The Penetrance of Paraganglioma and Pheochromocytoma in SDHB germline mutation carriers

Abstract

Germline mutations in SDHB predispose to hereditary paraganglioma syndrome type 4. The risk of developing paraganglioma (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. 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 twelve carriers (57.4%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (27.7%), 4 patients had a PHEO (2.1%), 26 patients an extra-adrenal PGL (13.3%). 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.

Graphical abstract

The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment.Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.The maximum likelihood estimate of the age-related penetrance of SDHB mutations for paraganglioma and/or pheochromocytoma (continuous line) and 95% confidence interval (dashed line).

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