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46,XY gonadal dysgenesis (GD) constitutes a rare group of disorders characterized by the presence of dysfunctional testes in genotypic males. The molecular etiology is not known in about 2 thirds of instances. The aim of this study was to identify the genetic cause in patients with 46,XY gonadal dysgenesis. Based on clinical, cytogenetic, and biochemical screening, 10 patients with 46,XY GD were recruited. Direct sequencing of SRY , NR5A1 , SOX9 , DAX1 , DHH , DMRT1 genes was carried out for molecular analysis. Among 10 patients, 5 were diagnosed with complete gonadal dysgenesis (CGD), 3 with partial gonadal dysgenesis (PGD), and 3 with testicular agenesis. Molecular analysis revealed 12 heterozygous genetic changes, 4 of which were novel. One (c.416T>A) was observed in evolutionary conserved region of DMRT1 gene in a patient with CGD and was found to be probably damaging on in silico analysis. Other 3 were identified in NR5A1 gene (c.990+22 C>A, c.1387+1403T>A and p.131P), but their association with gonadal dysgenesis is not evident from our study. These genetic changes were absent in parents and 50 healthy control samples, which were also studied. With targeted sequencing approach, a molecular diagnosis was made in only one patient with 46,XY GD. The application of new genomic technologies is required for the precise evaluation of these rare genetic defects.

BACKGROUND Ovarian germ cell tumors (oGCTs) are rare and highly heterogeneous with regard to their clinical and histologic appearance. The risk of tumor development is higher in children with aberrant sexual differentiation. Development of gonadoblastomas is seen in young women with 46,XY gonadal dysgenesis. At least 50 % of gonadoblastomas may develop into malignant oGCTs, mostly dysgerminomas. In this study, we evaluated bilateral oGCTs in clinically inapparent patients for sex chromosomal aberrations. PATIENTS AND METHODS We analyzed tumor samples of 15 patients with synchronous bilateral oGCTs enrolled onto the consecutive MAKEI trials for non-testicular GCTs. Paraffin embedded samples from the Kiel German Childhood Tumor Registry were evaluated for the presence of Y-chromosomal sequences. Molecular genetic techniques included comparative genomic hybridization, polymerase chain reaction, and fluorescence in situ hybridization. RESULTS Among 15 patients with bilateral oGCTs, Y-chromosomal DNA sequences were detected in 6 tumors. Both mature teratomas were negative for Y-chromosomal DNA. Thus, 5 of 12 malignant oGCTs and 1 immature teratoma (with elevated AFP) showed Y-chromosomal material. A 45(X,0) karyotype could not be demonstrated. CONCLUSIONS These investigations provide additional insight into the development of oGCTs: mature teratomas, which develop from postmeiotic germ cells, are not associated with gonadal dysgenesis. Bilateral immature teratomas, dysgerminomas and mixed malignant oGCTs may frequently show Y-chromosomal DNA, indicating underlying but clinically inapparent gonadal dysgenesis. Thus, the presence of aberrant Y-chromosomal sequences appears to be involved in tumor development in about half of these patients.

Introduction: Le risque de degeneration maligne est important en cas de dysgenesie des gonades. L'objectif de cette etude etait d'evaluer les indications et la faisabilite de gonadectomie prophylactique par coelioscopie video-assistee chez les enfants atteints du syndrome de Turner ou d'une dysgenesie des gonades de type 46,XY (GoDy). Methodes: De 1996 a 2002, une salpingo-oophorectomie ou une gonadectomie coelioscopique etait realisee chez cinq filles atteintes du syndrome de Turner et chez neuf patients de phenotype feminin ayant une dysgenesie des gonades de type 46,XY. Pour les sujets atteints du syndrome de Turner, une salpingo-oophorectomie etait realisee exclusivement en cas de translocation prouvee sur le chromosome Y. Chez 5 patientes GoDy 46,XY, la coelioscopie etait realisee apres une exploration chirurgicale ouverte associee a une gonadectomie chez 4 patientes. Resultats: Dans deux cas du syndrome de Turner, l'examen histopathologique mettait en evidence des tumeurs unilaterales de stade pT1a. Un neoplasme bilateral de stade pT1 b etait mis en evidence chez trois des patientes GoDy 46,XY. Les types tumoraux suivants etaient identifies: gonadoblastome, dysgerminome, neoplasme intraepithelial testiculaire, teratome mature. Discussion: L'exploration coelioscopique permet l'etude in situ des structures genitales et permet la resection en toute securite de gonades dysgenesiques au cours de la meme intervention. L'indication de gonadectomie precoce resulte de la frequence elevee de tumeurs des gonades.

The sex hormone-binding globulin (SHBG) androgen sensitivity test has been used as a simple method to assess androgen receptor function in vivo. After a short term oral administration of the anabolic-androgenic steroid stanozolol the mean nadir serum concentration of SHBG is used as a measure of androgen response. We performed this test in order to evaluate its applicability in 16 patients with intersexual genital status: eleven with 46,XY gonadal dysgenesis and three with true hermaphroditism (group I), and in two patients with androgen insensitivity syndrome (AIS, group II). Ten healthy adult volunteers served as controls. In the two patients with AIS (group II) we found a diminished decrease of serum SHBG to 80.1 % and 80.7 %, respectively, indicating slight residual androgen responsiveness. In eleven patients of group I who were not on hormone replacement therapy, a mean nadir level of 51.7 +/- 8.7 % was found. In the controls the mean nadir serum SHBG level was significantly higher (62.7 +/- 5.2 %), probably due to interference of endogenous androgens and contraceptive medication with the stanozolol-induced SHBG decrease. In three gonadectomised patients who were on hormone replacement therapy the initial SHBG concentration was increased (513.5 +/- 239.1 nmol/l); the mean nadir SHBG concentration of 45.6 +/- 9.8 % of the initial level indicates an increased sensitivity of the test in patients in whom the counteracting ovarian androgens are absent. Our findings confirm that under standard test conditions the SHBG androgen sensitivity test is a simple diagnostic tool for the detection of androgen receptor malfunction.

UNLABELLED Case of a 20-year-old patient with severe abdominal pain, right adnexal mass, positive beta-HCG titre and free fluid in the abdominal cavity, as diagnosed by ultrasound. Laparotomy resulted in a ruptured ovarian tumour (chorionic carcinoma). Despite chemotherapy, the tumour developed fulminant metastases with a follow-up of 3 months. FINAL DIAGNOSIS Gonadal dysgenesis, XY female type (Swyer-Syndrome).

A case is reported of a gonadoblastoma in a pure XY-gonadal dysgenesis which was HY antigen negative. The salient clinical features were amenorrhoea and tall stature. The FSH was markedly increased, combined with low E2 and testosterone values. Cytogenetically a 46-XY karyotype was found. The HY antigen titre was in a male level. The gonadal streaks which were removed showed microscopically islands of tumour cells with 2 cell lines which were interpreted as germ cells and granulosa cells. Newer concepts of the influence of the HY antigen on the differentiation of the testicles and differentiation of the ovaries are discussed. Treatment consists of removal of the gonadal streaks and estrogen treatment.