Genotype and clinical phenotype characteristics of germline mutation-associated pheochromocytoma/paraganglioma syndrome.

OBJECTIVE

The aim of this study was to investigate the genotypic and clinical phenotypic characteristics of germline mutation-associated pheochromocytoma (PCC) and paraganglioma (PGL).

METHODS

We retrospectively analyzed the family investigation data and clinical genetic characteristics of six individuals from three independent families with PCC carrying germline mutations from December 2005 to March 2024. A literature review was then conducted of the six carriers and another 103 carriers from the other 84 families with germline mutations reported previously.

RESULTS

There were 109 patients in 87 families with all five exons and 53 types of germline mutations. p.R33* (c.97C>T; 21.1%), p.R75* (c.223C>T; 13.8%), and p.A67D (c.200C>A; 7.3%), which accounted for 42.2% of mutations detected, were the most common mutations. Moreover, 101 (92.7%) patients developed PCCs, including 59 bilateral PCCs and 42 unilateral PCCs, and 19 (18.8%) patients showed metastasis. The mean age at diagnosis was 32.8 ± 12.6 (13-80) years. The male-to-female ratio was 1.3:1. In 11 (10.9%) patients, the PCC was accompanied by chest or abdominal PGL, and one other patient had sole head and neck PGL. Nine (8.3%) patients also had functional pituitary adenomas, 11 (10.9%) developed other neuroendocrine tumors (NETs), and 7 (6.4%) presented with concomitant non-NET. Meanwhile, -p.Q82Tfs*89 and p.E158A mutations are reported for the first time in this study.

CONCLUSION

germline mutations may cause new types of multiple endocrine neoplasia. A comprehensive baseline assessment of neural crest cell-derived diseases is recommended for all individuals with germline mutations. The risk of bilateral and metastatic PCCs should also be considered.