PURPOSE: Recently, familial paraganglioma (PGL) was shown to be caused
bymutations in the gene encoding succinate dehydrogenase subunit D (SDHD).
However, the prevalence of SDHD mutations in apparently sporadic PGL is
unknown. We studied the frequency and spectrum of germ-line and somatic
SDHD mutations in patients with parasympathetic PGL. EXPERIMENTAL DESIGH:
We studied 57 unselected patients who developed parasympathetic PGLs (n =
105 tumors) and who were treated between 1987 and 1999 at the Erasmus MC
(Rotterdam, the Netherlands). Thirty-eight (67%) of these patients (n = 51
tumors) lacked a family history of parasympathetic PGL. We used
conformation-dependent gel electrophoresis and sequence determination
analysis of germ-line and tumor DNA to identify SDHD mutations. We
compared the clinical and molecular characteristics of sporadic and
hereditary PGLs. RESULTS: Three different SDHD germ-line mutations were
identified in 32 of the 57 (56%) patients. These included 19 of 19 (100%)
patients with familial PGL and also 13 of 38 (34%) patients with
apparently sporadic PGL. All three mutations were characterized as
missense mutations (D92Y, L95P, and L139P) in highly conserved regions of
the SDHD gene and were not observed in 200 control alleles. No somatic
mutations were found. CONCLUSIONS: Germ-line mutations of the SDHD gene
are present in a significant number of patients with apparently sporadic
parasympathetic PGL. Somatic SDHD mutations do not play a significant role
in the sporadic form of this tumor. Genetic testing for SDHD germ-line
mutations should be considered for every patient presenting with this
tumor, even if a personal or family history of PGL is absent, to allow
appropriate clinical management