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Low penetrance of a SDHB mutation in a large Dutch paraganglioma family.

ABSTRACT: BACKGROUND: Germline mutations of the succinate dehydrogenase subunit B gene (SDHB) predispose carriers for paragangliomas, and current estimates of the chance of mutation carriers actually developing tumors (penetrance) are high. We evaluate the phenotype and penetrance of a germline SDHB mutation in a large and clinically well-characterized paraganglioma family. METHODS: Following identification of the mutation in a 31 year old index-patient, extensive clinical screening was performed in mutation carriers to evaluate the presence of head and neck, thoracic and abdominal paragangliomas. Presymptomatic DNA testing was performed in 19 family members. RESULTS: DNA analysis detected 14 further SDHB mutation carriers. Three mutation carriers (median age 78 years) declined clinical surveillance, but had no clinical signs or symptoms associated with paragangliomas. The remaining 11 mutation carriers (mean age 53, range 37-76 years) consented to clinical screening. In only two, aged 43 and 48 years, were subclinical vagal paragangliomas identified. CONCLUSIONS: Only three of the fifteen mutation carriers in this family have developed paraganglioma, which results in a calculated penetrance of 26% at 48 years of age. This figure is lower than current estimates, and we conclude that the co-operation of this family allowed an almost complete attainment of mutation carriers, and the extensive clinical evaluation carried out allowed us to identify all affected individuals.

SUBMITTER: Hes FJ

PROVIDER: S-EPMC2891715 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Low penetrance of a SDHB mutation in a large Dutch paraganglioma family.

Hes Frederik J FJ Weiss Marjan M MM Woortman Sanne A SA de Miranda Noel F NF van Bunderen Patrick A PA Bonsing Bert A BA Stokkel Marcel P M MP Morreau Hans H Romijn Johannes A JA Jansen Jeroen C JC Vriends Annette H J T AH Bayley Jean-Pierre L JP Corssmit Eleonora P M EP

BMC medical genetics 20100611

<h4>Background</h4>Germline mutations of the succinate dehydrogenase subunit B gene (SDHB) predispose carriers for paragangliomas, and current estimates of the chance of mutation carriers actually developing tumors (penetrance) are high. We evaluate the phenotype and penetrance of a germline SDHB mutation in a large and clinically well-characterized paraganglioma family.<h4>Methods</h4>Following identification of the mutation in a 31 year old index-patient, extensive clinical screening was perfo ...[more]

PMID: 20540712

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Project description:Abstract Background: SDHB immunostaining can be used to functionally characterize SDH status in PCC and PGL. Assessing SDHB expression on tumors is inexpensive and can be used as an alternative to genetic testing. More importantly, assessment of SDHB expression can be of value in interpreting Variant of Unknown Significance (VUS) in SDH related genes. Objective: To investigate the effectiveness of SDHB immunostaining as an initial screening tool in identifying germline SDH mutations and the value of SDHB assessment in the clinical characterization of our patient cohort. Design: Prospective and retrospective analysis of 57 randomly selected patients with PCC and PGL from the year 1997 to 2018. Setting: In our institution on patients referred from London and South East England including Kent, Surrey and Sussex. Patients: Predominant Caucasian Population with diverse ethnicities. 57 patients - 34 patients (14M & 20F) with PGL and 25 with PCC (15M &10F). Age (mean: 41years at diagnosis with range 9-80 years). 2 patients had both PCC & PGL and multifocal PGLs were identified in few patients with SDHD and SDHB mutation. There were 65 tumors in total included in this study. Intervention: Resected tumor SDHB immunostaining with Sigma prestige antibodies (HPA002868 100UL - Anti-SDHB Rabbit monoclonal antibody) at a dilution of 1:1000. Genetic testing performed on predominant candidate genes. Main outcome measures: Concordance of SDHB loss of expression with presence of pathogenic mutation in candidate SDH genes. Secondarily, to explore SDHB immunostaining in our patient cohort with VUS in candidate genes. Results: SDHB immunostaining was negative in 22/23 tumors in patients with confirmed SDH mutation (false negative = 1 SDHB PCC where it was weak (+)). The staining was positive in 23/24 sporadic tumors, 10/11 VUS (in SDH, MAX and TMEM genes - both PCCs & PGLs), 2/2 PCCs in MEN-2, 2/2 PCCs in NF-1 and 2/3 PCCs in VHL. The negative immunostaining in 1 PGL with VUS in SDHB may imply lack of SDH enzyme activity and hence suggestive of a pathological mutation. The sensitivity is 96% and the specificity approaches 93% if the weak positive SDHB immunostaining with SDHD and VHL tumors were to be considered concordant. The concordance was 95% in the PGL group alone. Conclusions: SDHB immunostaining is a cost effective addition to PGL and PCC tumor characterization and performs with high sensitivity and specificity. SDH functional characterization has an important role in the management of patients who do not satisfy the current criteria for genetic testing (UK genetics testing directory for PCC/PGL). 18% of patients had VUS in a SDH related gene and we have found that SDHB immunostaining provided helpful information to inform follow-up and cascade screening decisions in this group.

Dataset Information

Low penetrance of a SDHB mutation in a large Dutch paraganglioma family.

Publications

Low penetrance of a SDHB mutation in a large Dutch paraganglioma family.

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