title: The endemic paraganglioma syndrome type 1: origin, spread, and clinical expression.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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 SDHD c.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.
authors.affiliation: Department of Medicine, University of Padova, Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, Instituto di Ricovero e Cura a Carattere Scientifico, Via Gattamelata 64, 35128 Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.forename: Serena
authors.initials: S
authors.lastname: Demattè
authors.forename: Maria Enrica
authors.initials: ME
authors.lastname: Cecchini
authors.forename: Elisa
authors.initials: E
authors.lastname: Taschin
authors.forename: Sara
authors.initials: S
authors.lastname: Bobisse
authors.forename: Antonella
authors.initials: A
authors.lastname: Del Piano
authors.forename: Davide
authors.initials: D
authors.lastname: Donner
authors.forename: Mattia
authors.initials: M
authors.lastname: Barbareschi
authors.forename: Vittorio
authors.initials: V
authors.lastname: Manera
authors.forename: Stefania
authors.initials: S
authors.lastname: Zovato
authors.forename: Zoran
authors.initials: Z
authors.lastname: Erlic
authors.forename: Theodoros
authors.initials: T
authors.lastname: Savvoukidis
authors.forename: Susi
authors.initials: S
authors.lastname: Barollo
authors.forename: Franco
authors.initials: F
authors.lastname: Grego
authors.forename: Franco
authors.initials: F
authors.lastname: Trabalzini
authors.forename: Pietro
authors.initials: P
authors.lastname: Amistà
authors.forename: Cesare
authors.initials: C
authors.lastname: Grandi
authors.forename: Fabio
authors.initials: F
authors.lastname: Branz
authors.forename: Fabio
authors.initials: F
authors.lastname: Marroni
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
mesh_terms: D017668:Age of Onset; D019943:Amino Acid Substitution; D019353:Endemic Diseases; D005260:Female; D018703:Founder Effect; D006258:Head and Neck Neoplasms / Q000453:epidemiology* / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D009154:Mutation; D010235:Paraganglioma / Q000453:epidemiology* / Q000235:genetics / Q000503:physiopathology*; D019683:Penetrance; D010641:Phenotype; D015995:Prevalence; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: C491545:SDHD protein, human; D013385:Succinate Dehydrogenase