Endocrine Abstracts (2006) 11 OC38

Germline mutations in patients with apparently sporadic pheochromocytomas/paragangliomas

M Mannelli, MS Gaglianò, L Simi, T Ercolino, L Becherini, P Pinzani, R Sestini, GP Bernini, M Mascalchi & M Genuardi

Dept. Clinical Pathophysiology, Florence, Italy.

Paragangliomas (PGLs) and pheochromocytomas (PHEOs) are neural crest-derived tumors (NCD). PGLs can be localized in parasympathetic ganglia (in the head-neck region or in the anterior thorax) or in sympathetic ganglia (in the posterior thorax or in the abdomen). PHEOs can be considered PGLs arising in the adrenal gland.

NCD tumors can present as sporadic or familial. The percentage of hereditary forms is supposed to be 25%. The susceptibility genes predisposing to PGLs/PHEOs are: the proto-oncogene RET, the tumor-suppressor gene VHL, the tumor-suppressor gene NF1, the SDHB/C/D genes encoding three of the four subunits of the mithocondrial complex II.

In this study we evaluated 50 patients (20 males and 30 females) with non-syndromic PGLs/PHEOs and without a positive family history for the diseases. Overall, 71 NCD tumors were found: 39 PHEOs (4 bilateral) and 32 PGLs (20 in the head-neck region, 3 in the thorax and 9 in the abdomen). DNA was extracted from leucocytes and tested for germline mutations of RET, VHL, SDHB, SDHC and SDHD genes.

We found 9 subjects (18%) with SDHD mutations (5 with Q109X, 3 with P81L and 1 with G12S mutations), 1 patient (2%) with a novel SDHB mutation (IVS4+1 G>A) and 2 patients (4%) with an undescribed VHL mutation (T152I and L198V). All tumors associated to SDHD mutations were benign while the SDHB mutated patient was affected by malignant bilateral PHEO. NCD tumors were the first lesions in patients with VHL mutations.

In conclusion, in patient with an apparently sporadic PGL/PHEO genetic testing revealed that 24% was affected by germline mutations in the susceptibility genes for NCD tumors. Therefore, DNA analysis is recommended in all subjects affected by PGLs and/or PHEOs.

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