Genetics of pheochromocytoma and paraganglioma in Spanish pediatric patients.

Pheochromocytomas and paragangliomas are neuroendocrine tumors developed in the adrenal medulla and in the extra-adrenal thoraco-abdominal sympathetic and parasympathetic paraganglia, respectively. Although clinical diagnosis of these tumors is infrequent during childhood, there have been reports of pediatric patients either carrying germline alterations in one of ten major pheochromocytoma/paraganglioma susceptibility genes, or without known mutations. While new PCC/PGL susceptibility genes have recently been identified, little is known regarding their involvement in pediatric tumor development. We discuss here clinical and genetic criteria relevant to management of pheochromocytoma/paraganglioma patients diagnosed before age 18 years. Clinical and genetic data obtained from 36 pediatric non-related probands, tested for alterations in nine major pheochromocytoma/paraganglioma susceptibility genes (VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX), were compared to data obtained from 411 genetically characterized non-pediatric cases. Seventy percent of probands had germline mutations affecting SDHB, SDHD, VHL, RET or MAX, with an over-representation of truncating SDHB mutations in the pediatric cases compared to non-pediatric patients. Amongst cases without mutations, we found a significantly higher proportion of pediatric patients with clinical features (bilateral pheochromocytoma and coexistence of pheochromocytoma and paraganglioma) suggestive of a hereditary condition (p=0.008). Genetic screening for mutations in the susceptibility genes SDHB, SDHD, VHL, RET and MAX is strongly recommended in children developing PCC/PGL, starting with the metastasisrelated gene SDHB. Alterations affecting still unidentified PCC/PGL susceptibility genes are probably responsible for a high proportion of the mutation-negative pediatric cases. Page 2 of 15