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J Clin Endocrinol Metab. 2012 Apr;97(4):E637-41. doi: 10.1210/jc.2011-2597. Epub 2012 Mar 28.

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

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  • 1Department 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.

Abstract

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 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.

PMID:
22456618
[PubMed - indexed for MEDLINE]
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