Codon-specific Development of Pheochromocytoma in Multiple Endocrine Neoplasia Type 2

Context: Recent data suggest a codon-specific, age-related development of multiple endocrine neoplasia type 2.

Objective: The objective of this study was to delineate the codon-specific, age-related development of multiple endocrine neoplasia type 2-associated pheochromocytoma.

Design: We describe a cohort study with a mean observation period of 26.9 yr.

Setting: The study took place in a tertiary referral center at a university hospital.

Patients: Included in this study were 206 consecutive carriers (74 index, 132 nonindex) operated on at this institution who harbored point mutations in the RET (rearranged during transfection) protooncogene.

Intervention: The intervention was adrenalectomy for clinically confirmed pheochromocytoma.

Main Outcome Measure: The main outcome measure was time to histopathological diagnosis of pheochromocytoma.

Results: Pheochromocytomas developed in 28% (five of 18) of carriers with mutations in codon 918, 29% (20 of 68) of carriers with mutations in codon 634, 14% (three of 21) of carriers with mutations in codon 618, 13% (two of 16) of carriers with mutations in codon 620, and 13% (two of 16) of carriers with mutations in codon 791. Earliest age of manifestation for each genotype was 22, 18, 29, 22, and 39 yr. Contralateral pheochromocytomas developed after 4 yr (one carrier each had a mutation in codon 618 or 620) and 5.2 yr (six carriers had mutations in codon 634). No pheochromocytomas were identified in carriers of mutations in codons 609 (n = 2), 611 (n = 8), 630 (n = 2), 768 (n = 8), 790 (n = 22), 804 (n = 18), and 891 (n = 7).

Conclusions: Based on these and published preliminary data, annual screening for pheochromocytoma may be warranted from age 10 yr in carriers of RET mutations in codons 918, 634, and 630, and from age 20 yr in the remainder.