One genotype, many phenotypes: SDHB p.R90X mutation-associated paragangliomas

Abstract

Context: SDHB p.R90X germline mutation is the most common genetic alteration in our patients with familial or apparently sporadic pheochromocytoma/paraganglioma (PPGL).

Objective: To analyze the clinical and pathological characteristics, response to therapy, and outcome of patients with SDHB p.R90X-associated PPGL and describe the clinical phenotypic variability in the patients carrying this mutation.

Methods: We reviewed the clinical and pathological characteristics and analyzed the phenotypic variability of all 13 patients that have SDHB p.R90X mutation-associated PPGL.

Results: Thirteen patients (five females and eight males). The median age at diagnosis was 23 years (range 8-43). Although the mutation was the same, there was significant phenotypic variability between patients and even within the same family. Four patients (30.8%) had a family history of PPGL and six patients (46%) had distant metastasis. Surgery of the primary tumor was performed in 11 patients (84.6%). Two patients had inoperable PPGL. Patients with metastasis received different combinations of chemotherapy, Lu¹⁷⁷ radiotherapy, multikinase inhibitors, and external irradiation. Only five patients (38.5%) were in remission at a follow-up duration of 4-9 years. The other patients either died due to their disease progression (four patients, 30.8%) or continue to have progressive disease (two patients, 15.4%) or recurrence (one patient, 7.7%). Patients with distant metastasis were older, had larger primary tumors, were more likely to have a family history of PPGL and had a worse outcome.

Conclusion: SDHB p.R90X mutation-associated PPGL have significant phenotypic variability and are associated with a high risk of distant metastasis and mortality.

Keywords: Genotype; Mutation; Paraganglioma; Phenotype; SDHB; SDHx.