The endemic paraganglioma syndrome type 1: Origin, spread, and clinical expression

Francesca Schiavi, Serena Demattè, Maria Enrica Cecchini, Elisa Taschin, Sara Bobisse, Antonella Del Piano, Davide Donner, Mattia Barbareschi, Vittorio Manera, Stefania Zovato, Zoran Erlic, Theodoros Savvoukidis, Susi Barollo, Franco Grego, Franco Trabalzini, Pietro Amistà, Cesare Grandi, Fabio Branz, Fabio Marroni, Hartmut P H NeumannGiuseppe Opocher

Research output: Contribution to journalArticlepeer-review


Context: Anecdotal evidence suggests a high incidence in Trentino, Italy, of head and neck paragangliomas (HNPGL), a rare autosomal dominant disease called paraganglioma type 1 syndrome and caused by germ-line mutations of the SDHD gene. Objective: The aim of this study was to investigate the origin, spread, and clinical expression of the disease in this geographic region. Design, Setting, and Participants: Trentino natives with HNPGL were recruited for establishing clinical expression of the disease, presence of a founder effect, and age of common ancestor. A large sample of the local population was recruited for determination of mutation prevalence and spread. Main Outcome Measures: SDHD genetic testing was offered to first-degree relatives, and clinical surveillance was offered to at-risk carriers. The hypothesis of a founder effect was explored by haplotype analysis, and time to the most recent common ancestor was estimated by decay of haplotype sharing over time. Results: A total of 287 of the 540 recruited individuals from 95 kindreds carried the SDHDc.341A>G p.Tyr114Cys mutation. The prevalent phenotype was bilateral or multiple HNPGL, with low prevalence of pheochromocytoma and malignant forms. Penetrance was high. A common ancestor was dated between the 14th and 15th century, with the mutation spreading from the Mocheni Valley, a geographic, cultural and, presumably, a genetic isolate to 1.5% of the region's population. Conclusions: A combination of particular demographic, geographical, and historical conditions has resulted in the oldest and largest SDHD founder effect so far characterized and has transformed a rare disease into an endemic disease with major public health implications.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Issue number4
Publication statusPublished - Apr 2012

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism


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