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.
- Adrenal disorders
- Cancer: endocrine
- Genetic screening/counselling
- Molecular genetics
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Contributors NB, J-MM, KL-L, JF and A-PGR contributed to the project design, analysis of the data and/or the drafting of the manuscript. DD, LA, JB, IC, BD, IG, PH, VK, AT and NW recruited patients and family members, clinically characterised the subject and collected the samples. NB and JF performed the biochemical and molecular genetic studies. All authors critically revised the manuscript text and approved the final version. A-PGR supervised the study.
Funding NB is supported by the Cancer Research for Personalised Medicine project (Site de Recherche Intégré sur le Cancer).
Competing interests None declared.
Ethics approval Comité de Protection des Personnes Ile de France II.
Provenance and peer review Not commissioned; externally peer reviewed.