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 2 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 metanephrine 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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Clinical Genetics: an international journal of genetics and molecular medicine
Erasmus University Rotterdam

Eijkelenkamp, K. (K.), Olderode-Berends, M., van der Luijt, R., Robledo, M., van Dooren, M., Feelders, R., … van der Horst-Schrivers, A. (2018). Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas. Clinical Genetics: an international journal of genetics and molecular medicine. doi:10.1111/cge.13202