Biomedical subjects

Diana E Benn

Publications and source records attributed to Diana E Benn.

7 recordsLinked to original sources

PubMed2006

Genetic basis of phaeochromocytoma and paraganglioma.

Advances in the knowledge of the genetics of phaeochromocytoma have broadened our understanding about the mechanisms of tumorigenesis. Formerly it was believed that 10% of phaeochromocytomas were associated with familial cancer syndromes, but it is now recognised that up to 30% of these tumours may be familial. In particular, attention has been focused on those patients with apparently sporadic presentations where 12-24% of patients have been shown to carry germline mutations indicating hereditary disease. Consideration of genetic testing is now recommended for all apparently sporadic cases and, following the identification of a mutation-positive carrier, the offering of genetic testing to first degree relatives. There is a need for lifelong follow up of affected individuals and asymptomatic mutation-positive carriers, but validation of screening protocols has yet to be determined.

Adrenal Gland Neoplasms↗

PubMed2006

Genetic testing in pheochromocytoma- and paraganglioma-associated syndromes.

Genetic understanding of pheochromocytoma (PHEO) and paraganglioma (PGL) syndromes has recently expanded with the identification of the involvement of the mitochondrial complex II peptides, namely the succinate dehydrogenase subunit B (SDHB), subunit C (SDHC), and subunit D (SDHD). In patients with PHEO and/or PGL genetic testing for germline mutations in SDHD and SDHB has been recommended, in addition to the PHEO susceptibility genes VHL and RET. After careful clinical assessment of the patient, suspected familial disease may direct the clinician to the appropriate gene for testing. In the absence of obvious features of familial disease, the decision regarding the appropriate gene for testing is more difficult. Such testing can be costly and time consuming, but a rational prioritization of gene testing can streamline the process. Therefore in order to achieve this for apparently sporadic cases we propose a decision matrix based on site of tumor, functionality, and age at presentation.

Adrenal Gland Neoplasms↗

PubMed2005

Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.

CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations. OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations. DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland. MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined. RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008). CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.

Adolescent↗

PubMed2005

Phaeochromocytoma: current concepts.

The discovery of novel mutations in genes encoding succinate dehydrogenase subunits has revealed that familial phaeochromocytomas are much more common than previously thought. Genetic screening should be offered to patients with apparently sporadic phaeochromocytomas and their first-degree relatives. An increasing proportion of phaeochromocytomas present preclinically on genetic testing or as "incidentalomas" on abdominal imaging, rather than with classic symptoms and signs. Clinical suspicion should prompt measurement of plasma levels of free metanephrine or 24-hour urinary catecholamine and metanephrine levels, followed, if positive, by tumour localisation studies. With appropriate perioperative care, surgical management of phaeochromocytomas is safe and effective. Most tumours can be removed laparoscopically.

Adrenal Gland Neoplasms↗

PubMed2005

A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas.

Pheochromocytomas are neural crest-derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1alpha. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1alpha activity in tumors.

Journal Article↗

PubMed2004

K40E: a novel succinate dehydrogenase (SDH)B mutation causing familial phaeochromocytoma and paraganglioma.

OBJECTIVE: Germline mutations in succinate dehydrogenase (SDH)B, SDHC and SDHD, encoding three of the four subunits of mitochondrial complex II, have been implicated in the tumourigenesis of familial paragangliomas and phaeochromocytomas. Twenty-three SDHB mutations have been identified to date. PATIENTS: We present a novel missense SDHB exon 2 mutation (c.118 A > G; K40E) identified in an Australian family. The proband was diagnosed with phaeochromocytoma at an early age following an unexpected hypertensive crisis and was found to be SDHB mutation-positive. Subsequent genetic screening of 26 family members has identified 17 mutation-positive relatives. In addition to the proband, four mutation positive relatives were found to have clinical symptoms or a lesion and/or catecholamine excess after the identification of the mutation led to further evaluation. Both the proband and an uncle have required surgical removal of a tumour. CONCLUSIONS: This family indicates the importance of germline screening of first-degree relatives when a patient presents with an apparently sporadic extra adrenal phaeochromocytoma at a young age or whenever a patient with a nonsecretory paraganglioma is found.

Adrenal Gland Neoplasms↗

PubMed2003

Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas.

Phaeochromocytomas arising in adrenal or extra-adrenal sites and paragangliomas of the head and neck, in particular of the carotid bodies, occur sporadically and also in a familial setting. In addition to mutations in RET and VHL in familial disease, germline mutations in SDHD and SDHB genes that encode subunits of mitochondrial complex II have also been associated with the development of familial phaeochromocytomas. To further investigate the role of SDHD and SDHB in the development of these tumours we determined the occurrence of germline SDHD and SDHB mutations in four patients with a family history of phaeochromocytoma with associated head and neck paraganglioma, one patient with a family history of phaeochromocytoma only and two patients with apparently sporadic extra-adrenal phaeochromocytoma, one of whom had early onset disease. Secondly, we investigated whether somatic SDHB mutations correlated with loss of heterozygosity at 1p36 in a subgroup of 11 sporadic and three MEN 2-associated RET-mutation-positive phaeochromocytomas. Novel SDHB mutations were identified in the probands from four families and two apparently sporadic cases (six of seven probands studied), including two missense mutations, a single nonsense and frameshift mutation, as well as two splice site mutations, one of which was shown to have partial penetrance resulting in 'leaky' splicing. Further, five intronic polymorphisms in SDHB were found. No SDHD mutations were identified. In addition, no somatic SDHB mutations were found in the remaining allele of the 11 sporadic adrenal phaeochromocytomas with allelic loss at 1p36 or the three MEN 2-associated RET-mutation-positive phaeochromocytomas. Therefore, we conclude that SDHB has a major role in the pathogenesis of familial phaeochromocytomas, but the possible role of SDHB in sporadic tumours showing allelic loss at 1p36 has yet to be ascertained.

Adolescent↗