Bilateral Pheochromocytomas in MEN2A Syndrome: A Two‐Institution Experience

Lang, Brian Hung‐Hin; Yu, Hyeong Won; Lo, Chung‐Yau; Lee, Kyu Eun; Garcia-Barcelo, Maria Mercedes; Woo, Yu Cho; Lee, Chi H.; Wong, Kai Pun; Tam, Paul K. H.; Lam, Karen Siu Ling

doi:10.1007/s00268-015-3117-2

Cited by 7 publications

(6 citation statements)

References 28 publications

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“…The D631Y germline mutation in MEN2 have also been reported in Germany [13,23], the Netherlands [24], and Turkey [25] but they were excluded from this analysis because results of thyroidectomy and family screening were not provided. We found that PCC occurred in 58.8% and MTC in 32.3% of the RET D631Y variant MEN2 patients, and PHPT in only one case (2.9%) (Table 2) [1,2,6,24,[26][27][28][29][30][31][32][33][34][35]. This compares with previous reports that 90% of MEN2 patients developed MTC, 50% developed PCC, and 20% to 30% developed PHPT [1,5,6,15].…”

Section: Discussioncontrasting

confidence: 58%

Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)

Lee

Kim

et al. 2022

Korean J Intern Med

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Background/Aims: Germline mutations of the rearranged during transfection (RET) gene cause multiple endocrine neoplasia type 2 (MEN2). About 85% of RET mutations in MEN2 occur in codon Cys634. The RET D631Y mutation has recently been discovered, and we have studied its molecular expression and clinical consequences. Methods: We analyzed the clinical characteristics of a total of 34 D631Y variant MEN2 individuals from seven families. We also constructed wild-type and mutant C630Y, D631Y, and C634R/W expression vectors and investigated their effects on signaling pathways and ability to correct the phenotypes of RET mutant cells. Results:The median ages at diagnosis of pheochromocytoma and medullary thyroid carcinoma (MTC) were higher in patients with RET D631Y variant MEN2 than in those with the C634R/W variant (49:53.5 years vs. 33.5:27 years, respectively), and the penetration of the D631Y mutation with respect to MTC was lower than that of the C634R/W mutation (32.3% vs. 90%). The effects of the mutant vectors on phosphorylation of RET signaling molecules and focus formation were significantly different from those of wild type, but there were no significant differences between the mutants. D631Y scored significantly higher for chemotaxis and wound healing than C630Y, but lower than C634R and C634W. Conclusions:We suggest that the tumorigenic potential conferred by the D631Y mutation is lower than that conferred by the C634R/W mutation, but higher than that conferred by C630Y. Thus, the risk level of the RET D631Y variant appears to be higher than that of C630Y and lower than that of C634R/W.

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Section: Discussioncontrasting

confidence: 58%

Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)

Lee

Kim

et al. 2022

Korean J Intern Med

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“…We found 29 cases of MEN2 with metastatic PCC on literature search. The details of these cases, including our two cases, are summarized in Table 2 ( 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ).…”

Section: Resultsmentioning

confidence: 99%

Metastatic cluster 2-related pheochromocytoma/paraganglioma: a single-center experience and systematic review

Kumar¹,

Lila²,

Memon³

et al. 2021

Endocrine Connections

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Objective: Risk of metastatic disease in the cluster 2-related pheochromocytoma/paraganglioma (PPGL) is low. In MEN2 patients, identification of origin of metastases from pheochromocytoma (PCC) or medullary thyroid carcinoma (MTC) is challenging as both are of neuroendocrine origin. We aim to describe our experience and perform a systematic review to assess prevalence, demographics, biochemistry, diagnostic evaluation, management and predictors of cluster 2-related metastatic PPGL. Design: Retrospective study with systematic review of literature. Methods: Data of 3 cases from our cohort and 43 cases from world literature were analyzed. For calculation of prevalence, all reported patients (n=3063) of cluster 2 were included. Results: The risk of metastasis in cluster 2-related PPGL was 2.6% (2% in RET, 5% in NF1, 4.8% in TMEM127 and 16.7% in MAX variation). In metastatic PCC in MEN2, median age was 39 years, bilateral tumors were present in 71% and median tumor size was 9.7 cm (range 4-19) with 43.5% mortality. All patients had primary tumor size ≥4cm. Origin of primary was diagnosed by histopathology of metastatic lesion in 11(57.9%), 131I-MIBG scan in 6(31.6%), and selective venous sampling and computed tomography in one (5.3%) each. In subgroup of NF1, median age was 46 years (range 14-59) with median tumor size 6cm and 57% mortality. Conclusion: The risk of metastatic disease in cluster 2-related PPGL is 2.6%, being especially high in tumors with size ≥4cm and is associated with high mortality. One-third patients of NF1 with metastatic PPGL had presented in 2nd decade of life. Long-term studies are needed to formulate management recommendations.

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“…There are six different amino acid substitutions for the same cysteine on codon 634 (F/G/R/S/W/Y), and all of them display comparable transforming activity. The C634Y mutation is believed to confer lower penetrance of the MEN2A phenotype and less aggressive behaviour of MTC than does the C634R mutation 23‐25 . There is higher penetrance of MTC, phaeochromocytoma and hyperparathyroidism in patients harbouring C634R mutation.…”

Section: Discussionmentioning

confidence: 99%

The synergy of germline C634Y and V292M RET mutations in a northern Chinese family with multiple endocrine neoplasia type 2A

Zheng

Gross

et al. 2020

J Cellular Molecular Medi

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Genetic analysis for germline mutations of RET proto‐oncogene has provided a basis for individual management of medullary thyroid carcinoma (MTC) and pheochromocytoma. Most of compound mutations have more aggressive phenotypes than single point mutations, but the compound C634Y/V292M variant in MTC has never been reported. Thus, we retrospectively investigated synergistic effect of C634Y and V292M RET germline mutations in family members with multiple endocrine neoplasia type 2A. Nine of 14 family members in a northern Chinese family underwent RET mutation screening using next‐generation sequencing and PCR followed by direct bidirectional DNA sequencing. Clinical features of nine individuals were retrospectively carefully reviewed. In vitro, the scratch‐wound assay was used to investigate the difference between the cells carrying different mutations. We find no patients died of MTC. All 3 carriers of the V292M variant were asymptomatic and did not have biochemical or structural evidence of disease (age: 82, 62 and 58). Among 4 C634Y mutation carriers, 2 patients had elevated calcitonin with the highest (156 pg/mL) in an 87‐year‐old male. Two carriers of compound C634Y/V292M trans variant had bilateral MTC with pheochromocytoma or lymph node metastasis (age: 54 and 41 years, respectively). Further, the compound C634Y/V292M variant had a faster migration rate than either single point mutation in vitro (P < .05). In conclusion, the V292M RET variant could be classified as ‘likely benign’ according to ACMG (2015). The compound variant V292M/C634Y was associated with both more aggressive clinical phenotype and faster cell growth in vitro than was either single mutation.

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Bilateral Pheochromocytomas in MEN2A Syndrome: A Two‐Institution Experience

Cited by 7 publications

References 28 publications

Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)

Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)

Metastatic cluster 2-related pheochromocytoma/paraganglioma: a single-center experience and systematic review

The synergy of germline C634Y and V292M RET mutations in a northern Chinese family with multiple endocrine neoplasia type 2A

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