Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations.

BACKGROUND: Germline mutations in the succinate dehydrogenase B (SDHB) gene predispose to hereditary paraganglioma (PGL) syndrome type 4. The aim of this study was to evaluate the clinical characteristics and outcome of treatment strategies for patients with head and neck paraganglioma (HNPGL) carrying SDHB germline mutations. METHODS: This was a retrospective evaluation of patients with HNPGL carrying SDHB germline mutations in the Netherlands. RESULTS: In a Dutch nationwide cohort study of SDHB germline mutation carriers, 54 patients with a total of 62 HNPGLs were identified. Forty-one of 54 patients (76 per cent) visited the outpatient clinic because of associated complaints. Eight patients (15 per cent) had multiple PGLs. One patient (2 per cent) developed a phaeochromocytoma and three (6 per cent) developed a malignant PGL. Twenty-seven patients (50 per cent) had an operation for their HNPGL and 15 (28 per cent) received radiotherapy. Three patients with HNPGL (6 per cent) were diagnosed with additional non-paraganglionic tumours. CONCLUSION: If an SDHB germline mutation is identified in a patient with HNPGL, the clinician should be aware of the variable manifestations of the SDHB-linked tumour syndrome, the risk of catecholamine excess, concurrent phaeochromocytoma, and association with non-paraganglionic tumours.

The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers.

Germline mutations in succinate dehydrogenase B (SDHB) predispose to hereditary paraganglioma (PGL) syndrome type 4. The risk of developing PGL or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate. In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. A total of 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers). One hundred and twelve carriers (57%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (28%), 4 patients had a PHEO (2%), 26 patients an extra-adrenal PGL (13%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment. These estimates are lower than previously reported penetrance estimates of SDHB-linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.