Gonadal Mosaicism in Rhabdoid Tumor Predisposition Syndrome

Abstract

Rhabdoid tumor (RT) is a malignant tumor occurring in children with a peak incidence between 1-4 years of age. The tumor exhibits diverse subtypes: atypical teratoid rhabdoid tumor (ATRT), malignant rhabdoid tumors in the kidney (MRTK) and extrarenal tumors (MRT). These malignancies are associated with a pathogenic variant in SMARCB1 (98%) or SMARCA4 (2%). Within 25-35% there is a germline pathogenic variant leading to rhabdoid tumor predisposition syndrome (RTPS). These variants can be inherited in an autosomal dominant mode, but most occur de novo. Even with a multimodal treatment the prognosis is poor. We report on a family with 2 siblings diagnosed with RT due to a germline nonsense pathogenic variant in SMARCB1 caused by gonadal mosaicism. This germline variant was found in the 9-month-old brother who presented with metastatic MRTK and was absent in the parents. However familial recurrence of an RT occurred when a newborn sister presented with an ATRT. Both patients died from the disease. SNP haplotyping identified maternal gonadal mosaicism. Only seven families affected by RTPS due to gonadal mosaicism have been reported in the literature. The current new and more extensive genetic tests will probably identify more families with RTPS due to gonadal mosaicism. However, most germline pathogenic variants in children of healthy parents arise de novo, making it challenging to predict the risk of RT development in siblings. Therefore, extensive genetic testing in families with a child affected by RTPS is necessary to rule out gonadal mosaicism and to more accurately predict the possible recurrence risk of RT in siblings.