Females with Gonadal Dysgenesis: Cytogenetic and Molecular Analysis

Gonadal dysgenesis (GD) is a congenital defect in gonadal development related to abnormalities of genes controlling sexual differentiation and includes a wide spectrum of patients with variable phenotypes and chromosomal constitutions. This study aimed at studying the spectrum of chromosomal abnormalities as related to the phenotypic variability of GD cases and to detect the presence of Y-chromosome specific sequences in these patients by using molecular techniques in order to allow early prophylactic management. Seventy females presenting with female GD were referred to the Human genetic clinic, National Research Center for cytogenetic analysis and genetic counseling. Patients were subjected to clinical examination, pedigree construction, cytogenetic and molecular analysis. Hormonal studies, pelvic ultrasonogrophy, Laparoscopy and gonadal biopsy were performed whenever possible. Patients were classified according to their Karyotypes into 9 groups. The most frequent Karyotype, was 45, X (34.3%). The association of 45, X with other cell lines were found at a rate of 28.6%. The age of studied cases ranged between 15 days to 31.07 years (mean= 14:0.9 years). The total parental consanguinity rate reached 44.3%. Gonadal dysgenesis and short stature are the two cardinal signs in these patients. Skeletal features were detected among all studied groups with highest scores in patients having complete X monosomy (44.6%). Neck webbing was a characteristic sign of patients with non-mosaic 45, X karyotype. Dysmorphic features were detected in all groups with the exception of groups with 46, XX and 46, XY Karyotypes. Hirsutism and other virilizing signs were not commonly detected among the studied cases. Gonadoblastoma was detected in only one case among the 5 cases examined by Laparoscopic biopsy. Unidentified sex chromosomes markers constituted 35% of all our 45, X mosaic patterns. Molecular analysis of the markers using PCR technique proved the presence of Y specific sequences, SRY, in three cases. The over all rate of Y chromosomal material detected among these patients either by cytogenetic or molecular methods was 14,3%. INTRODUCTION The term gonadal dysgenesis (GD) is frequently used to describe all subjects with female genitalia, normal Mullerian structures and streak gonads. It includes a heterogeneous group with large phenotypic and cytogenetic spectrum. (1) It has been 371 Bull High Inst Public Health Vol.38 No.2 [2008] documented that Y-chromosome contains the sex determining gene (SRY) which is located on the short arm close to the pseudo-autosomal region. However, many other genes located on the X-chromosome and autosomes have crucial role for normal sexual development. (2) The cytogenetic spectrum of females with GD, may extend from apparently normal 46, XX chromosomal complement to 46, XY females and includes Turner syndrome (TS) patients with complete or partial Xmonosomy. (1) A variety of other cytogenetic abnormalities have been also found, such as Xp or Xq deletions, isochromy of the Xlong arm, ring X, and mosaicism that may include a cell line with Y-chromosome disclosed by DNA analysis. Further, 3% of cases may have an unidentified sex chromosomal marker in pure or mosaic form. (3) Turner syndrome is the major type of GD in females and is of extremely variable phenotype. The most consistent findings are gonadal dysgenesis, short stature, and lymph edema. (4) The pathogenesis of TS is complex and most authors believe that growth retardation, ovarian failure, and other physical abnormalities are separate and have distinct genetic effects. It was suggested that genes that play a role in the somatic stigmata are likely to be in Xp, where as gonadal dysfunction is likely to be due to inadequate dosage of X-linked genes and/or poor pairing of the sex chromosomes in meiotic prophase. (5) It has been proposed that all TS female with 45, X Karyotypes carry a cell line containing two sex chromosomes at a low level of mosaicism that is undetectable by standard cytogenetic methods. (3) Theoretically, this hidden mosaicism may have a Y-chromosome specific Ysequences which are highly associated (up to 30%) with the risk of gonadoblastoma. (6)