(CSEMP078) CHARACTERIZING CLINICAL AND GERMLINE GENETIC VARIANTS OF PATIENTS WITH PHEOCHROMOCYTOMAS ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1

Abstract:

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are the tumors with the highest heritability in adult patients, with identification of a germline mutation in more than 30% of cases. Up to 20 susceptibility genes for PPGLs are known including NF1. Neurofibromatosis type 1 (NF1) is an inherited disease affecting approximately 1 in 3000 people that predisposes to the development of tumors, such as pheochromocytomas (PHEO). Up to recently, the diagnosis of NF1 was mainly based on clinical manifestations and NF1 genetic characterization was not systematically performed.

Objectives: To investigate clinical characteristics and germline pathogenic variant mutations in the NF1 gene in patients with PHEO and NF1.

Methods: In this retrospective study, we reviewed the charts of patients with a pathology-proven diagnosis of PHEOs that were investigated at Centre hospitalier de l’Université de Montréal (CHUM) between 2000 and May 2023. Genetic analysis included gene sequencing by Sanger method or multigene sequencing by NGS with a panel.

Results: In our cohort of 220 PHEOs, 15 patients (6.8%) had a diagnosis of NF1. Among these patients, 6 were male and 9 were females. Mean age at diagnosis of PHEO in NF1 patients was 50  13 years contrasting to the mean age of 38,7  15.2 years in patients carrying germline mutations in non-NF1 genes most likely reflecting lack of systematic biochemically screening of PHEO in NF1. Urinary metanephrines were elevated in 7/15 patients. 2/15 (13,3%) NF1 patients had bilateral PHEO and 1/15 (6,7%) metastatic disease. Mean tumour diameter was 3.5cm (min-max 1.2 – 9.5 cm). Seven out of 15 NF1 patients underwent NF1 genetic analysis. NF1 germline pathogenic variants were found in all of them: 2 deletions, including one encompassing the entire gene, 4 premature stop codons leading to truncated proteins or loss of function, and 1 splicing defect.

Conclusions: We report a large cohort of patients with NF1 and PHEO. The older age at diagnosis of PHEO in NF1 is expected based on lack of systematic biochemical screening for PHEO in NF1 clinical guidelines. We report 7 germline NF1 mutations associated with PHEOs. Further studies are required to fully understand the impact of genetic pathogenic variants in this population and to unreveal a possible genotype-phenotype correlation.