgens and aggressive behavior, in which changes in serum T following an aggressive interaction (∆T) were negatively correlated with aggression in LD males, while ∆DHEA was positively correlated with aggression in SD males. Collectively, these findings suggest that SD males transition from synthesis to metabolism of circulating androgens following an aggressive encounter, a mechanism that is modulated by MEL.

Our objective was to identify the distribution of cytogenetic abnormalities of 175 Turkish women with primary amenorrhea (PA) or premature ovarian insufficiency (POI). A retrospective study was performed using medical records of 94 patients with PA and 81 patients with POI at the Genetics Department, Zeynep Kamil Women's and Children's Research and Training Hospital, Istanbul, Turkey. G-banded metaphase karyotype analysis were prepared and analyzed. Chromosomal abnormalities were present in 44 of 175 cases (25%). 15 were full blown or mosaic numerical X chromosome abnormalities (8.5%), 10 were full blown or mosaic X-chromosome structural anomalies (5.7%), one was X-autosome translocation (0.5%), 3 were autosomal anomalies (1.7%), 12 were XY karyotype (6.8%), one was 45,X/46,XY mosaic and 2 were full blown or mosaic structural anomalies of Y chromosome (1.7%). The prevalence of chromosomal abnormalities was 25% in this large series of Turkish women with primary amenorrhea or premature ovarian insufficiency, most cases involving X-aneuploidy or X-structural abnormalities or 46,XY karyotype. High prevalence of chromosomal abnormalities is associated with POI starting at an early age (average age: 26 years).

Objective To identify a contralateral testicular cut-off size that would predict monorchism (intra-abdominal vanishing testis or inguinal/scrotal nubbin) in boys with unilateral nonpalpable testis (NPT). Materials and methods Boys with cryptorchidism, treated by a single surgeon at a tertiary care center from 2009 to 2013, were grouped based on intra-operative findings: boys with a solitary gonad (monorchism group, M) and two control groups: intra-abdominal testis (IAT) and palpable undescended testis (pUDT). Immediately before the procedures, the contralateral descended testes were measured using callipers. Boys with NPT underwent diagnostic laparoscopy. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and receiver operating characteristic (ROC) curves were calculated. Results Out of the 324 boys with cryptorchidism, 58 were found to have pUDT and 85 had NPT. Of these 85 boys with NPT, 50 had an IAT and 35 had monorchism. Mean ages at surgery for groups M, IAT and pUDT were similar (28.0, 31.3 and 30.4 months, respectively; P = 0.4). Mean length of the contralateral descended testes in groups M, IAT and pUDT was 24.3, 16.5 and 18.8 mm, respectively. Contralateral testicular cut-off lengths of 18, 19 and 20 mm had positive likelihood ratios (LR+) of 6.5, 7.4 and 10.1, respectively. The area under the ROC curve was 95% (95% CI: 91–100%). Conclusion A contralateral testicular cut-off length of 19–20 mm had the best accuracy in predicting monorchism in boys aged 11–30 months with unilateral NPT.

Background Steroidogenic factor-1 (SF-1) gene (NR5A1) mutations cause disorders of sexual development due to gonadal dysgenesis, particularly in 46,XY individuals. In cases exhibiting this mutation, the phenotype is heterogeneous, and it may vary within a spectrum ranging from complete female appearance to an infertile male. Virilization observed in some cases in the pubertal age group may lead to diagnostic difficulties. Case The present case report describes the clinical, histopathologic, and genetic characteristics of a 46,XY case, who was born with a female phenotype and raised as a girl, presented with findings of virilization in the pubertal period. She had no germ cells and very few Leydig cells with atrophic testis on biopsy and in whom a novel heterozygous mutation in the SF-1 gene (a heterozygous 7-bp deletion mutation in exon 7 [c.1308-1314del7bp] causing frameshift) was identified. Summary and Conclusion Although the gonads are very dysgentic in patient with SF-1 mutations, sufficient androgen synthesis can cause severe virilization during puberty.

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 β-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.

Background: Swyer syndrome (46XY complete gonadal dysgenesis) is an uncommonly encountered condition in our population. Gonadectomy is recommended upon diagnosis due to a significant risk of malignant transformation of the dysgenetic gonads, typically to dysgerminoma. Cases: We present 3 cases of women who underwent gonadectomy following a diagnosis of Swyer syndrome. Two of these patients had dysgerminoma confirmed on histopathology. In particular we discuss the macroscopic appearance of the affected gonads and the further management of each case. Summary and Conclusion: Individuals with Swyer syndrome require gonadectomy upon diagnosis of their condition, as part of their multidisciplinary management. For treatment of early stage dysgerminoma, surgical resection of the involved gonad and fallopian tube is curative, again highlighting the need for early intervention.

The goals of this study are to define the spectrum, incidence, and relative frequency of testicular and paratesticular lesions in a typical North American population of 6 million based on the analysis of pathology specimens. Twenty years of pathology reports from 1990 to 2009 of all testicular and paratesticular specimens were retrieved and analyzed from computerized databases of the single major pediatric hospital in the state of Indiana. We showed that the three most common benign lesions were vanishing testis, atrophy/cryptorchidism, and testis torsion, all showed left-sided predominance. The incidence and trends of the major pathology entities were also studied. Neoplasms represented roughly 10% of the total, with leukemia, rhabdomyosarcoma, teratoma, and mixed germ cell tumor occurring in decreasing frequency. Many of the neoplasms occurred at characteristic narrow age ranges, with overall interesting bimodal distribution or some with unique genetic background.

Disorders of Sex Development (DSD) among 46,XY individuals are rare and challenging conditions. Abnormalities of karyotype, gonadal formation, androgen synthesis, and androgen action are responsible for the multiple disorders that result in undervirilization during development. Phenotypic appearance and timing of presentation are quite variable. The focus of treatment has shifted from early gender assignment and corrective surgery to careful diagnosis, proper education of patients and their families, and individualized treatment by a multi-disciplinary team. The modern management of these patients is difficult and controversial. Conflicting data on long-term outcomes of these individuals have been reported in the literature. The various etiologies of 46,XY DSD, current approaches to diagnosis and treatment, and reported long-term results are reviewed.

Objective To review the current management of boys with bilateral anorchia and assess whether surgical exploration is necessary when endocrine investigation indicates absent testicular function. Patients and methods The medical records of 11 boys being managed for bilateral anorchia were reviewed in relation to clinical presentation, pituitary-gonadal function, surgical and histological findings. Results All boys had absence of testicular function based on undetectable levels of serum anti-Mullerian hormone, elevated basal or peak follicle-stimulating hormone and luteinising hormone levels and no testosterone response to human chorionic gonadotrophin stimulation. All boys underwent abdominal exploration, ten of whom showed no macroscopic signs of testis tissue, confirmed histologically in seven. Histology was not available in the remaining three boys. Abnormally small intra-abdominal testes were found bilaterally in one boy. These were sited in the scrotum at orchidopexy but had subsequently atrophied. Endocrine tests confirmed absent testicular function. Conclusion Based on the high degree of concordance between the surgical and histological findings and the results of the endocrine tests, it is suggested that surgery is unnecessary in bilateral anorchia when endocrine tests confirm the absence of functioning testicular tissue.

Despite advances in our understanding of the mechanisms involved in sex determination and differentiation, the specific roles of many genes in these processes are not completely understood in humans. Both DMRT1 and FGF9 are among this group of genes. Dmrt1 controls germ cell differentiation, proliferation, migration and pluripotency and Sertoli cell proliferation and differentiation. Fgf9 has been considered a critical factor in early testicular development and germ cell survival in mice. We screened for the presence of DMRT1 and FGF9 mutations in 33 patients with 46,XY gonadal dysgenesis. No deletions in either DMRT1 or FGF9 were identified using the MLPA technique. Eight allelic variants of DMRT1 were identified, and in silico analysis suggested that the novel c.968-15insTTCTCTCT variant and the c.774G>C (rs146975077) variant could have potentially deleterious effects on the DMRT1 protein. Nine previously described FGF9 allelic variants and six different alleles of the 3’ UTR microsatellite were identified. However, none of these DMRT1 or FGF9 variants was associated with increased 46,XY gonadal dysgenesis. In conclusion, our study suggests that neither DMRT1 nor FGF9 abnormalities are frequently involved in dysgenetic male gonad development in patients with non-syndromic 46,XY disorder of sex development.

Biological assessment of abnormal genitalia is based on an ordered sequence of endocrine and genetic investigations that are predicated on knowledge obtained from a suitable history and detailed examination of the external genital anatomy. Investigations are particularly relevant in 46,XY DSD where the diagnostic yield is less successful than in the 46,XX counterpart. Advantage should be taken of spontaneous activity of the pituitary-gonadal axis in early infancy rendering measurements of gonadotrophins and sex steroids by sensitive, validated assays key to assessing testicular function. Allied measurement of serum anti-Mullerian hormone completes a comprehensive testis profile of Leydig and Sertoli cell function. Genetic assessment is dominated by analysis of a plethora of genes that attempts to delineate a cause for gonadal dysgenesis. In essence, this is successful in up to 20% of cases from analysis of SRY and SF1 (NR5A1) genes. In contrast, gene mutation analysis is highly successful in 46,XY DSD due to defects in androgen synthesis or action. The era of next generation sequencing is increasingly being applied to investigate complex medical conditions of unknown cause, including DSD. The challenge for health professionals will lie in integrating vast amounts of genetic information with phenotypes and counselling families appropriately. How tissues respond to hormones is apposite to assessing the range of genital phenotypes that characterise DSD, particularly for syndromes associated with androgen resistance. In vitro methods are available to undertake quantitative and qualitative analysis of hormone action. The in vivo equivalent is some assessment of the degree of under-masculinisation in the male, such as an external masculinisation score, and measurement of the ano-genital distance. This anthropometric marker is effectively a postnatal readout of the effects of prenatal androgens acting during the masculinisation programming window. For investigation of the newborn with abnormal genitalia, a pragmatic approach can be taken to guide the clinician using appropriate algorithms.

SummaryMale sex determination in mammals is induced by Sry, a gene whose regulation is poorly understood. Here we show that mice mutant for the stress-response gene Gadd45g display complete male-to-female sex reversal. Gadd45g and Sry have a strikingly similar expression pattern in the genital ridge, and they are coexpressed in gonadal somatic cells. In Gadd45g mutants, Sry expression is delayed and reduced, and yet Sry seemed to remain poised for expression, because its promoter is demethylated on schedule and is occupied by active histone marks. Instead, p38 MAPK signaling is impaired in Gadd45g mutants. Moreover, the transcription factor GATA4, which is required for Sry expression, binds to the Sry promoter in vivo in a MAPK-dependent manner. The results suggest that a signaling cascade, involving GADD45G → p38 MAPK → GATA4 → SRY, regulates male sex determination.

Campomelic dysplasia (CD) is a rare autosomal dominant skeletal malformation with or without sex reversal. About 10% of cases that present with milder skeletal features are referred to as acampomelic campomelic dysplasia (ACD). CD and ACD are caused by mutations in SOX9. We report a patient of homozygous SOX9 deletion with minimal skeletal anomaly and female external genitalia in the presence of a male karyotype. The mechanisms explaining the homozygous deletion include a de novo mutation followed by gene conversion, uniparental disomy, or somatic crossing over. Our report highlights the possibility of ACD in XY sex-reversed patients with minimal skeletal presentation.

Male to female sex reversal in patients with 46,XY karyotype results from the failure of development of testis which may be due to mutations in the SRY gene. Only 10-15% of cases of 46,XY gonadal dysgenesis are accounted for by different types of mutations in the SRY gene. Hence, majority of such patients may have mutations in other genes involved in the testicular differentiation pathway. Besides SRY, other autosomal and X-linked genes are also involved in sexual development during embryogenesis. We describe here the first report from India wherein, two cases of 46,XY complete gonadal dysgenesis that could be attributable to mutations in the Desert hedgehog (DHH) gene. The mutations found in these two patients were a homozygous deletion (c.271_273delGAG) that resulted in deletion of one amino acid (p.D90del) and a homozygous duplication (c.57-60dupAGCC) that resulted in premature termination resulting in non-functional DHH protein. The structure-function implications of the p.D90del mutation were predicted using computational tools. Structural studies on the p.D90del mutant revealed that the mutation could seriously perturb the interaction of DHH with its binding partners. This is the second report in literature showing homozygous mutation in cases with 46,XY complete gonadal dysgenesis.

Monosomy 9p syndrome, also known as Alfi syndrome, has been described as a contiguous syndrome characterized by mental retardation, developmental delay, and facial dysmorphisms. Males with monosomy 9p often express variable degrees of feminization, although the genitalia of females will be normal. In the present report, we describe a case of ambiguous genitalia and intra-abdominal testicular development, with a derivative chromosome 9 arising from a translocation between 9p23 and Yq heterochromatin. Pathologic examination of the testes showed germ cell hypoplasia of the seminiferous tubules. fluorescence in situ hybridization, spectral karyotyping, and array comparative genomic hybridization were used to characterize the genetic changes.

Patients Eleven patients with 46,XY PGD were divided into two groups. Six symptomatic girls (group 1) were referred for amenorrhea (n = 3), gonadal tumor (n = 2) or campomelic dysplasia (n = 1). Five asymptomatic screened patients (group 2) were diagnosed as 46,XY PGD after familial investigation of the two probands with gonadal tumor. Bilateral gonadectomy was performed in all patients. Results In group 1, pathologic examination revealed an association of dysgerminoma with gonadoblastoma (n = 2), bilateral gonadoblastoma (n = 2) and streak gonads (n = 2). Prophylactic gonadectomy in asymptomatic patients (group 2) also showed asymptomatic dysgerminoma with gonadoblastoma (n = 1), bilateral gonadoblastoma (n = 2) and streak gonads (n = 2). Conclusions A gonadal tumor arising in a girl with pubertal delay may be related to dysgenesis of the gonad. Primary amenorrhea or diagnosis of dysgerminoma should warrant karyotype, and familial study if 46,XY PGD is found. Considering the high incidence of gonadoblastoma and the early occurrence of dysgerminoma, early bilateral gonadectomy is recommended.

Disorders of androgen production can occur in all steps of testosterone biosynthesis and secretion carried out by the foetal Leydig cells as well as in the conversion of testosterone into dihydrotestosterone (DHT). The differentiation of Leydig cells from mesenchymal cells is the first walk for testosterone production. In 46,XY disorders of sex development (DSDs) due to Leydig cell hypoplasia, there is a failure in intrauterine and postnatal virilisation due to the paucity of interstitial Leydig cells to secrete testosterone. Enzymatic defects which impair the normal synthesis of testosterone from cholesterol and the conversion of testosterone to its active metabolite DHT are other causes of DSD due to impaired androgen production. Mutations in the genes that codify the enzymes acting in the steps from cholesterol to DHT have been identified in affected patients. Patients with 46,XY DSD secondary to defects in androgen production show a variable phenotype, strongly depending of the specific mutated gene. Often, these conditions are detected at birth due to the ambiguity of external genitalia but, in several patients, the extremely undervirilised genitalia postpone the diagnosis until late childhood or even adulthood. These patients should receive long-term care provided by multidisciplinary teams with experience in this clinical management. Fil: Mendonca, Berenice B.. Universidade de Sao Paulo; Brasil Fil: Costa, Elaine M.F.. Universidade de Sao Paulo; Brasil Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rivarola, Marco Aurelio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Domenice, Sorahia. Universidade de Sao Paulo; Brasil

We screened 100 individuals with anomalies of testicular development or function for mutations in the TSPYL1 gene. A 46,XY female with complete gonadal dysgenesis carried a p.K320R mutation in the highly conserved NAP domain, and a 46,XY male with idiopathic azoospermia harbored a p.R89H mutation, and this data supports the hypothesis that mutations in TSPYL1 may contribute to anomalies of testicular development/function.

Objective To characterize the phenotypic spectrum of males with bilaterally descended testes and a 45,X/46,X,(r)Y karyotype. Design Retrospective review of patient records; cytogenetic and molecular analysis. Setting Tertiary medical center setting. Participant(s) Five males, two prepubertal and three postpubertal, with a 45,X/46,X(r)Y karyotype and bilaterally descended testes. Intervention(s) Linear growth evaluation, testicular endocrine and exocrine studies, cytogenetic and molecular analysis on each patient. Main Outcome Measure(s) Clinical phenotype versus genotype. Result(s) Both prepubertal males had short stature and low testosterone. All three adults had normal puberty and normal testosterone levels. Two of the adults (one with short stature and one with normal stature) had elevated gonadotropins and azoospermia. The third adult had normal stature, severe oligospermia, normal gonadotropins, and normal serum testosterone. Conclusion(s) The phenotypic spectrum of males with a 45,X/46,X(r)Y karyotype and bilaterally descended testes varies greatly from males with short stature and spermatogenic failure to males without short stature and less severely affected spermatogenesis. This broad spectrum of phenotypic findings needs to be taken into account when the clinical geneticist encounters a prenatal diagnosis of a 45,X/46,X(r)Y karyotype. This information will also be helpful for pediatric and reproductive endocrinologists in counseling males with bilaterally descended testes and a 45,X/46,X(r)Y karyotype.

46,XY pure gonadal dysgenesis, first described in 1955 by Swyer, results from testicular tissue loss during the first 8 weeks of fetal life, a critical period for male differentiation. We describe a case of an 18 years old patient presented to us with a chief complain of primary amenorrhea. Chromosomal analysis revealed a 46,XY karyotype. A molecular investigation was undertaken in an attempt to determine mutations in SRY and AR genes through DNA sequencing. Mutations were shown to be absent. The molecular basis of Swyer syndrome is still unknown, although the presence of mutations in testicular organizing genes downstream of SRY is still to rule out. The patient, who is considered as female, was placed on estrogen replacement therapy, while bilateral prophylactic laparoscopic gonadectomy was programmed due to the high prevalence of gonadal tumors in this syndrome. No signs of malignance were detected in the gonadal tissue, which predicts that an intact SRY gene is usually, but not always, not related to the formation of malignancies like dysgeminomas or gonadoblastomas.

Objective To investigate sexual function in women with complete androgen insensitivity syndrome (CAIS) and to investigate the prevalence of factors that might contribute to sexual difficulties. Design Cross sectional survey and clinical examination. Setting Tertiary hospital multidisciplinary intersex clinic and an international peer support group for CAIS. Patient(s) Sixty-six adult women with CAIS. Intervention(s) Self-completed survey of sexual function, genital normality perceptions, and compliance and satisfaction with vaginal hypoplasia treatments. Hospital case notes review, and genital examination for prevalence of vaginal and clitoral hypoplasia. Main outcome measure(s) Golombok-Rust Inventory of Sexual Satisfaction (GRISS) scores of study participants were compared against the scores of the test validation population (as control). In physical examination participants, anatomical dimensions were assessed against published normal values for clitoral and vaginal sizes. Result(s) We found that 90% of women with CAIS in this study had sexual difficulties when compared with the general female population, most commonly sexual infrequency and vaginal penetration difficulty; 77% perceived their vagina as small, but on genital examination only 35% had vaginal hypoplasia. Conclusion(s) Androgen deficiency leads to sexual problems. Vaginal hypoplasia and negative psychological adaptation to living with an intersex condition are likely to have contributed to the high rates of sexual problems found in this study. Treatments for vaginal hypoplasia need to be evaluated with outcome studies of long-term sexual function, quality of life, and satisfaction. Clinical services for the management of intersex conditions need to be multidisciplinary and aim to optimize the patient's physical and psychological health.

Objective To describe a case of XY gonadal dysgenesis with Tanner stage 4 breast development in the absence of a hormone-producing gonadal neoplasm and with Graves’ disease and low bone mass. Methods The clinical features, laboratory results, and cytogenetic findings in the patient are presented, and the potential mechanisms of breast development are discussed. A MEDLINE search was performed, and related articles in the English-language literature published between 1955 and 2001 were reviewed. Results A 23-year-old African American woman was referred to the University of Louisville Hospital for evaluation of hyperthyroidism. About 4 months before this referral, hyperthyroidism was diagnosed, and treatment with methimazole was initiated. She continued to have thyrotoxicosis. Additionally, systemic review disclosed a history of primary amenorrhea. Physical examination revealed a tall phenotypic female patient with Tanner stage 4 breast development. Pelvic examination showed normal findings except for sparse pubic hair. Laboratory evaluation confirmed the diagnosis of Graves’ disease as well as primary gonadal failure. Pelvic ultrasonography revealed a small uterus and bilateral adnexal masses (0.9 by 0.6 cm). On chromosomal analysis, a 46,XY karyotype was found. Further analysis of Y-DNA by polymerase chain reaction confirmed the presence of an intact Y chromosome, and no microdeletions were identified. Dual-energy x-ray absorptiometry demonstrated a Z-score of -4.7 and -4.2 at the lumbar spine and right hip, respectively. Graves’ disease was successfully treated with 131I. Laparoscopy was performed to resect streak gonads. On histologic examination, no typical ovarian, testicular, or neoplastic tissue was identified. The breast development in this patient remains unexplained. Conclusion To the best of our knowledge, this is the first case report of a tall XY female patient with breast development in the absence of a hormone-producing gonadal neoplasm and without clearly identifiable gonads. Breast development was most likely related to estrogens, possibly produced by either streak gonads at the time of puberty or peripheral conversion of androgens, or to increased sensitivity of breast tissue to estrogens. Graves’ disease is likely coincidental and could contribute to bone loss in such subjects. (Endocr Pract. 2003;9:220-224)

Sex determining Region of the Y chromosome ( SRY ) is the Y-borne gene required for male sex determination. Many XY females with complete gonadal dysgenesis carry SRY mutations. We describe here the effects of eight clinically isolated point mutations on the DNA-binding and -bending functions of SRY. We found that the seven mutations in the HMG domain affected the protein's DNA-binding and -bending activities to varying degrees, although all cause complete gonadal dysgenesis. DNA binding was abolished by the R75N and L94P mutations, severely disrupted by the F67V mutation and reduced by the M64R (6-fold), R76P (4-fold), A113T (3-fold), and M78T (1.7-fold) mutations. Of these, variant M64R showed no DNA-bending activity, while M78T caused a mild reduction in DNA bending. The S18N mutation, a familial mutation that lies outside the HMG domain and caused partial gonadal dysgenesis in one patient, had minimal effect on DNA binding and bending. Analysis of the NMR solution structure of the SRY HMG domain bound to DNA suggests that mutations disrupt the protein's conformation (helicity, packing), or interactions at the DNA interface. The degree to which mutations causing complete gonadal dysgenesis affect the DNA-binding activity varies. We propose that there is a threshold level of SRY activity or expression required for testis determination, as we observe that familial mutations have the least effect on SRY activity.

We acknowledge that gonadal management of DSD patients, like many other DSD-related issues, is controversial. Bilateral gonadectomy in children with DSD conditions with known high germ cell cancer (GCC) risk is indeed a safe option, but at a significant price in terms of need for puberty induction and subsequent hormone replacement therapy, and definite loss of fertility. For patient and parent counseling procedures it is regrettable that reliable figures on gonadal GCC risk in many DSD conditions are either lacking or at best roughly known. Especially in rare DSD conditions, like the WT-1 mutations linked to Frasier and DenyseDrash syndromes, reported incidence rates on gonadal malignancy are based on a limited number of case studies. This, together with assumed publication bias which is inherent to case reports, and inconsistent or unverified patient classification has led that reported figures on gonadal GCC risk in rare DSD conditions are inaccurate and hazardous for individual patient management purposes. As individual patient care cannot be postponed until global knowledge level has improved, we propose a semi-quantitative approach, in which DSD patients are stratified into four categories according to their putative gonadal GCC risk level: high, intermediate, equal to the general population and unknown. We admit that this classification is provisional, though reflective of the present knowledge on gonadal GCC risk in the various DSD subgroups. We would like to reiterate that all streaklike gonads of the DSD population at risk, like in patients with mosaic Turner syndrome harboring Y-chromosomal material, should be removed. Concerning all other, non-streaklike gonads at risk: our proposal, namely to bring these gonads to an extra-abdominal (inguinal or preferably scrotal) position allowing monitoring by self-examination and imaging, is in our view a valid alternative to immediate gonadectomy. Taking representative biopsies during this repositioning procedure is mandatory for a thorough histopathological examination, of which the results will be crucial for future gonadal management: retention or gonadectomy. While postponement or even abrogation of gonadectomy is by definition creating some uncertainty, it has undeniable advantages like spontaneous pubertal development, endogenous sex hormone supply, involvement of the patient self in decision making, and possibly even fertility preservation. Let us strive to fill the knowledge gaps in the field of gonadal malignancy risk by global collaboration in preferentially prospective studies, thereby increasing the level of evidence of our treatment protocols and improving the quality of life for patients with DSD.

Objective To report a case of a successful pregnancy and delivery of a patient with 46,XY pure gonadal dysgenesis (Swyer syndrome) and preexisting chronic hypertension who underwent in vitro fertilization (IVF) and embryo transfer (ET). Design Case report and review of the literature. Setting 2nd Department of Obstetrics and Gynecology, University of Athens, Medical School, "Aretaieion" Hospital. Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery. Patient(s) A 35-year-old woman with Swyer syndrome and chronic idiopathic hypertension. Intervention(s) Karyotype analysis due to primary amenorrhea; gonadectomy, hormone therapy, investigation of hypertension, IVF using donor oocytes, embryo transfer and caesarean delivery for fetal distress. Main Outcome Measure(s) Successful pregnancy and live birth. Result(s) We present a rare case of a successful pregnancy of a patient with Swyer syndrome accompanied by idiopathic chronic hypertension. Conclusion(s) A woman with Swyer syndrome, hypoplastic uterus, and chronic hypertension delivered a healthy newborn.

Cardiovascular and endocrine complications in male or sexually-ambiguous patients carrying a 45,X/46,XY mosaicism are rarely discussed in the medical literature. However, young female patients with a diagnosis of Turner's disease usually benefit from regular cardiologic and endocrine follow-up, in accordance with current international guidelines. We report the case of a male patient, aged 23 years, with an ambiguous phenotype known to harbor a mixed gonadic 45,X/46,XY type dysgenesis. The patient was admitted to the cardiology ward for investigation and management of cardiac failure secondary to both a biscupid aortic valve and ascending aorta aneurysm. This case report, and the few others, which have been previously reported in the literature, emphasizes the importance of cardiologic and endocrine follow-up in male carriers of 45,X/46,XY mosaicism.

Distal chromosome 9p contains a locus that, when deleted, is a cause of 46,XY gonadal dysgenesis in the absence of extragenital anomalies. This locus might account for the frequently observed cases of 46,XY pure gonadal dysgenesis who do not harbor mutations in SRY, the sex master regulator gene found in mammalian species. The genomic organization of 9p positional candidate genes is currently being studied and mutational screens are ongoing. Among other positional candidates, including two additional doublesex-related genes, the evidence to support a role for the gene DMRT1 in vertebrate male sexual development is accumulating. Although formal proof of the requirement of DMRT1 in gonadal sex fate choice has not been obtained so far, the particular interest in this gene and perhaps other doublesex-related genes identified in vertebrates lies in that they may provide an entry point to a conserved mechanism of sex determination across animal phyla. We discuss recent results and emerging views on the genetics of sex determination, while stressing that the majority of cases of 46,XY gonadal dysgenesis remain unexplained. The latter is likely to be efficiently addressed by positional cloning efforts, particularly by considering the wealth of sequence data provided by the Human Genome Project.

The absence of a testis occurs for various reasons in children, but testicular prosthesis implantation in children is uncommon. The optimal time for prosthesis placement is still unclear, and its complication rate has been poorly studied in children.The aim of this study was to determine the risk factors of complications in cases of testicular prosthesis implantation in children.A monocentric, retrospective review was performed of children implanted with a testicular prosthesis between 2008 and 2014. All implantations were performed through an inguinal incision with a standardized procedure. Children were divided into two groups depending on the interval after orchiectomy: (A) early implantation (delay between surgeries1 year); and (B) delayed surgeries (delay ≥1 year). Statistical analysis was performed with Student and Fisher tests.Twenty-six patients (A, 15; B, 11) had a total of 38 testicular prostheses placements. Mean follow-up was 36.2 months. First surgery was performed at the mean age of 11.8 years (range 0-17.9) (A, 14.1; B, 8.1; P = 0.01) and testicular prosthesis implantation at the mean age of 14.7 years (range 9-18) (A, 14.3; B, 14.6) with a mean delay of 36.1 months (A, 1.3; B, 80.3). Indications were mainly spermatic cord torsion (27%), bilateral anorchia (27%), and testicular atrophy after cryptorchidism surgery (19.2%). Complications (10.5%) included two cases of extrusion, one infection and one migration. Patient 1 had a history of acute lymphoblastic leukemia with testicle relapse 2 years after induction therapy. High-dose chemotherapy, total body irradiation and bilateral orchiectomies were performed, and bilateral prostheses were implanted 12 years after the end of chemotherapy. Complications happened 85 days after surgery. Patient 2 was followed-up for a proximal hypospadias. The tunica vaginalis flap, which was used during a redo urethroplasty, lead to testicular atrophy. Thirteen years after the last penile surgery, a testicular prosthesis was placed through an inguinal incision, and extrusion occurred 203 days after surgery. Bacterial cultures of the prostheses were sterile and histological review showed no sign of granuloma or graft rejection. The complication rate was significantly higher if the delay between the two surgeries exceeded 1 year (P = 0.01). Indications of orchiectomy, prior scrotal incision, and prosthesis size were not risk factors.Testicular prosthesis implantation was relatively safe in a pediatric cohort. The complication rate was significantly higher if the delay between the orchiectomy and the prosthetic placement exceeded 1 year. These results suggest that reducing the delay between orchiectomy and prosthesis implantation may lead to fewer complications.

Summary Objectives Testicular hypertrophy has previously been evaluated as a predictor of monorchism. However, its implication in clinical practice is not well evaluated. The aim of the present study was to examine its value in planning the operative time. Patients and methods Medical charts of prospectively recorded data of 76 consecutive patients with unilateral impalpable testis from 2011 to 2014 were reviewed at the present institute. Inclusion criteria included prepubertal patients with non-palpable testes by examination under anesthesia. Contralateral testes were prospectively measured using a Takihara orchidometer. Orchiectomy or orchiopexy was performed according to the viability of the undescended testis (UDT). Collected data included age of surgery, contralateral testicular size, surgical time and laparoscopic findings. A ROC curve was used to define the best cut-off volume of the contralateral testis that can predict ipsilateral testicular viability. The Student's t-test was used to examine if this cut-off volume would be useful in allocating the operative time. Results Of 76 patients, four palpable testes by examination under anesthesia were excluded. The remaining 72 patients were included in the study. Ipsilateral normal viable testes were found in 26 (36.1%) patients, while 46 (63.9%) had non-viable testes (testicular nubbins or vanishing testes) (Figure). A contralateral testicular volume >2 ml was significantly predictive for monorchism with 71.7% sensitivity and 100% specificity (P 2 ml was 50 min, which was significantly shorter than that for UDT with a contralateral size ≤2 ml, which was 88 min (P Discussion In previously published reports, the cut-off value for testicular hypertrophy that predicts monorchism greatly varied. This is likely due to the different methods used for testicular measurements that make it impractical to make a direct comparison. The usefulness of predicting monorchism before surgery has not previously been used as a guide for allocating operative time in the management of a unilateral non-palpable testicle. This study had some limitations, including a relatively small sample size and involvement of different surgeons, which may have affected the operative time. Conclusion Using the cut-off volume of a contralateral testis >2 ml as a predictor for monorchism can reduce the allocated operative time by approximately one third.

The androgen receptor belongs to the family of steroid-thyroid hormone-retinoid nuclear receptors. It contains 3 major domains: a hormone-binding region, a DNA-binding region and an amino-terminal region. Cloning of the cDNA encoding the androgen receptor and elucidation of the androgen receptor gene structure enabled the characterization of the molecular defects associated with androgen insensitivity. Mutations of the androgen receptor in 46,XY individuals cause a spectrum of androgen insensitivity syndromes, ranging from female phenotype (testicular feminization) to minor degrees of undervirilization or infertility. Reports on androgen receptor gene structure in patients with complete or partial forms of androgen insensitivity demonstrate that gene deletions are very rare. Several categories of mutations have been reported and are reviewed in this paper. Nucleotide substitutions in the androgen-binding domain or the N-terminal region that cause insertion of premature termination codons result in failure to form a functional protein. Missense mutations within the androgen-binding domain are responsible for a decrease or absence of receptor-binding activity. Mutations within the DNA-binding domain are associated with a positive receptor-binding form of androgen insensitivity. Analysis of described mutations indicates that they are spread throughout the gene, either associated with partial or complete androgen insensitivity. Furthermore, the same point mutation was reported to be associated with variable phenotypic expression of androgen insensitivity syndrome. It is thus difficult to define a genotype/phenotype relationship. However, mutations causing androgen insensitivity will certainly yield important new insights into the molecular basis of androgen action.

Although girls with Turner's syndrome (45,X) are not at risk for malignancy, patients with feminizing testicular syndrome with XY chromosome composition and patients with "mixed gonadal dysgenesis" are at risk for malignancy, and bilateral gonadectomy is performed. We have treated seven girls with "Turner-like" syndrome, who we believe are also "at risk" for development of malignancy and in whom gonadectomy should be performed. We present seven cases of phenotypically typical females, without sexual ambiguity, who presented with primary amenorrhea and short stature (5) and/or minor dysmorphic features (2). Chromosome analysis showed 45,X karyotype plus a fragment that we could not rule out as being part of a Y chromosome (in one patient a complete Y chromosome). In two patients, the fragment was subsequently positively identified as a Y, using a DNA probe. In view of the known high incidence of development of gonadoblastoma in the dysgenetic gonads of phenotypic females with a Y chromosome, bilateral gonadectomy was performed in these girls. Bilateral genital streaks with normal uterus and Fallopian tubes were found in all patients. In two patients unsuspected gonadoblastoma, without metastases, was found. In five cases, Leydig cells and tubular structures resembling rete testes were found, cells that are associated with Y-chromosomal tissue. We stress the need for complete chromosomal evaluation of phenotypically female patients with primary amenorrhea or features of Turner's syndrome. If a Y chromosome or the possibility of a Y chromosome cannot be excluded, gonadectomy should be performed because of the risk of malignancy.

Study Objective To understand the timing and factors affecting diagnosis of phenotypically female 46XY children. Design, Setting, and Participants We studied all phenotypically female 46XY children who attended our multidisciplinary disorders of sexual differentiation (DSD) clinic in Nottingham England in a 3-year period since its inception. Case notes from a prospectively maintained database were reviewed and data were analyzed on the age at presentation, family history, findings on genital examination, and underlying endocrine abnormality. Results Eleven children were studied, all of whom were being raised as girls. The median age of presentation was 18 months (range birth-15 years). Although the newborn examination detected the possibility of DSD in only 3 cases; 10 of 11 children had at least one significant abnormality in their external genitalia at presentation. Conclusion Careful neonatal genital examination can identify children with DSD. However, not all children with these conditions are identified early. Early diagnosis, when possible, is important, as it has the potential to make the management of this difficult condition more straightforward.

Hypogonadism affecting the male pediatric population is uncommon, with that attributed to multiple unrelated etiologies being exceedingly rare. We report a case of septo-optic dysplasia, an atypical cause of delayed puberty, with subsequent workup unveiling 2 coexistent conditions: hypogonadotropic hypogonadism and anorchia. Primary and secondary etiologies must be considered in patients with undescended testes. Thorough evaluation is mandatory to ensure proper diagnosis and care, because Occam's razor can, on unique occasions, be double-edged.

2 An 18-year-old phenotypic female with normal external enitalia and secondary sexual characteristics but as well a chromosome had primary amenorrhea. Vaginal examinaion showed the presence of a cervix. Diagnostic laparosopy showed a very primitive uterus with normal fallopian ubes arising from it. Both gonads were long, flat, and treak-like, and they were closely approximated to the falopian tubes. There was an elongated uterine attachment rising from the caudal end of the gonad and a short infunibulopelvic ligament from the gonad’s cranial end. Lapaoscopic bilateral adnexectomy was performed to ensure omplete removal of the gonads. The rudimentary uterus

Objective To investigate a cohort of patients with gonadal disorders of sex development (DSD) for causative CBX2 gene mutations and or gene copy number changes. Design Genetic association study. Setting University laboratory and tertiary university-based referral center. Patient(s) 47 patients with different forms of 46,XY or 46,XX gonadal DSD. Intervention(s) CBX2 gene sequencing and development of a synthetic probe set for multiplex ligation probe amplification (MLPA) to detect CBX2 copy number changes, and reverse-transcriptase polymerase chain reaction (RT-PCR) to evaluate CBX2 expression in two different cell-line types. Main Outcome Measure(s) Gene sequence alteration and or partial or complete gene copy number variations, and detection of CBX2 mRNA isoforms. Result(s) We detected 10 sequence alterations, 9 reported single nucleotide polymorphisms (SNPs), and a previously unreported variant. This was a silent c.1356G>A transition that may represent a normal variant. A rare SNP (c.1411C>G, p.471Pro>Ala) was found in heterozygous form in one patient. No deletions or duplications were detected by MLPA. Expression of both CBX2 mRNA isoforms was documented in gonadal fibroblasts and Epstein Barr virus (EBV)-transformed lymphocytes. Conclusion(s) No pathogenic CBX2 mutation was detected. Both CBX2 isoforms are expressed in gonadal fibroblasts and EBV-transformed lymphocytes. This study does not support CBX2 gene disruption as a common cause of gonadal DSD.

Objective To investigate the familial segregation, role, and function of a novel SRY missense mutation c.347T>C in two half-sisters affected by 46,XY complete gonadal dysgenesis (CDG) compatible with a successful pregnancy outcome. Design Phenotypic, mutational, and functional study. Setting Academic research unit. Patient(s) Two half-sisters, their common father, and 100 healthy control individuals. Intervention(s) Chromosome, molecular cytogenetic analysis, and Sanger sequencing of the SRY gene in blood lymphocytes of the proband, her affected half-sister, and in inflammatory tissue of the father postmortem. Cloning and expression of high mobility group box carboxy-terminal domains of Sry and electrophoretic mobility shift assay were performed. Main Outcome Measure(s) Not applicable. Result(s) A novel SRY missense mutation c.347T>C (p.Leu116Ser) was identified in two half-sisters and segregates with the CGD phenotype. It is present in the common healthy father in a mosaic state. Functional analyses demonstrate the pathogenic effect of the mutation by a strong reduction of DNA affinity for the mutant p.Leu116Ser SRY protein. Conclusion(s) The missense mutation c.347T>C in the high mobility group domain of SRY causes 46,XY CGD. Paternal gonadal mosaicism is likely to explain the familial occurrence of 46,XY CGD suggesting a de novo mutational event during the early stages of embryonic development. This novel mutation is compatible with a successful pregnancy outcome.

Objective To report a case of successful pregnancy and delivery after IVF and ET in a patient with Swyer syndrome. Design Case report. Setting Unit of Assisted Reproduction, Gynecology and Obstetrics Institute, University of Belgrade. Patient(s) A 30-year-old patient with 46,XY gonadal dysgenesis. Intervention(s) Chromosomal analysis, diagnostic laparoscopy, IVF using donor oocytes, ET, and cesarean delivery. Main Outcome Measure(s) Successful pregnancy and live birth. Result(s) Successful treatment, pregnancy, and delivery. Conclusion(s) A patient with 46,XY gonadal dysgenesis in a donor oocyte program, can maintain a normal pregnancy and delivery.

Objective To report a translocation between chromosomes 3 and 4: 46,XY,t(3;4)(p25;q31.3) in a male infant with a disorder of sexual development. Design Case report. Setting University hospital. Patient(s) A 1-year-old infant who presented with abnormal location of the urethral meatus. Intervention(s) Cytogenetic analysis, fluorescence in situ hybridization (FISH), and serum concentrations measurement (using peripheral blood), and clinical examination. Main Outcome Measure(s) Karyotype and clinical findings. Result(s) On clinical examination, bilateral testicular volume and phallus were determined to be undersized. Serum concentrations of T and DHEAS were low. G-banding of his chromosomes showed that the patient had a balanced translocation involving chromosomes 3 and 4: 46,XY,t(3;4)(p25;q31.3). This karyotype finding was confirmed by FISH. The FISH analysis revealed the presence of sex-determining region (SRY). The proband inherited this translocation from his father. His sister had the same translocation. However, the father and sister of the proband were clinically normal. Conclusion(s) The presence of this chromosomal anomaly and hypospadias was unique to our patient compared with others with the 46,XY,t(3;4) translocation. Although no such association has been reported to date, we think that the severe hypospadias in our case might be associated with this translocation.

Objective To determine the genetic cause of primary amenorrhea in a 46,XY adolescent girl. Design Case report. Setting Pediatric endocrinology and gynecologic unit of an academic hospital. Patient(s) A 16-year-old adolescent referred for primary amenorrhea. Intervention(s) Endocrine and surgical investigation, SRY mutational analysis. Main outcome measure(s) Plasma gonadotropin levels, estradiol and testosterone levels, and pathologic findings. Result(s) We report a new mutation of the SRY gene in a 46,XY sex-reversed patient. We observed two unusual features. First, partial pubertal development has rarely been described in association with SRY gene mutation. Second, the location of the mutation was in the HMG box region of the SRY gene, in contrast to the other partial cases of 46,XY gonadal dysgenesis. In addition, the presence of a gonadoblastoma underlines the necessity of removing the gonads quickly in 46,XY sex-reversal cases, and raises several questions about the role of the SRY gene in the development of such tumors. Conclusion(s) Partial pubertal development in a 46,XY sex-reversed patient does not exclude SRY gene mutation.

Objective To present a case of successful pregnancy after conservative bilateral gonadectomy without adjuvant chemotherapy and radiotherapy in a 46,XY gonadal dysgenetic woman with gonadoblastoma and malignant germ cell tumor. Design Case report. Setting Infertility center in university hospital. Patient(s) An 18-year-old female with 46,XY karyotype underwent bilateral gonadectomy, and the pathology revealed gonadoblastoma with malignant mixed germ cell tumor. Intervention(s) Chromosomal analysis, bilateral gonadectomy, donor oocyte, and IVF program. Main Outcome Measure(s) Tumor markers and pregnancy result. Result(s) The patient was free from tumor recurrence after 13 years' follow-up. A successful twin pregnancy was achieved after oocyte donation and IVF. Conclusion(s) Gonadectomy without adjuvant therapies could be done in 46,XY gonadal dysgenetic women with gonadoblastoma in view of preservation of future fertility.

A case of a 19-year-old female with 46 XY gonadal dysgenesis and five different histological subtypes of germ cell malignancies is described. Both adnexa were removed, preserving the uterus. Pathology revealed gonadoblastoma with dysgerminoma differentiation present in both gonads and in the left gonad mature teratoma, embryonal carcinoma, and endodermal sinus tumor were identified as well. She received no adjuvant treatment and has remained well 30 months after diagnosis.

The risk of gonadal neoplasia in XY gonadal streaks is high, dictating early prophylactic removal of the streaks. Laparoscopic removal of the streaks is recommended.