PMS2-related constitutional mismatch repair deficiency in a patient with unilateral retinoblastoma and negative germline RB1.

Abstract

Background: Retinoblastoma, the primary ocular tumor in childhood, arises from the photoreceptor cells of the retina caused by pathogenic loss-of-function variants in both alleles of the RB1 gene, which can be either germline or somatic. The predisposition to hereditary retinoblastoma is primarily linked to germline variants in the RB1 gene.

Material and methods: Here, we describe a two-year-old girl from a Mennonite community who presented at 6 months of age with unilateral Group E retinoblastoma and underwent enucleation. She had a strong family history of cancer: a third elder sister deceased at age 4 with concurrent Burkitt lymphoma and medulloblastoma, and father diagnosed with carcinoid tumor at age 27.

Results: RB1 gene testing detected two pathogenic variants in the RB1 gene (c.299dup, c.1959del) in the tumor tissue. These variants were not identified in blood, indicating somatic changes. Testing of 49 genes associated with cancer predisposition identified a germline homozygous likely pathogenic variant in PMS2 (c.2095 G>T, p.Asp699His) in the proband, consistent with the diagnosis of constitutional mismatch repair deficiency (CMMRD). The proband's fourth elder sister who also tested homozygous for the PMS2 variant, was diagnosed with low grade glioma identified during screening as a part of surveillance for CMMRD.

Conclusions: This case highlights the importance of considering CMMRD in retinoblastoma with normal germline RB1 sequence, particularly with additional factors like family cancer history, consanguinity, or multiple childhood malignancies. Given retinoblastoma's association with CMMRD, screening for it in children with CMMRD is recommended.