High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients

OBJECTIVE: The precise penetrance of pheochromocytoma (PHEO) in multiple endocrine neoplasia type 2 (MEN2) has not been reported in a large cohort. In this study, we aimed to clarify the codon-specific penetrance of PHEO in MEN2. DESIGN: We established a study group designated the 'MEN Consortium of Japan' in 2008 and asked physicians and surgeons to provide clinical and genetic information on patients they had treated up to 2011. METHODS: Data were collected on patients identified as carriers of the RET mutation or diagnosed with medullary thyroid carcinoma (MTC) and/or PHEO with family history from 52 institutions all over Japan. RESULTS: Of 493 registered MEN2 patients, RET mutation data were available for 390. Of these, 144 developed PHEOs, while 246 did not. The penetrance of PHEO was 25% by age 30 years, 52% by age 50 years, and 88% by age 77 years in RET mutation carriers with a codon 634 mutation. All patients with a codon 918 mutation (MEN2B) developed PHEO by age 56 years. Less than 32%penetrance of PHEO was seen in patients with mutations at codons other than 634 and 918. CONCLUSIONS: Most patients with a codon 634 mutation develop PHEOs as well as MTC during their lifetime.