Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes

Abstract

Kabuki syndrome is a well-recognized syndrome characterized by facial dysmorphism and developmental delay/intellectual disability and in the majority of patients a germline variant in KMT2D is found. As somatic KMT2D variants can be found in 5–10% of tumors a tumor predisposition in Kabuki syndrome is discussed. So far less than 20 patients with Kabuki syndrome and a concomitant malignancy have been published. Here we report on a female patient with Kabuki syndrome and a c.2558_2559delCT germline variant in KMT2D who developed an embryonal rhabdomyosarcoma (ERMS) at 10 years. On tumor tissue we performed DNA-methylation profiling and exome sequencing (ES). Copy number analyses revealed aneuploidies typical for ERMS including (partial) gains of chromosomes 2, 3, 7, 8, 12, 15, and 20 and 3 focal deletions of chromosome 11p. DNA methylation profiling mapped the case to ERMS by a DNA methylation-based sarcoma classifier. Sequencing suggested gain of the wild-type KMT2D allele in the trisomy 12. Including our patient literature review identified 18 patients with Kabuki syndrome and a malignancy. Overall, the landscape of malignancies in patients with Kabuki syndrome was reminiscent of that of the pediatric population in general. Histopathological and molecular data were only infrequently reported and no report included next generation sequencing and/or DNA-methylation profiling. Although we found no strong arguments pointing towards KS as a tumor predisposition syndrome, based on the small numbers any relation cannot be fully excluded. Further planned studies including profiling of additional tumors and long term follow-up of KS-patients into adulthood could provide further insights.

Primary CNS Burkitt Lymphoma Presenting as Sudden Bilateral Blindness in a Patient With Underlying Kabuki Syndrome: A Case Report

“…Several previous reports have associated KS with various types of cancers, suggesting a cancer predisposition. These reports include associations with hepatoblastoma, leukemia, neuroblastoma, synovial sarcoma, giant cell fibroblastoma, pilomatricoma, Wilms tumor, and desmoid fibromatosis [ 10 - 12 ]. Two previous reports have associated KS with BL originating from the abdomen and the rhinopharyngeal area [ 13 , 14 ].…”

Chromatinopathies: insight in clinical aspects and underlying epigenetic changes

“…However, some general clinical characteristics are observed across different CP subtypes. These include neurodevelopmental delay and intellectual disability, seizures, facial dysmorphism, growth and feeding difficulties, and abnormalities of heart or skeleton (Parenti and Kaiser 2021;Fazio et al 2019;Björkman et al 2018;Boot et al 2018a;Karagianni et al 2016;Litwin and Wysocki 2018;Aukema et al 2023;Ciptasari and van Bokhoven 2020). CP syndromes often require long-term monitoring as the phenotype changes over time.…”