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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.

Disorders of sex development (DSD) are defined as discrepancy between chromosomal, gonadal and anatomic sex. The basic principles for the management of DSD include a multidisciplinary approach for gender assignment. Clinical assessment includes a detailed history and examination of external genitalia. Most of the disorders with symmetrical gonades indicate hormonal cause while asymmetrical gonades are found in chromosomal DSDs. Karyotyping will indicate a 46XX DSD, 46 XY DSD or mosicism. Internal anatomy is defined by ultrasonography, genitoscopy and laparoscopy. Human chorionic gonadotrophins (hCG) stimulation test is carried out in under-virilised males to see the function of Leydig cells in testes. The Most common cause of 46XX DSD is congenital adrenal hyperplasia (CAH). The decision of gender assignment surgery is to be taken in a multidisciplinary environment and with informed consent of the parents. Most of 46 XX CAH patients, even if markedly virilised, and 46 XY complete androgen insensitivity syndrome are raised as females. Similarly, most of 5-α reductase deficiency and 17-β hydroxysteroid dehydrogenase deficiency patients are assigned to the male gender. The decision in cases of mixed gondal dysgenesis and ovotesticular DSD is based on the development of external and internal genitalia. Patients with androgen biosynthetic defects, partial androgen insensitivity syndrome are usually assigned to the male gender.

Patients with complete XY gonadal dysgenesis (GD) show a high predisposition to germ cell tumors (GCT). Patients with coexistence of GCT and GD have been reported previously. Here we present a 15-year-old girl with mixed GCT and GD who also developed an intra-abdominal synovial sarcoma one year after the treatment. This is the first report, to our knowledge, of synovial sarcoma associated with XY GD.

Study Question: What is the optimal protocol of management for phenotypic female patients with Y chromosome or Y-derived sequences, in particular for adult patients?, Summary Answer: Immediate gonadectomy, long-term hormone therapy and psychological care are suggested to be the optimal management for older phenotypic female patients with Y chromosome or Y-derived sequences., What Is Known Already: Phenotypic female patients with Y chromosome or Y-derived sequences are at increasing risk of developing gonadal tumors with age. Early diagnosis and safe guidelines of management for these patients are needed., Study Design, Size, Duration: One hundred and two phenotypic women with Y chromosome or Y-derived sequences were included in a straightforward, retrospective-observational study conducted over a period of 26 years from January 1985 to November 2010., Participants/materials, Setting and Methods: Patients aged 16-34 years presenting to our Academic Department of Gynecology with symptoms of disorders of sex development were subjected to history taking, hormonal evaluation, conventional cytogenetic analysis, PCR, histopathology and immunohistochemistry. Features of the gonads were examined and the outcome of prophylactic gonadectomy evaluated., Main Results and the Role of Chance: Among the patients recruited in our study, 48 patients (47.1%) were diagnosed with complete/partial androgen insensitivity syndrome (CAIS/PAIS) (46XY), 33 cases (32.4%) with gonadal dysgenesis (46XY) and the remaining subjects (20.1%) with mixed gonadal dysgenesis (with sex chromosome structural abnormalities). The total incidence of malignancy was 17.6%. Seventeen patients (16.7%) had gonadoblastoma, while one patient (1.0%) with gonadal dysgenesis had dysgerminoma. Gonadoblastoma were observed in 2/21 patients with sex chromosome structural abnormalities (9.5%), 3/33 patients with gonadal dysgenesis (9.1%), 9/30 patients with CAIS (30.0%) and 3/18 patients with PAIS (16.7%)., Limitations, Reasons for Caution: Selection bias in this cohort study may affect data interpretation due to the low incidence of disorders of sex development in the general population., Wider Implications of the Findings: The risk for malignant transformation may occur in early life and highly increase with age in patients with Y chromosome or Y-derived sequences. Optimal timing of gonadectomy should be decided by multiple factors including the subgroup of disorder, age and degree of patient's maturity. In addition, gonadal biopsy is suggested when the disease is diagnosed and any evidence of premalignancy warranties gonadectomy., Study Funding/competing Interest(s): This work was supported by the National Key Scientific Research Project (2013CB967404), Natural Science Funds of Zhejiang Province (Y13H04005), Zhejiang Qianjiang talent plan (2013R10027), the Fundamental Research Funds for the Central Universities and Key Projects in the National Science & Technology Pillar Program during the Eleventh Five-Year Plan Period (2012BAI32B04). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER None.

Objective: To report a case of persistently elevated low levels of hCG to increase awareness of pituitary origin of persistently elevated hCG in patients with gonadal failure., Design: Case report and literature review., Setting: Large university-affiliated infertility practice., Patient(s): A 16-year-old patient with primary amenorrhea, normal secondary sex characteristics, ovarian failure, and a 46,XY karyotype. Her past medical history was significant for focal segmental glomerulosclerosis, leading to a diagnosis of Frasier syndrome., Intervention(s): At age 31 years, she desired pregnancy by oocyte donation and was found to have persistently elevated low levels of hCG (>35 mIU/mL)., Main Outcome Measure(s): Pituitary hCG., Result(s): Both serum free β-hCG and hyperglycosylated hCG were undetectable. Total serum hCG diluted appropriately was not blocked by blocking agent and was detected in the urine. Subsequent treatment with exogenous E(2), in preparation of a donor oocyte cycle, suppressed her hCG levels (down to 8 mIU/mL). These results indicated a pituitary source of the serum hCG., Conclusion(s): This report reinforces the need to consider pituitary hCG as the origin of persistently elevated hCG levels in patients with gonadal failure. Although levels of hCG <14 mIU/mL have been considered normal in postmenopausal women, our case suggests that patients with gonadal failure at younger ages might have a higher pituitary output of hCG., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Gonadoblastoma (GB) is regarded as an in situ form of germ cell tumor in dysgenetic gonads, and 30% of patients with GB develop a dysgerminoma/seminoma tumor., Objective: Determine whether OCT3/4 and β-catenin are expressed in dysgenetic gonads before GB development and whether TSPY participates in the OCT3/4-β-catenin pathways in the malignant invasive behavior., Methods: dysgenetic gonads of Disorders of sex differentiation (DSD) patients with mixed gonadal dysgenesis were analyzed by immunohistochemistry and immunofluorescence for comparison with GB and dysgerminoma/seminoma., Results: Our results suggest that the development of GB is secondary to the interaction of OCT3/4 and TSPY, that β-catenin does not participate in this process., Conclusions: The use of this biological markers detects the potential high risk gonads.

Objective: To determine the frequency of XY karyotypes among females with complete gonadal dysgenesis (CGD) and to investigate the frequency of both gonadal tumors and SRY mutations., Design: Retrospective study based on data from all patients with CGD seen in our service from 1989 to 2010., Setting: Clinic for disorders of sex development, University Hospital, State University of Campinas., Patient(s): Thirty-two patients with hypergonadotropic hypogonadism, streak gonads, internal and external female genitalia, and normal karyotype (46,XX or 46,XY); 31 were index cases and 29 did not have a previously determined karyotype., Intervention(s): None., Main Outcome Measure(s): None., Result(s): The percentage of XY karyotypes among patients with CGD was 34.5% (10/29). Mean age at diagnosis among XY and XX patients was 17.4 years and 19.9 years, respectively. Gonadal tumors were found in 4 of 9 XY girls, and 7 of 10 had SRY gene mutations., Conclusion(s): The previously unreported finding of an elevated frequency of 46,XY karyotype among patients with CGD and the high risk of gonadal neoplasia in such cases indicate that this diagnosis must be kept in mind by clinicians and strengthen the importance of karyotype analysis in females with primary hypogonadism. In addition, the frequency of SRY mutations in XY CGD might be higher than previously considered., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: The association of müllerian anomalies with concomitant gonadal development abnormalities is very rare. The literature revealed only a few cases of unicornuate uterus with unilateral ovarian agenesis. The pathophysiology of this rare combination is not clear., Case Report: A 31-year-old primiparous woman at 38 weeks' gestation admitted to our labor room due to painful uterine contractions. An emergency cesarean section was performed and a 3,100-g healthy male infant was delivered. At cesarean delivery, she was found to have unicornuate uterus with no evidence of a rudimentary horn and the absence of a left (unilateral) ovary. The right fallopian tube, round ligament, and ovary were all normal. The left fallopian tube, round ligament, and ovary were all absent. Intraabdominal exploration, intravenous pyelography, postoperative abdominal and transvaginal ultrasonography were failed to reveal additional gynecologic, renal and urinary tract anomalies., Conclusion: To our best knowledge this case is unique since the incidental diagnosis of unicornuate uterus with ipsilateral ovary was made during cesarean delivery.

The pathways leading to female sexual determination in mammals are incompletely defined. Loss-of-function mutations in the WNT4 gene appear to cause developmental abnormalities of sexual differentiation in women and mice. We recruited six patients with different degrees of Müllerian abnormalities, with or without renal aberrations and a normal female 46,XX karyotype. A clear androgen excess was found only in one patient. This 19-year-old woman was affected by primary amenorrhoea, absence of Müllerian ducts derivatives, clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess. Direct sequencing of her WNT4 gene followed by functional studies in human ovarian cells (OVCAR3) was performed. This patient carried the novel R83C loss-of-function dominant negative mutation in her WNT4, confirming the role of WNT4 in the development and maintenance of the female phenotype in women. Our study can also help refine the phenotype of WNT4 deficiency in humans. In fact, it appears that at least in this limited casuistic small group of patients, the absence of a uterus (and not other Müllerian abnormalities) and the androgen excess are the pathognomonic signs of WNT4 defects, suggesting that this might be a clinical entity distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome.

Background: Sudden infant death syndrome (SIDS) constitutes the most frequent cause of death in the postperinatal period in Germany. Recently, a lethal phenotype characterized by sudden infant death with dysgenesis of the testes syndrome (SIDDT) was identified to be caused by loss of function mutations in the TSPYL1 gene., Purpose: The study's purpose was to reveal a possible role of TSPYL1 in SIDS., Methods: DNA samples of 126 SIDS cases and 261 controls were investigated., Results: We found five sequence variations, each of them causing an amino acid substitution. No Hardy Weinberg disequilibrium and no significant difference in allele frequencies between patients and controls were observed for any variation. In one female patient a p.F366L amino acid polymorphism was found heterozygous, which could not be displayed in controls. A pathogenic implication of this substitution, which is conserved in primates and rodents, cannot be ruled out completely. Because SIDDT is the result of homozygous TSPYL1 mutations, this heterozygous exchange cannot solely explain the sudden death in this child. The reported mutation associated with SIDDT (457&#95;458insG) was not detectable in our cohort., Conclusion: No association of sequence variations in the TSPYL1 gene and SIDS has been found in a German cohort. Genetic analysis of TSPYL1 seems to be of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.

103 patients aged 11-20 with short stature and/or with delayed puberty were studied. Among all patients classical form of gonadal dysgenesis was diagnosed in 31 patients (karyotype 45,X- 17 patients, 45,X/46,XX- 14), "mixed" gonadal dysgenesis in one patient (karyotype 45,X/46,XY)-, "pure" gonadal dysgenesis- in 5 cases (karyotype 46,XY-in 4 , 45,X -- in one). The majority of cases (66) were diagnosed as ovarian dysgenesis with the mosaic karyotype- 46,XX/45,X. In the clinical diagnostics of ovarian dysgenesis some difficulties were aroused because of slight reduction of height and delayed sexual development, mild appearance absence or somatic anomalies. The main diagnostic criteria for the various forms of gonadal dysgenesis are detection of characteristic karyotype and hypogonadotropic hypogonadism. Characteristic phenotype is more informative in the cases of classical and "mixed" forms of gonadal dysgenesis. Early diagnosis of gonadal dysgenesis is very important for effective correction of height and sexual development. Timely begin hormonal therapy may avoid complications induced bihypoestrogenia, such are: osteoporosis, cardiovascular diseases and etc. Karyotype investigation and in the cases of revealing Y chromosome material, and therefore gonadectomy must precede the beginning of hormonal therapy.

Müllerian agenesis, a congenital malformation of the genital tract is the second most common cause of primary amenorrhoea. Its etiology is poorly understood. It may be associated with renal, skeletal or other abnormalities. The diagnosis is often made radiologically or laparoscopically. Three-dimensional ultrasound is a useful diagnostic tool. The hormonal profile and karyotype in these patients are normal. The management varies, but the treatment of choice is non surgical aimed at creating a neovagina. These patients require psychological support due to the implications for reproduction. Here, we present the case of a 24-year-old married woman with primary amenorrhoea with this malformation.

Congenital genital anomalies are a very complex pathology. In order to clarify its causes it is important to revert to the genetic conditions and regularities of embriological development. The genital disturbances are mostly determined by chromosomal or endocrinic disorders or by impaired biochemical processes. Clinical problems arise when the genetical sex is in discrepancy with ambiguous genitalia. True hermaphroditism, congenital adrenal hyperplasia, testicular feminization and gonadal dysgenesis are the most common syndromes. Diagnostic criteria applied are similar for all (establishment of karyotype, investigation of hormones and their derivates, genital ultrasound and endoscopy, if needed - radiological examination), but medical and surgical treatment is applied to each patient individually.

Objective: To describe a patient with bilateral ovarian agenesis associated with the atypical form of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome., Design: Case report., Setting: Unit of Endocrinology, Fundación Hospital Alcorcón. Madrid (Spain)., Patient: A 17-year-old woman who presented with primary amenorrhea and lack of mammary development., Intervention(s): An endocrine study including pituitary, ovarian, adrenal, and thyroid evaluation was performed. Genetic study was done by karyotype and fluorescence in situ hybridization (FISH) analysis to detect the presence of Y chromosome material. Bone study, intravenous urography, pelvic ultrasound, and laparoscopic study were ordered to evaluate the associated genitourinary and skeletal anomalies., Main Outcome Measure(s): Anatomic, endocrine, and genetic description of the patient., Result(s): The gynecologic examination showed a normal vagina ending in a blind pouch. The endocrine evaluation disclosed gonadotropin levels in the menopausal range and nonautoimmune subclinical primary hypothyroidism. The laparoscopic study revealed a single pelvic kidney and an absence of gonads, fallopian tubes, and uterus. The karyotype was 46,XX; no Y chromosome was found in FISH analysis., Conclusion(s): To our knowledge, this is the first report of gonadal agenesis 46,XX associated with the atypical form of MRKH syndrome. The primary hypothyroidism may be coincidental.

The management of undescended testes remains variable, and the use of laparoscopy for localisation is controversial. This study reviews the need for laparoscopy and also assesses the current practice among a cohort of surgeons.A retrospective review of all patients undergoing orchidopexy was performed, together with a postal survey of all members of the Welsh Surgical Society. Of the 139 orchidopexies performed, the testis was deemed impalpable in 39 (28%) cases. All patients were treated with groin exploration, and only in two (5%) patients was the testis not located. From the survey, replies were received from 90 (81%) surgeons, of whom 65 (72%) were still performing orchidopexy. Forty eight (74%) surgeons performed orchidopexy between the age of 2 and 3, and only 32 (36%) performed preoperative investigations. The follow up period was variable with the majority of patients seen at six weeks. Laparoscopy for the impalpable testis is not initially warranted. An inguinal exploration is regarded as the definitive investigation. This has the advantage of providing the diagnosis and treatment in the majority of cases.

Objective: To clarify the role of sexual related Y (SRY) gene detection in the diagnosis of gonadal dysgenesis., Methods: Sixteen cases of gonadal dysgenesis were included in this study: 5 with androgen insensitivity syndrome, 1 with 17-alpha-hydroxylase deficiency, 4 with true hermaphrodite, 2 with 45, X/46, XY gonadal dysgenesis, 1 with 45, X gonadal dysgenesis, 1 with XY pure gonadal dysgenesis, 1 with testicular regression, and 1 XY female who gave birth to a normal baby. SRY gene was detected by using polymerase chain reaction (PCR) in blood and gonad samples and by direct sequencing of the SRY motif., Results: Among the 16 cases, 15 were blood SRY positive, among which 13 (86.7%) showed the presence of testicular tissue, and 2 showed ovaries without testicular tissue. One SRY negative case showed the presence of testicular tissue. In 3 cases, SRY detection in gonadal tissue correlated with pathological findings but not with blood karyotype. The correlation between peripheral blood SRY and the pathology of the gonads was 81.25% and the correlation between the presence of peripheral blood Y chromosome and pathology of the gonads was 68.75%. Sequencing of the SRY motif in an XY female who gave birth to a normal baby showed no mutation., Conclusions: SRY detection is more sensitive and specific than blood karyotype in the prediction of the presence of testicular tissue. Peripheral blood karyotype does not necessarily reflect gonadal type. There may be testicular related factors other than the SRY gene.

Fluorescent in situ hybridization (FISH) using dual color X chromosome- and Y chromosome-specific probes was employed to assess further the sex chromosome copy number in cells of a phenotypic female patient with hypergonadotropic hypogonadism, primary amenorrhea and growth retardation. The GTG-banding analysis of peripheral blood lymphocytes had revealed the presence of predominantly 46,XY cells. A FISH analysis, undertaken to assess further the contribution of a minor cell line, yielded frequencies of 87% cells with the 46,XY constitution and 9% with the 45,X constitution. To establish unequivocally the presence of mosaicism, a skin biopsy was obtained for fibroblast culture, which further corroborated the results of the peripheral blood study. Fluorescent in situ hybridization analysis revealed 74% of the cells to be 46,XY and 12% to be 45,X. The unequivocal presence of XY cells puts the patient at risk for neoplastic transformation of the gonads. Laparoscopy and surgical removal of the patient's presumptive streak gonads were therefore undertaken. Cytogenetic results derived from the gonadal tissues further strengthened findings of previous cytogenetic analyses. It is our experience that FISH is a useful adjunct to established cytogenetic techniques in the management and monitoring of patients similar to the proband described in this study.

We undertook an international survey of prenatally diagnosed 45,X/46,XY mosaicism to ascertain the phenotypic spectrum of this condition. Ninety-two cases were obtained by means of a questionnaire sent to over 730 cytogenetic laboratories. Seventy-six cases (75 males and 1 female) had physical examinations after delivery or termination of pregnancy. Among these, there were four significant genital anomalies: three hypospadias and one female with clitoromegaly. Gonadal histology was abnormal in three (27%) of 11 cases, all of whom had normal male external genitalia. Other anomalies were noted in five cases: one cystic hygroma in a male, two cardiac anomalies, one spina bifida with multiple other defects, and one intrauterine growth retardation. There was no relationship between the percent mosaicism and the presence or degree of abnormalities. We conclude that 95% of 45,X/46,XY fetuses will have normal male genitalia, although there will also be a significant risk (27%) for abnormal gonadal histology. Long-term follow-up studies of prenatally diagnosed cases of 45,X/46,XY mosaicism are needed to study, without ascertainment bias, stature, pubertal development, tumor risk, and fertility.

Two sisters, ages 16 and 17, presented with secondary amenorrhea. In addition, primary ovarian failure, gonadal dysgenesis, and normal karyotypes were demonstrated. The most significant finding was a history of mumps, which they caught at the same time, 10 years before the onset of the amenorrhea. This disorder suggests that etiologic and environmental factors could prevail either in utero or during childhood. These patients are presented to emphasize the importance of considering gonadal dysgenesis as a differential diagnosis in patients with secondary amenorrhea, especially when the menstrual life has been a short one.

The role of the clinical laboratory in the diagnosis of abnormalities in gonadal development is reviewed, beginning with a description of the normal differentiation of the ovary and testis and the major types of disorders encountered. The conditions are classified as resulting from abnormal gonadal differentiation, defective endocrine function or excessive endocrine activity. Germ cell neoplasms are also reviewed. Laboratory procedures utilized in evaluation of gonadal abnormalities include cytogenetic, hormonal, and histopathologic studies. Standard procedures are described as well as newer method which have undergone increasing use in recent years and other specialized procedures which are under investigation for possible clinical application.

The advantages of the emergence and development of chorionic villi sampling (CVS) for early prenatal diagnosis are evident, but there are a host of new diagnostic problems caused by the use of extraembryonic tissues. We report a case in which 45X/46XY mosaicism was diagnosed by cultivation of chorionic villi and fetal cells. Direct chromosomal preparations of chorionic villi failed to diagnose the abnormality.