Concurrent Germline RB1 & Mosaic TP53 in a Child With Multiple Childhood Cancers

ABSTRACT

We report a patient with a pathogenic germline variant (PGV) in RB1 and somatic mosaicism for a pathogenic TP53 variant who developed three distinct types of childhood cancer: retinoblastoma, osteosarcoma, and myelodysplastic syndrome (MDS) before the age of 6 years. The patient presented with bilateral retinoblastoma at age 4 weeks and a PGV in RB1 was found. At the very young age of 3 years, she developed an osteosarcoma. A pathogenic variant in TP53 was initially found in bone marrow as part of the diagnostic workup for the patient's third cancer, MDS rapidly progressing to acute myeloid leukemia (AML). Due to the unusual clinical phenotype, cultured fibroblasts from a skin biopsy were examined and identified somatic TP53 mosaicism, with a VAF of 7%. The early debut of osteosarcoma at age 3 years indicates a stronger predisposition than only heritable retinoblastoma would explain, but the development of subsequent MDS could implicate a vulnerability to chemotherapy due to digenic cancer predisposition. This unusual clinical course underlines the need for a better understanding of genetic predisposition to cancer and the interplay between genetic predisposition and treatment effects in optimizing therapeutic strategies and improving long‐term outcomes for these patients.