Homozygous TMEM127-mutations in two patients with bilateral pheochromocytomas

Abstract

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane-protein-127 (TMEM127) is one of the PCC/PGL susceptibility genes with an autosomal dominant inheritance pattern. Here we report two patients with bilateral PCC who both harbored a homozygous TMEM127-mutation. In a 31-year old mentally retarded patient the homozygous c.410-2A>G mutation was discovered during an update of DNA-analysis. A 26-year old mentally retarded patient was found to have a homozygous c.3G>A mutation. The parents of both patients were consanguineous. We reviewed previously reported clinical features of TMEM127-mutation carriers and compared our findings with case descriptions of homozygous mutations in other PGL/PCC susceptibility genes. Homozygosity for an autosomal dominant inherited disorder is an extremely rare phenomenon and has, to our knowledge, not been reported before for the gene encoding TMEM127. In the present cases, the clinical picture does not seem to be very different from heterozygous TMEM127-mutation carriers, except for a relatively large tumor size and more pronounced plasma metanephrines concentration. It is unclear whether the mental retardation is causally related to homozygosity of the TMEM127-mutations. Updating genetic screening in patients in whom PCC/PGL has been diagnosed in the past should be considered as it might provide clinically relevant information.

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