Ivana Jochmanova1,2, Katherine I Wolf1, Kathryn S King1, Joan Nambuba1, Robert Wesley3, Victoria Martucci1, Margarita Raygada4, Karen T Adams1, Tamara Prodanov1, Antonio Tito Fojo5, Ivica Lazurova2, Karel Pacak6. 1. Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, 1E-3140, Bethesda, MD, 20892-1109, USA. 2. 1st Department of Internal Medicine, Medical Faculty of P. J. Šafárik University in Košice, Trieda SNP 1, 04011, Košice, Slovakia. 3. Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA. 4. Section on Developmental Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA. 5. Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. 6. Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, 1E-3140, Bethesda, MD, 20892-1109, USA. karel@mail.nih.gov.
Abstract
PURPOSE: Succinate dehydrogenase subunit B (SDHB) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma (PHEO/PGL). Limited information is available concerning PHEO/PGL penetrance among SDHB mutation carriers with regards to primary tumor location, specific mutation type, and gender. We assessed PHEO/PGL penetrance in SDHB mutation carriers and described the clinical presentation and disease course. METHODS: Asymptomatic relatives (N = 611) of 103 index patients were tested for SDHB mutations. Mutation carriers (N = 328) were offered PHEO/PGL screening, of which 241 participated and were included in penetrance analysis. For additional disease outcome analysis, the 103 index patients and 40 screened individuals who developed PHEO/PGL were included. Clinical data were collected between October 2004 and June 2016. RESULTS: Forty (16.60%) of the 241 screened individuals developed PHEO/PGL during the study. The penetrance estimate in this population was 49.80% (95% CI 29-74.9) at 85 years. A significantly higher age-related penetrance of disease was observed in males compared to females, with 50% penetrance achieved at age 74 vs. not reached. Age-related penetrance analysis demonstrated 4 mutations (Ile127Ser, IVS1+1G>T, Exon 1 deletion, Arg90X) presenting with a slower rate of disease development (50% penetrance ages, respectively: not achieved, 70, 63, 61 years) compared to Arg46X and Val140Phe mutations (50% penetrance at 38 years). CONCLUSIONS: Here, we found a higher estimated penetrance compared to several other studies, and a striking difference in age-related penetrance between male and female SDHB mutation carriers with no association between mutation and gender or tumor location.
PURPOSE:Succinate dehydrogenase subunit B (SDHB) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma (PHEO/PGL). Limited information is available concerning PHEO/PGL penetrance among SDHB mutation carriers with regards to primary tumor location, specific mutation type, and gender. We assessed PHEO/PGL penetrance in SDHB mutation carriers and described the clinical presentation and disease course. METHODS: Asymptomatic relatives (N = 611) of 103 index patients were tested for SDHB mutations. Mutation carriers (N = 328) were offered PHEO/PGL screening, of which 241 participated and were included in penetrance analysis. For additional disease outcome analysis, the 103 index patients and 40 screened individuals who developed PHEO/PGL were included. Clinical data were collected between October 2004 and June 2016. RESULTS: Forty (16.60%) of the 241 screened individuals developed PHEO/PGL during the study. The penetrance estimate in this population was 49.80% (95% CI 29-74.9) at 85 years. A significantly higher age-related penetrance of disease was observed in males compared to females, with 50% penetrance achieved at age 74 vs. not reached. Age-related penetrance analysis demonstrated 4 mutations (Ile127Ser, IVS1+1G>T, Exon 1 deletion, Arg90X) presenting with a slower rate of disease development (50% penetrance ages, respectively: not achieved, 70, 63, 61 years) compared to Arg46X and Val140Phe mutations (50% penetrance at 38 years). CONCLUSIONS: Here, we found a higher estimated penetrance compared to several other studies, and a striking difference in age-related penetrance between male and female SDHB mutation carriers with no association between mutation and gender or tumor location.
Entities:
Keywords:
Paraganglioma; Penetrance; Pheochromocytoma; SDHB; Sex differences
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