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

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.

Analysis of a case with disappearance of the primary gastrointestinal stromal tumor and progressive liver metastases under long-term treatment with tyrosine kinase inhibitors.

The response of gastrointestinal stromal tumors (GISTs) to tyrosine kinase receptor inhibitors (TKR-I) has been a breakthrough for small molecular therapy. We report here on the very different long-term outcome of a synchronous metastatic GIST with complete remission of the primary tumor and progressive liver metastases under TKR-I therapy. In 2003, a 52-year-old patient was diagnosed with gastric GIST and synchronous multiple liver metastases. Therapy with imatinib, 400 mg daily, was started immediately. Fifteen months later, the primary was no longer detectable by endoscopy. In 2006, progression of the liver metastases was observed. Mutation analysis of the initial biopsy specimen from the primary, as well as the biopsy from the three main liver metastases after 3 years of imatinib treatment, revealed the common KIT exon 11 deletion (W557_K558del) in all tumor samples. Two of the metastases had a separate secondary mutation in KIT exon 14 and 17, respectively, while the largest cystic metastatic lesion had no other mutation. Imatinib was then increased to a daily dose of 800 mg, and in April 2007 the treatment was changed to sunitinib. Fifty-two months after initial diagnosis, the patient died of liver failure. At no time point, relapse of the gastric primary tumor was observed. Whilst TKR-Is are commonly very effective in treating GISTs, the present case illustrates their varying effects regarding the clinical behavior and genetic variations within different tumors of the same patient after long-term treatment.

Paraganglioma syndrome: SDHB, SDHC, and SDHD mutations in head and neck paragangliomas.

Paraganglioma syndrome includes head and neck paraganglioma and pheochromocytoma, and is classified according to the three susceptibility genes involved, SDHB, SDHC, and SDHD. This study assessed the prevalence of germline mutations in SDHB, SDHC, and SDHD genes in a consecutive population admitted to Padova Hospital consisting of 20 patients with head and neck paraganglioma (HNP). Mutations were identified in the three genes in four affected individuals, three sporadic cases and one with family history of HNP. The novel SDHB p.R242C mutation was identified in a sporadic monolateral carotid body tumor. The SDHC p.Q147X mutation, the first to be described in Italy, was detected in a sporadic monolateral jugulotympanic paraganglioma. The SDHD p.Y114C mutation was identified in two unrelated patients, one familial case of bilateral carotid body tumor and one multiple paraganglioma. SDHB, SDHC, and SDHD molecular screening is important in all HNPs, with or without primary indicators of paraganglioma syndrome, to orient mutation-driven clinical screening for additional HNPs and pheochromocytoma.