Contrasting clinical manifestations of SDHB and VHL associated chromaffin tumours.

Mutations in succinate dehydrogense-B (SDHB) and the von Hippel-Lindau (VHL) genes result in an increased risk of developing chromaffin tumours via a common aetiological pathway. The aim of the present retrospective study was to compare the clinical phenotypes of disease in subjects developing chromaffin tumours as a result of SDHB mutations or VHL disease. Thirty-one subjects with chromaffin tumours were assessed; 16 subjects had SDHB gene mutations and 15 subjects had a diagnosis of VHL. VHL-related tumours were predominantly adrenal phaeochromocytomas (22/26; 84.6%), while SDHB-related tumours were predominantly extra-adrenal paragangliomas (19/25; 76%). Median age at onset of the first chromaffin tumour was similar in the two cohorts. Tumour size was significantly larger in the SDHB cohort in comparison with the VHL cohort (P=0.002). Multifocal disease was present in 9/15 (60%) of the VHL cohort (bilateral phaeochromocytomas) and only 3/16 (19%) of the SDHB cohort, while metastatic disease was found in 5/16 (31%) of the SDHB cohort but not in the VHL cohort to date. The frequency of symptoms, hypertension and the magnitude of catecholamine secretion appeared to be greater in the SDHB cohort. Renal cell carcinomas were a feature in 5/15 (33%) of the VHL cohort and 1/16 (6%) of the SDHB cohort. These data indicate that SDHB-related tumours are predominantly extra-adrenal in location and associated with higher catecholamine secretion and more malignant disease, in subjects who appear more symptomatic. VHL-related tumours tend to be adrenal phaeochromocytomas, frequently bilateral and associated with a milder phenotype.

[1]  C. Ricketts,et al.  Germline SDHB mutations and familial renal cell carcinoma. , 2008, Journal of the National Cancer Institute.

[2]  D. Berney,et al.  Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH‐B) gene mutation carriers , 2008, Clinical endocrinology.

[3]  J. Bertherat,et al.  Mutations associated with succinate dehydrogenase d‐related malignant paragangliomas , 2008, Clinical endocrinology.

[4]  K. Pacak,et al.  Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. , 2007, The Journal of clinical endocrinology and metabolism.

[5]  E. Maher,et al.  Genotype–phenotype correlations in von Hippel‐Lindau disease , 2004, Human mutation.

[6]  G. Stamp,et al.  Expression of HIF-1α, HIF-2α (EPAS1), and Their Target Genes in Paraganglioma and Pheochromocytoma with VHL and SDH Mutations , 2006 .

[7]  K. Byth,et al.  Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. , 2006, The Journal of clinical endocrinology and metabolism.

[8]  G. Stamp,et al.  Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. , 2006, The Journal of clinical endocrinology and metabolism.

[9]  S. Richard,et al.  Genetic testing in pheochromocytoma or functional paraganglioma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  W. Kaelin,et al.  Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. , 2005, Cancer cell.

[11]  David G. Watson,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[12]  Eyal Gottlieb,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[13]  W. Kaelin.  The Von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer , 2004, Clinical Cancer Research.

[14]  C. Eng,et al.  Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. , 2004, JAMA.

[15]  A. Grossman,et al.  Familial paraganglioma: a novel presentation of a case and response to therapy with radiolabelled MIBG. , 2004, Hormones.

[16]  L. Aaltonen,et al.  Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. , 2004, American journal of human genetics.

[17]  D. Evans,et al.  Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility , 2003, Clinical endocrinology.

[18]  J. Strauchen.  Germ-line mutations in nonsyndromic pheochromocytoma. , 2002, The New England journal of medicine.

[19]  E S Husebye,et al.  Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. , 2001, American journal of human genetics.

[20]  S. L. Chew.  Paraganglioma genes , 2001, Clinical endocrinology.

[21]  P. Ratcliffe,et al.  Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. , 2001, Human molecular genetics.

[22]  H. Neumann,et al.  The challenge of kidney lesions in von Hippel-Lindau disease. , 2001, Contributions to nephrology.

[23]  B. Terris,et al.  [Pancreatic lesions in von Hippel-Lindau disease]. , 2000, Annales de pathologie.

[24]  P. Choyke,et al.  Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. , 1999, The Journal of urology.

[25]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[26]  P. Choyke,et al.  von Hippel-Lindau disease: genetic, clinical, and imaging features. , 1995, Radiology.

[27]  H. Neumann,et al.  Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. , 1993, The New England journal of medicine.

[28]  J. Gnarra,et al.  Identification of the von Hippel-Lindau disease tumor suppressor gene. , 1993, Science.

[29]  M. Ferguson-Smith,et al.  Clinical features and natural history of von Hippel-Lindau disease. , 1990, The Quarterly journal of medicine.

[30]  K. Melmon,et al.  Lindau's disease: Review of the literature and study of a large kindred , 1964 .