ClinVar

In 7 members of a family with autosomal dominant inheritance of pheochromocytoma (171300), originally reported by Dahia et al. (2005), Qin et al. (2010) identified a heterozygous germline A-to-C transversion in intron 3 of the TMEM127 gene, resulting in a frameshift and premature termination. Two affected individuals from another unrelated family carried the same mutation, but haplotype analysis excluded a common ancestor. Analysis of all tumor tissues showed loss of heterozygosity at the TMEM127 locus, consistent with a 2-hit model of tumor suppressor inactivation. Age at onset ranged from 34 to 54 years in the first family and from 34 to 42 years in the second family. TMEM127 expression was decreased, consistent with a loss of function.

Toledo et al. (2015) offered genetic counseling, testing, and follow-up to 151 members of the 6-generation family carrying the c.410-2A-C mutation studied by Qin et al. (2010) and Dahia et al. (2005). Forty-seven individuals were found to carry the mutation. Clinical data were available for 34 mutation-positive individuals who were followed for 1 to 20 years (mean 8.7 years). Pheochromocytoma was diagnosed in 11 (32%) at a median age of 43 years. Two patients were asymptomatic, and 9 had symptoms starting on average at age 29 (range 10-55 years). Tumors were multicentric in 5 and bilateral in 5 patients. Over half had at least 1 adrenomedullary nodule less than 10 mm. No paragangliomas, distant metastases, or other manifestations were reported.