Background: Several susceptibility genes have been found to be associated with development of pheochromocytoma (PHEO): RET, VHL, SDHB and SDHD. We investigate the frequency of germ-line mutations in SDHB and VHL genes in patients with apparently sporadic PHEO.
Material and methods: Fifty patients (38 women, mean age 42) with apparently sporadic adrenal and extra-adrenal PHEO were screened. DNA was extracted from whole blood and from paraffin embedded tumors using standard phenol-chloroform method. For detection of SDHB and VHL mutations PCR method followed by direct sequencing gene was used.
Results: In 5/50 (10%) patients, five novel germ-line variants were identified: four heterozygous germ-line mutations (nonsense: W218X; frameshift: c.661delG, p.Asp221ThrfsX27; splicing:c.424-12delTCTT and missense: R116M) of the SDHB gene and one heterozygous germ-line mutation (V84M) of the VHL gene. In the patient with adrenal PHEO and heterozygous germ-line W218X mutation, the same heterozygosity state in the tumor tissue was found. The patient with c.661delG mutation was found to have extra-adrenal retroperitoneal malignant PHEO. Family members were also tested and they are negative for the mutation.The patient with c.424-12delTCTT is 12 years old boy with adrenal PHEO. He inherited the mutation from his father who is clinically asymptomatic for PHEO. The patient with V84M mutation was found to have adrenal PHEO. His family history is negative and he doesnt have any other tumors associated with VHL syndrome.
Conclusion: Patients with SDHB mutations are in an increased risk for the development of extra-adrenal and malignant PHEO. Our patient with extra-adrenal disease needs careful follow-up, since he is in higher risk for the development of metastases or novel adrenal/extra-adrenal PHEO. The patient with VHL mutation (V84M) is apparently classified as 2C. Until now genotipe/phenotipe correlation is not proven. This patient may develop some other tumors than PHEO.