Purpose: To genotype patients with headneck paragangliomas (HNPGL) and evaluate the percentage and types of germ-line mutations in patients classified according to family history (FH) and clinical presentation.
Design: In total, 101 consecutive patients with HNPGL were examined for mutations in SDHB, SDHC, SDHD. SDHAF2 and VHL genes by PCR/sequencing.
According to a careful FH, clinical, laboratory (including metanephrines) and instrumental examinations patients were divided in three groups: a) with a positive FH for HNPGL; b) with a negative FH and multiple/recurrent HNPGL; c) with negative FH and single HNPGL.
Results: Group a) included 33 patients (8 index cases, 25 affected relatives) resulted SDHD mutation carriers; seven presented a single HNPGL, 26 presented HNPGL which were multiple (18 patients) or associated with a secreting paraganglioma (sPGL) (eight patients).
All the 16 patients (100%) of group b) resulted SDHD mutation carriers. Four patients presented also a sPGL. Among the 52 patients of group c) 9 (17.3%) presented germ-line mutations (two SDHB, three SDHD, two VHL, two SDHAF2). Of the two SDHAF2 mutations one is missense and the same described in one Dutch and Spanish family and one is a novel frame-shift mutation.
A sPGL was found at diagnosis or during the follow up in 12 patients (11.9%); all were SDHD mutation carriers and none presented a missense mutation. No SDHC mutations were found.
Conclusions: A positive FH or the presence of multiple/recurrent HNPGL are strong predictors for germ-line mutations, which are also present in 17.3% of patients clinically classified as sporadic.
By far, the most frequently mutated gene is SDHD but other, including SDHB, SDHAF2 and VHL, may be affected
In SDHD mutation carriers the risk of an associated sPGL is significantly higher for nonsense, frame-shift or insertion/deletion than for missense mutations.
30 Apr - 04 May 2011
European Society of Endocrinology