Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and plateletderived growth factor receptor-a (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the

We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis.

Background: Germline mutations of the SDHD, SDHB and SDHC genes, encoding three of the four subunits of succinate dehydrogenase, are a major cause of hereditary paraganglioma and pheochromocytoma, and demonstrate that these genes are classic tumor suppressors. Succinate dehydrogenase is a heterotetrameric protein complex and a component of both the Krebs cycle and the mitochondrial respiratory chain (succinate:ubiquinone oxidoreductase or complex II).

Multiple GISTs and other tumors may be caused by germline PDGFRA gene mutations; the V561D mutation can occur in the germline state and lead to a syndrome that should not be confused with other genetic conditions associated with a predisposition to NETs and other tumors. A number of chromosomal loci are likely to be involved in the PDGFRA V561D-dependent tumorigenesis, as shown by CGH and other DNA analyses.

Background: The multiple cutaneous and uterine leiomyomatosis syndrome (MCUL) is a rare autosomal dominant condition characterized by cutaneous leiomyomatosis in both sexes and uterine leiomyomas in women. This syndrome overlaps with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Methods: We report an Italian family in which the finding of multiple cutaneous leiomyomas in the proband, a 46-year-old woman, led to the diagnosis of Reed’s syndrome and to a general and genetic screening. Results: DNA sequencing in the proband disclosed a missense mutation designated p.Asp341Tyr that has not been reported previously. Interestingly, the patient’s mother had a clear-cell-type renal cancer removed at the age of 57 years. Conclusion: Cutaneous leyomiomas are the clinical and histological clue leading to the diagnosis of MCUL or HLRCC. Dermatologists should be aware that a correct evaluation of a patient with cutaneous leiomyomas involves a complete medical and family history, physical examination and a genetic counseling.