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

Abstract

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.

Genetic analysis and clinical investigation of a pedigree with multiple endocrine neoplasia type 2A: A case report

“…PHEO mainly occurs in association with codon 634 and 918 mutations, but rarely in association with codon 618, codon 620 or other mutations (6)(7)(8). A previous study reported that the majority of patients with a codon 634 mutation will develop PHEO and MTC during their lifetime (9), as occurred in the case in the present study. A patient with a codon 634 mutation is prone to develop PHEO and MTC at the same time.…”

“…The diagnosis of PHEO may be determined prior to MTC (12.9-25.1% of patients), simultaneously with MTC (34.7-38.9% of patients) or following the diagnosis of MTC (40.2-48.2% of patients) (10). In addition, half of all patients with PHEO may be asymptomatic at diagnosis (9,10). However, the patient and son in the present study were diagnosed with labile hypertension, which is the typical manifestation of PHEO.…”

A novel RET gene mutation in a patient with apparently sporadic pheochromocytoma

“…In a continuous series of 246 RET mutation carriers, Imai et al, described that the age-dependent penetrance of Pheo was 32% by age 50 and 50% by age 76 [9].…”

“…In MEN 2A, the onset of Pheo is usually concomitant or subsequent to MTC [10], but in 13-27% of cases it represents the first manifestation of the syndrome [9,11]; moreover it has also been reported a codon specific age-related onset of Pheo [12,13].…”

Przełom katecholaminowy jako pierwsza manifestacja rodzinnego obustronnego guza chromochłonnego w przebiegu mutacji protoonkogenu RET w kodonie C 634R

“…Meanwhile, pheochromocytoma as a first manifestation of MEN 2A occurs in 9-27% of cases [11,13]. Mutation in codon 634 particularly predisposes to this tumour [11,14]. At the same time, pheochromocytoma related to the mutation in codon 634 is very likely to develop in young age, even in children less than ten years old [15].…”