Nelly Burnichon1,2,3, Jean-Michaël Mazzella1, Delphine Drui4, Laurence Amar2,3,5, Jérôme Bertherat2,6,7, Isabelle Coupier8, Brigitte Delemer9, Isabelle Guilhem10, Philippe Herman11, Véronique Kerlan12, Antoine Tabarin13, Nelly Wion14, Khadija Lahlou-Laforet15, Judith Favier2,3, Anne-Paule Gimenez-Roqueplo1,2,3,7. 1. Service de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 2. Faculté de Médecine, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France. 3. INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France. 4. Service d'Endocrinologie, Centre Hospitalier Universitaire de Nantes, Hôpital Nord Laënnec, Nantes, France. 5. Unité d'Hypertension artérielle, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 6. Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service d'Endocrinologie "Centre de référence maladies rares de la surrénale", Paris, France. 7. Centre Expert National COMETE-Cancer de la surrénale, Paris, France. 8. Service de Génétique Médicale, unité d'Oncogénétique, Centre Hospitalier Universitaire de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, Cedex, France. 9. Centre Hospitalier Universitaire de Reims, Département d'Endocrinologie, Diabétologie et Nutrition, Reims, France. 10. Service d'Endocrinologie-Diabétologie-Nutrition, Centre Hospitalier Universitaire de Rennes, Hôpital Sud, Rennes, France. 11. Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Département d'Oto-rhino-laryngologie et de Chirurgie de la tête et du cou, Paris, France. 12. Service d'Endocrinologie-Diabétologie-Nutrition, Centre Hospitalier Universitaire de Brest, Hôpital de la Cavale Blanche, Brest, France. 13. Département d'Endocrinologie, Centre Hospitalier Universitaire de Bordeaux, Hôpital de Haut-Lévêque, Pessac, France. 14. Centre Hospitalier Universitaire de Grenoble, Hôpital Nord, Service d'Endocrinologie-Diabétologie-Nutrition, Grenoble, France. 15. Service de Psychiatrie de l'Adulte et du Sujet Agé, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité de Psychiatrie de Liaison, Paris, France.
Abstract
BACKGROUND: Germline mutations in the SDHD tumour suppressor gene (11q23.1) predispose to phaeochromocytomas and paragangliomas (PPGL) mainly on a paternal transmission. However, PPGL have been recently reported in three carriers of a maternally inherited SDHD mutation. OBJECTIVE: To assess the risk of PPGL occurrence on maternal transmission of SDHD mutation. METHODS: Pedigrees of 80 SDHD-related families have been reviewed. 35 asymptomatic subjects carrying a maternally transmitted SDHD mutation were identified. 20 of them accepted to benefit from a PPGL imaging screening. RESULTS: A unique histologically proven biochemically negative phaeochromocytoma has been diagnosed in a 35-year-old woman. Molecular investigations carried out on tumour tissue revealed that the loss of heterozygosity encompassed the paternally derived q arm and the maternally derived p arm of chromosome 11. CONCLUSIONS: This study demonstrates that the risk of developing PPGL for a subject carrying a germline SDHD mutation on the maternal allele remains a rare scenario but does exist. Our data suggest an adjustment of current genetic counselling and clinical care recommendations for at-risk subjects. A targeted familial genetic test should be proposed from the age of 18 years to every subject having a mother carrying a germline SDHD mutation and a first medical workup, including imaging, should be recommended to SDHD-positive mutation carriers. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
BACKGROUND: Germline mutations in the SDHD tumour suppressor gene (11q23.1) predispose to phaeochromocytomas and paragangliomas (PPGL) mainly on a paternal transmission. However, PPGL have been recently reported in three carriers of a maternally inherited SDHD mutation. OBJECTIVE: To assess the risk of PPGL occurrence on maternal transmission of SDHD mutation. METHODS: Pedigrees of 80 SDHD-related families have been reviewed. 35 asymptomatic subjects carrying a maternally transmitted SDHD mutation were identified. 20 of them accepted to benefit from a PPGL imaging screening. RESULTS: A unique histologically proven biochemically negative phaeochromocytoma has been diagnosed in a 35-year-old woman. Molecular investigations carried out on tumour tissue revealed that the loss of heterozygosity encompassed the paternally derived q arm and the maternally derived p arm of chromosome 11. CONCLUSIONS: This study demonstrates that the risk of developing PPGL for a subject carrying a germline SDHD mutation on the maternal allele remains a rare scenario but does exist. Our data suggest an adjustment of current genetic counselling and clinical care recommendations for at-risk subjects. A targeted familial genetic test should be proposed from the age of 18 years to every subject having a mother carrying a germline SDHD mutation and a first medical workup, including imaging, should be recommended to SDHD-positive mutation carriers. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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