Ni et al. (2008) found that 74 (20%) of 375 individuals with a Cowden-like syndrome who were negative for PTEN (601728) mutations had increased manganese superoxide dismutase (MnSOD; 147460) expression, a manifestation of mitochondrial dysfunction. Among these 74 ... Ni et al. (2008) found that 74 (20%) of 375 individuals with a Cowden-like syndrome who were negative for PTEN (601728) mutations had increased manganese superoxide dismutase (MnSOD; 147460) expression, a manifestation of mitochondrial dysfunction. Among these 74 individuals, 3 had germline mutations or variants in the SDHB gene. Clinical manifestations in these 3 patients included breast cancer in 1, thyroid cancer in 2, uterine leiomyoma in 1, and benign uterine tumors in 2. All 3 patients reported a family history of similar cancers. Overall, 10 of the 74 patients (13.5%) had germline mutations or variants in either SDHB or SDHD (602690). Compared to PTEN mutation-positive Cowden syndrome patients, those with SDH mutations or variants were enriched for carcinomas of the female breast (6/9 SDH vs 30/107, p less than 0.001), thyroid (5/10 vs 15/106, p less than 0.001), and kidney (2/10 vs 4/230, p = 0.026).
In 3 unrelated patients with a Cowden-like syndrome, Ni et al. (2008) identified 2 different heterozygous germline mutations in the SDHB gene (185470.0014; 185470.0015). They also identified 3 different heterozygous germline mutations in the SDHD gene (602690.0011; 602690.0019; ... In 3 unrelated patients with a Cowden-like syndrome, Ni et al. (2008) identified 2 different heterozygous germline mutations in the SDHB gene (185470.0014; 185470.0015). They also identified 3 different heterozygous germline mutations in the SDHD gene (602690.0011; 602690.0019; 602690.0028) in 7 unrelated patients. In the absence of PTEN alteration, SDH mutations/variants resulting in Cowden-like syndrome showed increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Ni et al. (2008) concluded that germline SDH mutations/variants occur in a subset of PTEN mutation-negative Cowden syndrome and Cowden-like syndrome individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. The authors suggested that SDH testing be considered for germline PTEN mutation-negative Cowden syndrome and Cowden syndrome-like individuals, especially in the setting of breast, thyroid, and/or renal cancers. Bayley (2011) commented that the findings of Ni et al. (2008) require independent confirmation, and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling.