Penetrance and clinical consequences of a gross SDHB deletion in a large family

Authors

  • DC Solis,

    1. Reproductive and Adult Endocrinology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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  • N Burnichon,

    1. Department of Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
    2. INSERM, U772, Collège de France, Paris, France
    3. Faculté de Médecine, Université Paris Descartes, Paris, France
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  • HJLM Timmers,

    1. Reproductive and Adult Endocrinology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
    2. Department of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
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  • MJ Raygada,

    1. Laboratory of Clinical Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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  • A Kozupa,

    1. Reproductive and Adult Endocrinology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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  • MJ Merino,

    1. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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  • D Makey,

    1. Reproductive and Adult Endocrinology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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  • KT Adams,

    1. Reproductive and Adult Endocrinology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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  • A Venisse,

    1. Department of Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
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  • A-P Gimenez-Roqueplo,

    1. Department of Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
    2. INSERM, U772, Collège de France, Paris, France
    3. Faculté de Médecine, Université Paris Descartes, Paris, France
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  • K Pacak

    Corresponding author
    1. Reproductive and Adult Endocrinology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
      Karel Pacak, MD, PhD, DSc, Head, Section on Medical Neuroendocrinology, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, 10 Center Drive, Building 10, CRC, RM 1-E 3140, MSC 1109, Bethesda, MD 20892-1109, USA.
      Tel.: (301) 402-4594;
      fax: (301) 402-4712;
      e-mail: karel@mail.nih.gov
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Karel Pacak, MD, PhD, DSc, Head, Section on Medical Neuroendocrinology, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, 10 Center Drive, Building 10, CRC, RM 1-E 3140, MSC 1109, Bethesda, MD 20892-1109, USA.
Tel.: (301) 402-4594;
fax: (301) 402-4712;
e-mail: karel@mail.nih.gov

Abstract

Mutations in the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) are inherited in an autosomal dominant manner and are associated with hereditary paraganglioma (PGL) and pheochromocytoma. The phenotype of patients with SDHB point mutations has been previously described. However, the phenotype and penetrance of gross SDHB deletions have not been well characterized as they are rarely described. The objective was to describe the phenotype and estimate the penetrance of an exon 1 large SDHB deletion in one kindred. A retrospective and prospective study of 41 relatives across five generations was carried out. The main outcome measures were genetic testing, clinical presentations, plasma catecholamines and their O-methylated metabolites. Of the 41 mutation carriers identified, 11 were diagnosed with PGL, 12 were found to be healthy carriers after evaluation, and 18 were reportedly healthy based on family history accounts. The penetrance of PGL related to the exon 1 large SDHB deletion in this family was estimated to be 35% by age 40. Variable expressivity of the phenotype associated with a large exon 1 SDHB deletion was observed, including low penetrance, diverse primary PGL tumor locations, and malignant potential.

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