Four new novel mutations in SRY (sex determining region) and WT1 (Wilms tumor 1) genes in two sisters with sex reversal and gonadal tumor formation with 46,XY chromosomal constitution.

A23 In mammals, a master gene located on the Y-chromosome, the testis-determining gene SRY, controls sex determination. Mutation in testis-determining gene (SRY) result in XY sex reversal with pure gonadal dysgenesis. XY gonadal dysgenesis can be classified as either complete or incomplete according to gonadal morphology. The disease is a sex reversal disorder resulting from embryonic testicular regression sequences and is induced by mutations in the sex determining region (SRY) gene. Mutation in SRY gene has been considered to account for only 10-15% of 46,XY gonadal dysgenesis cases whereas the remaining majority may have mutation (s) in the SRY regulatory elements or other genes involved in sex differentiation pathways. Using polymerase chain reaction (PCR), single strand conformational polymorphism (SSCP) and automated DNA sequencing, we searched the mutations in SRY and WT1 genes from two sisters with complete form of XY gonadal dysgenesis and detected four novel mutations in SRY and WT1 genes. Patient no. 1 demonstrated two mutations (Nucleotide G_>C substitution and T deletion at codon no 118 and 127, replacing Alanine (A)at codon 118 with proline (P) and Tyrosin (T) at codon 127 with Ileucin (I) respectively) with in HMG-box of SRY with WT1 genes. On the other hand patient no. 2 also showed one mutation (Nucleotide A ⋄ T substitution at codon no. 92 replacing lysine (K) with methione (M) within HMG box of SRY gene without any mutation in WT1 gene. Altered SSCP pattern were also observed in these patients. Histological examination of gonads in patient revealed the formation of gonadoblastoma. In present study we observed malignant dysgenesis germinoma lesion was observed in patient no 1 (28 yrs) with aberrant SRY and WT1 genes but no tumor formation was observed in another younger patient (22 yrs) with aberrant SRY and normal WT1 genes. Therefore the incidence of gonadoblastoma formation increases with age in XY sex reversal patients. On the basis of these results it is recommend that XY female should be identified prepubertally because delay diagnosis may bring about the development of gonadal tumor and clinician carefully examine and observe the gonads of patients with aberrant SRY and WT1 genes.