Complex MAX Rearrangement in a Family With Malignant Pheochromocytoma, Renal Oncocytoma, and Erythrocytosis.

Context: Familial pheochromocytoma (PCC) has been associated with germline mutations in 16 genes. Here we investigated three siblings presenting with bilateral pheochromocytomas. In addition, the index patient also exhibited renal oncocytoma and erythrocytosis, whereas the second sibling presented with a lymph node metastasis. Design: First, single-nucleotide polymorphism array and exome sequencing were performed on germline and PCC-derived DNA to identify genomic alterations in the index patient. Second, alterations were confirmed and validated by Sanger sequencing, analyzed by (multiplexed) PCR to determine the loss of the wild-type allele, and investigated by immunohistochemistry in the tumors of the three siblings. Results: The index patient's germline DNA revealed a large complex genomic alteration encompassing the intragenic and promoter regions of Myc-associated factor X (MAX) and alpha-(1,6)-fucosyltransferase (FUT8). In all three siblings the MAX alteration was confirmed, and the loss of the wild...