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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.

Reproductive health of men has declined over time including reduced semen quality specifically sperm count, increased incidence of infertility, and testicular cancers. Our recent findings suggest that these disease states possibly arise as a result of disruption of testicular stem cells biology by perinatal insults including exposure to endocrine disrupting chemicals. Testicular stem cells include relatively quiescent, very small embryonic-like stem cells (VSELs), and actively dividing spermatogonial stem cells (SSCs). Both VSELs and SSCs express estrogen receptors and are directly vulnerable to endocrine disruption. Exposing mice pups to estradiol (20 μg/pup/day on days 5-7) or diethylstilbestrol (2 μg/pup/day on days 1-5) affected spermatogenesis during adult life with reduced numbers of tubules in stage VIII, tetraploid cells and sperm. These mice were infertile and majority of diethylstilbestrol treated mice revealed testicular cancer-like changes. An increase in VSEL numbers, observed by both flow cytometry and qRT-PCR, was associated with marked reduction of c-KIT positive spermatogonial cells. VSELs undergo epigenetic changes due to endocrine disruption that results in blocked differentiation (impaired spermatogenesis) leading to reduced sperm count and infertility, and their excessive self-renewal initiates cancer-like changes in adult life. Thus, testicular dysgenesis syndrome (TDS) has a stem cell rather than a genetic basis.

Pfaffia glomerata (Spreng.) Pedersen, popularly known as "Brazilian ginseng," is used as medicinal plant in Brazil to treat inflammatory diseases in general. Previous studies showed that its extract increases the nitric oxide (NO) levels. Knowing that NO downregulates steroidogenesis and that alterations in the action/production of androgens during perinatal life could alter testis development, the present studies sought to investigate the reproductive toxicity of Pfaffia glomerata on male mice exposed to hydroalcoholic extract in utero and during lactation. The present study shows that P. glomerata extract does not alter body weight, tubular diameter and testis function in male mice. Although a reduction in the testis weight was observed in the animals that received the highest dose directly in early post-natal life, our findings show clearly that P. glomerata may not act as an endocrine disruptor, and it is not an "antiandrogenic" compound that could lead to testicular dysgenesis syndrome., (© 2019 Blackwell Verlag GmbH.)

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.

The differential diagnosis of differences or disorders of sex development (DSD) belongs to the most complex fields in medicine. It requires a multidisciplinary team conducting a synoptic and complementary approach consisting of thorough clinical, hormonal and genetic workups. This position paper of EU COST (European Cooperation in Science and Technology) Action BM1303 ‘DSDnet’ was written by leading experts in the field and focuses on current best practice in genetic diagnosis in DSD patients. Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step. Subsequently, further analyses comprise molecular studies of monogenic DSD causes or analysis of copy number variations (CNV) or both. Panels of candidate genes provide rapid and reliable results. Whole exome and genome sequencing (WES and WGS) represent valuable methodological developments that are currently in the transition from basic science to clinical routine service in the field of DSD. However, in addition to covering known DSD candidate genes, WES and WGS help to identify novel genetic causes for DSD. Diagnostic interpretation must be performed with utmost caution and needs careful scientific validation in each DSD case., (© 2018 The authors)

Purpose: In this report, we characterize the timing and behavior of malignant ovarian germ cell tumors (GCTs) in pediatric patients with dysgenetic gonads compared to those with normal gonadal development., Patients and Methods: Patients from the Children's Oncology Group AGCT0132 with malignant ovarian GCTs were included. Within this population, we sought to identify patients with gonadoblastoma, streak ovaries, or other evidence of gonadal dysgenesis (GD). Patients with malignant GCTs containing one or more of the following histologies-yolk sac tumor, embryonal carcinoma, or choriocarcinoma-were included. Patients were compared with respect to event-free survival (EFS) and overall survival (OS)., Results: Nine patients with GD, including seven with gonadoblastoma (mean age, 9.3 years), were compared to 100 non-GD patients (mean age, 12.1 years). The estimated 3-year EFS for patients with GD was 66.7% (95% CI 28.2-87.8%) and for non-GD patients was 88.8% (95% CI 80.2-93.8%). The estimated 3-year OS for patients with GD was 87.5% (95% CI 38.7-98.1%) and for non-GD patients was 97.6% (95% CI of 90.6-99.4%)., Conclusion: Patients presenting with nongerminomatous malignant ovarian GCTs in the context of GD have a higher rate of events and death than counterparts with normal gonads. These findings emphasize the importance of noting a contralateral streak ovary or gonadoblastoma at histology for any ovarian GCT and support the recommendation for early bilateral gonadectomy in patients known to have GD with Y chromosome material. In contrast to those with pure dysgerminoma, these patients may represent a high-risk group that requires a more aggressive chemotherapy regimen., (© 2017 Wiley Periodicals, Inc.)

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.

We present two new cases of Warsaw Breakage Syndrome (WABS), an autosomal recessive cohesinopathy, in sisters aged 13 and 11 years who both had compound heterozygous mutations in DDX11. After exclusion of Fanconi anemia, Bloom syndrome and Nijmegen breakage syndrome, whole exome sequencing revealed two novel variants-c.1523T>G, predicting (p.Leu508Arg) and c.1949-1G>A (IVS19-1G>A), that were confirmed with Sanger sequencing in both affected individuals. DDX11 encodes an iron-sulfur-containing DNA helicase, and mutations in this gene have been reported in the five WABS cases previously identified to date. The sisters reported here display the distinguishing clinical features of WABS: pre- and post-natal growth restriction, microcephaly, intellectual disability, sensorineural hearing loss with cochlear abnormalities, and facial dysmorphic features. In addition, our cases had early menarche at 8 and 10 years of age, bilateral small thumbs, and the younger, more severely affected sister had small fibulae. These findings broaden the WABS phenotype and the limb malformations demonstrate further clinical overlap with Fanconi anemia and other cohesinopathies, such as Roberts Syndrome., (© 2017 Wiley Periodicals, Inc.)

We report a novel syndromic disorder of sex development observed in three male siblings, presenting with the association of micropenis without hypospadias, cryptorchidism, very low level of antimüllerian hormone in the neonatal period, and no persistent müllerian duct structures, suggesting a progressive regression of testicular function. The patients described here showed a striking neurological involvement including bilateral periventricular cysts observed in the anterior part of the frontal horns prenatally and increasing in size and number over time, associated with infra and supratentorial parenchymal atrophy, dilated ventricular system, corpus callosum hypoplasia, severe intellectual disability, and epilepsy. Associated features included a distinctive facies, joint contractures, retinopathy, and hearing loss. Pathological examination was consistent with testicular dysgenesis and leukoencephalopathy with spongiosis and microcalcifications. To the best of our knowledge, this disease, characterized by a recognizable pattern of malformations, has not been previously reported. An exhaustive genetic and metabolic evaluation was normal. Autosomal recessive inheritance was considered to be likely, on the basis of SNP studies. We hope that the detailed description provided here of the clinical, radiological, and pathological findings observed in this family will help to identify further unrelated patients, and ultimately, to clarify the genetic basis of this condition. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Recent studies on gonadal histology have improved the understanding of germ cell malignancy risk in patients with disorders of sex development (DSD), and evidence-based gonadal management strategies are gradually emerging. Especially in 46,XY DSD and 45,X/46,XY DSD, which are characterized by gonadal dysgenesis, the risk of germ cell malignancy is significantly increased. This paper summarized the progress over the past 10 years in malignancy risk assessment in patients with DSD, and its implications for optimal surgical handling of the involved gonads., (Copyright © 2016 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Mutation of the Wilms tumor suppressor gene (WT1) has been recognized as one of the etiologies of steroid-resistant nephrotic syndrome (SRNS). The mutation is also responsible for gonadal dysgenesis in 46,XY individuals. Early recognition of the presence of Y chromosome is of particular importance because of the high risk of gonadal tumor. We present here three cases of steroid-resistant nephrotic syndrome with WT1 mutation and 46,XY karyotype. Patient 1 and 2 have intron splice site (IVS9+5G A) mutation. Patient 3 has c.1301GA (p. R434H) mutation. All cases had normal female external genitalia at birth and eluded the diagnosis of gonadal dysgenesis until later in life. We suggest that chromosomal analysis should be promptly performed in female patients with early-onset steroid-resistant nephrotic syndrome.
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The co-occurrence of gonadal agenesis alongside hypoplastic derivatives of the paramesonephric ducts has rarely been observed., Patient(s): 16-year-old dizygotic twin sisters were referred to our department because of primary amenorrhea. X-ray, bone densitometry, ultrasonography, pelvic MRI and measurement of pituitary, ovary, and thyroid hormones were performed. Both twins showed hypergonadotropic hypogonadism, bilateral gonadal agenesis, fallopian tube, uterus, and vaginal hypoplasia but normal kidney and urinary tract structures and skeletal system. Analysis of Q-banded chromosomes in peripheral blood for the search for centromeric X-chromosome DNA and SRY gene was normal as well as the molecular analysis of FMR1, GDF9, and BMP15 genes. Estradiol gel was administered for one year followed by estroprogestin treatment. Both twins growth increased; breast development was stimulated and first menses occurred. Deregulation in the expression of the various HOX genes along the axis of the developing reproductive tract in a determinate time of development may be one of the mechanisms involved in the origin of this complex and rare association.

Matthew-Wood syndrome (MWS), also termed Microphthalmia, syndrome 9 (MCOPS9, MIM 601186), Spear syndrome, or pulmonary hypoplasia, diaphragmatic hernia, anophthalmia and cardiac defects syndrome (PDAC syndrome), is an autosomal recessive disorder characterised by ocular, respiratory and cardiac abnormalities. Mutations in retinoic acid 6 gene (STRA6) have been reported in clinically diagnosed patients with MWS. Here we presented a case with MWS, who has characteristic findings of the syndrome as well as dextrocardia as an undescribed feature, and bilateral streak gonads which was described only in one patient previously. Molecular analysis showed a homozygous exonic missense mutation in the STRA6 gene.

Puberty is a defining time of many adolescents' lives. It is a series of events that includes thelarche, pubarche, and menarche. Primary amenorrhea is the absence of menarche. There are numerous etiologies including outflow tract obstructions, gonadal dysgenesis, and anomalies of the hypothalamic axis. This review's aims are to define primary amenorrhea and describe the various causes, their workups, associated comorbidities, and treatment options. At the end, a generalist should be able to perform an assessment of an adolescent who presents with primary amenorrhea and, if warranted, begin initial treatment.

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.

Malouf syndrome is a rare congenital disorder involving the heart, genitalia, skin and skeletal characteristics. In the present study, we report on the sporadic case of a young female with dilated cardiomyopathy, hypergonadotropic hypogonadism, a small chin, bilateral blepharoptosis, marfanoid elongated fingers and hypothyroidism. Malouf syndrome may be caused by heterozygous mutations in the lamin A/C (LMNA) gene. Genetic analyses and autopsy were performed. In spite of the patient's features, sequence analysis of the coding region of the LMNA gene including exon-intron boundaries identified only one benign polymorphism: homozygous silent variant 1698C>T (H566). There is a possibility that the sequence analysis may have not detected intronic mutations or mutations in portions of the 5'- and 3'-untranslated regions, which would confirm the clinical diagnosis.

Telomeric associations (TAs) are fusions between two telomeres of two different chromosomes without visible loss of chromosomal material. Constitutional telomeric associations are rare chromosomal anomalies. We report on the cytogenetic and molecular analyses of a TA involving chromosomes Y and 7 in a child with a female phenotype. Prenatal cytogenetic analysis showed a 45,X chromosome complement in all cells. No fetal abnormality was identified at ultrasound examinations and the pregnancy went to term. During childhood, the proband had gonadal dysgenesis but no other phenotypic manifestations of Turner syndrome. Molecular genetic analyses showed the presence of genomic DNA of the SRY gene without any mutation. Karyotyping and fluorescent in situ hybridization (FISH) analyses on blood showed two cell lines: one cell line with a TA involving chromosomes Y and 7 [46,X,tas(Y;7)(p11.32;q36.3)] and a second cell line with a 45,X pattern. A human pantelomeric repeat TTAGGG probe hybridized to the junction of the TA within the derivative chromosome. FISH and array comparative genomic hybridization (aCGH) analyses demonstrated that tas(Y;7) occurred without detectable loss of any sequence at the derivative chromosome. SNP array analysis excluded an uniparental isodisomy of chromosome 7. Knowing more about TAs will help geneticists to deliver accurate genetic counseling., (Copyright © 2013 Wiley Periodicals, Inc.)

Isochromosome involving the long arm of X chromosome is a rare structural rearrangement of the X chromosome, leading to Gonadal dysgenesis. These patients present as phenotypic females with amenorrhea and growth failure. Often other associated features like endocrine abnormalities and skeletal deformities are found. They are chromatin positive cases and are only diagnosed by karyotyping. Hashimoto's thyroiditis is a rare association with isochromosome X.

Congenital uterine anomalies are often asymptomatic. They may present with infertility, recurrent miscarriage, preterm delivery, abnormal lie in pregnancy and other obstetric complications. We report the case of a 38-year old patient with unicornuate uterus without rudimentary horn and with unilateral left ovarian agenesis and unilateral left renal agenesis who gave birth to eleven children. Anomaly was incidentally diagnosed during laparoscopic sterilization.

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.)

Polyorchidism, the presence of more than two testes, is a very rare anomaly. We report the color Doppler ultrasonography and magnetic resonance imaging findings of the case of a 20-year-old man with polyorchidism, presenting with an asymptomatic scrotal mass. Ultrasonography showed double testes with double separate epididymides sharing a common vas deferens in the left side of the scrotum. The double testes demonstrated similar echo texture and vascular flow as the normal testis, but smaller in size. Magnetic resonance imaging showed three testes very clearly and confirmed the diagnoses. After 2 years of follow-up, he was managed with surgical intervention. Pathology report revealed polyorchidism., (Copyright © 2013 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.

Incomplete polyorchidism (also called bilobed testicle) is an extremely uncommon congenital anomaly. Only 3 cases of bilobed testicle were previously reported in the available literature. We describe a case of a 4-year-old boy who presented with a 6-month history of an asymptomatic scrotal mass located in the upper pole of the left testicle mimicking testicular tumour. After partial orchiectomy, macroscopic and pathological examination of the lesion confirmed the diagnosis of normal testicular tissue., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Determination of a mammal’s sex begins at conception with the establishment of genotype and continues from there as the expression of specific genes directs the bipotential gonad to develop. The gonad further directs the sexual differentiation of the individual. Deviations from either of these pathways at any stage results in disorders of sexual development. Definitive diagnosis minimally requires a karyotype, histopathologic evaluation of the gonads, and gross description of the genital anatomy, with more complete diagnostic answers achieved through other diagnostic tests. This article covers normal and abnormal development of the reproductive organs with emphasis on diagnosis and treatment.

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.)

Purpose: Diagnosis of dysgerminoma in the paediatric age group is uncommon, and most cases arise from dysgenetic gonads of 46, XY pure gonadal dysgenesis (PGD) patients. Bilateral gonadectomy is mandatory in these patients. So, the preoperative diagnosis of PGD is important in order to avoid multiple surgical procedures and delayed patient information in the case of a suspected 'ovarian' tumour. Our aim was to discuss preoperative clues that can lead to suspicion of dysgerminoma in the context of PGD., Materials and Methods: We reviewed the charts of six patients treated for dysgerminoma associated with 46, XY PGD. We focused on particularities of clinical and biological evaluations., Results: Median age at diagnosis was 11 years. Pubertal development was absent or incomplete even at late ages. Dysgerminoma was associated with gonadoblastoma foci in all cases. Tumoral marker profile was a normal alfafetoprotein level, a high lactate dehydrogenase level and normal or moderate human chorionic gonadotropin (βHCG) secretion, except for one patient who had a mixed tumour with notably a choriocarcinoma share (high βHCG). Follicle-stimulating hormone (FSH) level was very high in all patients tested and, interestingly, also in one prepubertal patient., Conclusions: In the case of a suspected ovarian tumour, delayed pubertal development, moderate βHCG level and elevated FSH level are clinical and biological clues to a diagnosis of dysgerminoma in the context of PGD and should prompt karyotype analysis before surgery. Because FSH is an efficient indirect marker of this condition, we suggest including this analysis in the management of gonadal tumours., (Copyright © 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: The study aimed to estimate the incidence of increased nuchal translucency in the first trimester ultrasound scan results (cut-off limit 2.5 mm) and to evaluate the predictive value of increased nuchal translucency as a screening test for the detection of fetal chromosomal abnormalities., Methods: We used the ultrasound scan results of nuchal translucency evaluation and the results of chromosomal analysis of the invasive prenatal control performed as a result of increased nuchal translucency., Results: We collected 2183 nuchal translucency ultrasound scans in which we detected 21 embryos with a pathologic value (0.96%). We collected the data of 168 cases of invasive prenatal control due to increased nuchal translucency from which 122 cases were found. A total of 122 cases of pregnant women undergone an invasive prenatal diagnostic method due to increased nuchal translucency, of which 11 fetuses were found with trisomy 21 (Down syndrome) (9%), 3 fetuses with trisomy 13 (Patau syndrome) (2.45%), 3 fetuses with monosomy 45XO (Turner syndrome) (2.45%) and 1 fetus with translocation (0.8%)., Conclusions: The positive predictive value of the increased fetal nuchal translucency as a screening test for the detection of fetal chromosomal abnormalities based on the results of the chromosomal-genetic analysis of the invasive prenatal diagnostic procedures is 14.8%.

Objective: To explore the applications of fluorescence in situ hybridization (FISH) in the diagnosis for the patients with gonadal dysgenesis., Methods: After routine gynecologic examination, ultrasonography and endocrine examination, 5 cases of gonadal dysgenesis and hypogonadism were analyzed by using chromosomal diagnoses including G-banding, Q-banding, multiplex FISH and BAC-FISH analyses., Results: Among the 5 cases of gonad agenesis patients, 2 were pure gonadal dysgenesis with 46, XY karyotype, 3 were mixed gonadal dysgenesis with mos 45, X/47, XXX; 45, X/46, XY or 46, X, der(Y) karyotype., Conclusion: Sex chromosomal abnormalities resulted in gonadal dysgenesis symptoms. Applications of FISH and BAC-FISH analyses can correctly diagnose the sex chromosomal abnormalities for patients with gonad agenesis and provide accurate medical genetic data for clinical diagnosis and therapy.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome) is characterized by Müllerian duct structures agenesis: the vagina atresia is the commonest variant. There can be some anomalies associated, such as renal, skeletal, spine malformations and others. Patients with MRKH can show different presentation from newborn period to adolescence. We report our experience in treatment of the vaginal atresia presenting in two young girls as a sign of MRKH syndrome.

In human sexual development, the female phenotype represents the default pathway. Therefore, a failure of testis determination results in the development of the female phenotype, while genetic alterations resulting in partial testicular development can give rise to a wide spectrum of masculinization. In addition to defects in peptide hormones and their receptors, timing of hormonal exposure is also critical to appropriate development. Although much work remains to be done, recent advances in our knowledge have begun to unravel the molecular basis of disorders of sexual development. Consensus statements from investigators have recommended changes in the nomenclature, and further investigations have examined the role of the female and male psyche in patients with these disorders. This review focuses on the diagnosis and management of conditions related to disorders of sexual development.

Normal sexual differentiation occurs in three sequential steps--establishment of chromosomal (genetic) sex, development of gonadal sex, and development of phenotypic sex. Errors in the establishment of chromosomal, gonadal, or phenotypic sex cause abnormal sexual differentiation. Affected individuals are identified with a wide variety of patterns from ambiguous genitalia, to apparently normal genitalia with sterility or infertility. When a patient is suspected of having a disorder of sexual development, analysis of the chromosomal constitution and complete gross and histopathologic description of the gonads, internal and external genitalia are required to correctly categorize the type of disorder.

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.

Congenital absence of uterus and vagina, Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, is mullerian agenesis and is the second most frequent cause of primary amenorrhea. Only atypical form of MRKH (type B) is associated with renal skeletal and ovarian abnormalities. We report the management of an unusual case of atypical MRKH, unilateral gonadal agenesis, and solitary ectopic pelvic kidney with pelviureteric junction obstruction (PUJO). After doing thorough Medline search, to the best of our knowledge, this is the first case reported with this combination.

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.

A 15-month-old boy was discovered to have internal female genitalia during an operation for bilateral inguinal hernia. The biopsies showed normal testicular tissue and the karyotyping result was 46XY, so the diagnosis of persistent mullerian duct syndrome (PMDS) was made. At the second operation, the uterine fundus and fallopian tubes were excised. Then, he underwent bilateral orchiopexy. We discuss a rare presentation of this disorder, its management, and genetic implications together with a review of the literature.

New nomenclature of disorders of sexual development is provided. Contemporary the management and the quality of life in the patients with pure gonadal dysgenesis and mixed gonadal dysgenesis is assessed.

Objective: To emphasize the difficulties to distinguish between uterine agenesis and extreme uterine hypotrophy in the context of primary amenorrhoea with delayed puberty., Patients and Methods: Among adolescents who consulted with our center because of primary amenorrhoea, from 1997 to 2005, three patients were referred for a suspicion of Mayer-Rokitansky-Kuster-Hauser Syndrome, after ultrasonography had failed to visualize the uterus. The 3 patients underwent endocrine and genetic evaluations. Transabdominal ultrasonography and MRI performed pelvic examination. Patients were placed under estrogen treatment., Results: Endocrine evaluation indicated primary ovarian failure for patient 1, and hypogonadotrophic hypogonadism for patients 2 and 3. Karyotype was 46,XX in all patients. Initial pelvic ultrasonography revealed the absence of uterus. MRI allowed visualizing prepubertal uterus for patient 1, a hypotrophic uterus for patient 3 and concluded to uterine agenesis for patient 2. In all cases estradiol substitutive therapy induced uterine growth and confirmed retrospectively the diagnosis of extreme uterine hypotrophy., Discussion and Conclusion: Pelvic ultrasonography can be misleading in the evaluation of primary amenorrhoea. No visualization of uterus on ultrasonography can occur in the context of delayed puberty and should not induce a premature diagnosis of Mayer-Rokitansky-Kuster-Hauser syndrome. Indeed, such a diagnosis has therapeutic, reproductive and psychological consequences.

We report on a girl who, despite her 45,X/46,X,der(Y) karyotype, showed no signs of virilization or physical signs of the Ullrich-Turner syndrome (UTS), except for a reduced growth rate. After prophylactic gonadectomy due to the risk of developing gonadoblastoma, the gonads and peripheral blood samples were analyzed by fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) to detect Y-specific sequences. These analyses allowed us to characterize the Y-derived chromosome as being an isodicentric Yp chromosome (idic(Yp)) and showed a pronounced difference in the distribution of the 45,X/46,X,idic(Yp) mosaicism between the two analyzed tissues. It was shown that, although in peripheral blood almost all cells (97.5%) belonged to the idic(Yp) line with a duplicated SRY gene, this did not determine any degree of male sexual differentiation in the patient, as in the gonads the predominant cell line was 45,X (60%).

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.