Генетика человека и эмбриология

Objectives: Fetal gonadoblastoid testicular dysplasia is a rare finding. The combination with typical features of Noonan syndrome has never been described so far. We performed genetic testing including whole exome sequencing in two cases with fetal hydrops, congenital heart disease and gonadoblastoid testicular dysplasia.

Methods: Exome sequencing was performed in the index case, where high quality DNA was isolated from fetal blood. In the second case and in five further gonadoblastoma samples, conventional Sanger sequencing was performed on DNA isolated from formalin fixed, paraffin embedded tissue.

Results: Whole exome sequencing of the index case revealed a pathogenic mutation in the RIT1 gene (c.270G>A (p.Met90Ile)), leading to the diagnosis of Noonan syndrome type 8. In case 2, Sanger sequencing of RIT1 did not show any disease causing mutations. Sequencing of PTPN11 revealed a heterozygous frameshift mutation (c.1098delA, p.K366Nfs*12). Successful sequencing of four gonadoblastoma samples revealed mutations in RIT1 in two cases.

Conclusion: Here we present a lethal form of Noonan syndrome in two fetuses with typical features combined with severe hydrops and gonadoblastoid testicular dysplasia. Gonadoblastoid testicular dysplasia may be an additional feature of Noonan syndrome, which has not been described so far, but analysis of more cases is needed. Moreover, we have demonstrated a potential role of RIT1 in the pathogenesis of gonadoblastoma.