Paraganglioma And Gastric Stromal Sarcoma

A number sign (#) is used with this entry because paraganglioma and gastric stromal sarcoma can be caused by germline mutation in the SDHB gene (185470) on chromosome 1p36, the SDHC gene (602413) on chromosome 1q23, and the SDHD gene (602690) on chromosome 11q23.

Clinical Features

Carney and Stratakis (2002) reported 12 patients (7 male and 5 female) from 5 unrelated families with paraganglioma and gastric stromal sarcoma. The condition appeared to be inherited in an autosomal dominant manner, with incomplete penetrance. Seven patients had paraganglioma, 4 had paraganglioma and gastric stromal sarcoma, and 1 had gastric stromal sarcoma. The tumors were multicentric (paraganglioma), multifocal (gastric stromal sarcoma), and of early onset. The average age of the patients was 23 years. Based on these observations, the authors suggested that there is a familial syndrome consisting of gastric sarcoma and paraganglioma, which should be considered distinct from the Carney triad (604287).

Boccon-Gibod et al. (2004) reported a 12-year-old boy who presented with abdominal pain and underwent surgical removal of a paraganglioma of the organ of Zuckerkandl; the following year, his 13-year-old monozygotic twin was found to have a gastric stromal tumor with hepatic metastases for which he underwent chemotherapy followed by surgical removal and radiotherapy. Both twins were alive at age 18; the first was apparently free of disease, and the second had stable hepatic and peritoneal lesions with no evidence of paraganglioma. The parents and an older sister had no history of tumors or other unusual conditions. The authors suggested that the cases likely represented the Carney-Stratakis dyad.

Molecular Genetics

In 6 families with the Carney-Stratakis dyad of paraganglioma and gastric stromal sarcoma, including a family with monozygotic twins previously described by Boccon-Gibod et al. (2004), McWhinney et al. (2007) identified 6 different germline mutations in the SDHB (see, e.g., 185470.0012 and 185470.0013), SDHC (see, e.g., 602413.0004), and SDHD (602690.0027) genes. None of the patients had mutations in the KIT (164920) or PDGFRA (173490) genes, which have been associated with gastrointestinal tumors. In addition to the 8 mutation-positive patients, the authors identified 4 unaffected mutation carriers.

Pasini et al. (2008) provided additional clinical and molecular genetics information for 7 patients from 6 families with paraganglioma and gastrointestinal stromal tumors (GISTs) previously reported by McWhinney et al. (2007), with mutations in the SDHB, SDHC, and SDHD genes. DNA analysis of tumors from patients with germline mutations in SDHB and SDHC showed loss of heterozygosity in all samples available for study, suggesting that the gene defects act in a recessive manner.