One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: Is this a new syndrome—MEN 2C?

Shifrin, Alexander; Xenachis, Cristina; Fay, Aaron; Matulewicz, Theodore J.; Kuo, Yen-Hong; Vernick, Jerome

doi:10.1016/j.surg.2009.09.021

Cited by 33 publications

(22 citation statements)

References 25 publications

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“…Therefore, genotype-based surgery [6,10] of FMTC regarding the extent of lymph node dissection and the recommended age of prophylactic thyroid surgery is based on the American Thyroid Association (ATA) risk levels [A (low) to D (high)] [6] . The p.Val804Met mutation [11,12] has been described in multiple independent patients, is located within exon 14, and is known to be pathogenic [13] and classified as risk level A according to the ATA classification. Of note, a very wide clinical variability has been described for heterozygous carriers of p.Val804Met with a clinical manifestation of highly aggressive medullary thyroid cancer at the age of 5 years on one hand up to asymptomatic carriers at the age of 86 years on the other [12,14] .…”

Section: Discussion Of the Available Literature In The Absence Of Funmentioning

confidence: 99%

How to Assess the Clinical Relevance of Novel RET Missense Variants in the Absence of Functional Studies?

et al. 2016

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known to cause FMTC and multiple endocrine neoplasia type 2a/b. The clinical significance of other novel missense variants within this hotspot region of exon 14 is not delineated. Case Description: A three-generation pedigree of FMTC is presented with the co-occurrence of two missense variants within exon 14 of the RET gene, the known variant p.Val804Met and the novel variant p.Val826Met. The female index patient developed medullary thyroid cancer at the age of 42 years and was heterozygous for both missense variants.Her younger sister was also tested to be compound hetero- Key Words What Is Known about This Topic?• The pathogenic effect of the p.Val804Met missense mutation of the RET proto-oncogene is well described in familial medullary thyroid cancer. In contrast, the clinical significance of the novel missense variant p.Tyr826Ser in exon 14 is unclear and no scientific publications on this genotype have been published so far. What Does This Case Report Add?• In the absence of functional studies, the plausibility of pathologic significance of a detected endocrine genetic variant can be estimated by in silico methods such as computational analysis of protein structure and biophysical differences or a comparative database search for evolutionary conservation. This family report supports a functional role of p.Tyr826Ser as predisposing RET variant. Patients with a compound heterozygosity of an established pathogenic RET mutation in combination with this novel variant seem to be at a higher risk of developing FMTC. The malignant risk of patients carrying only the heterozygous novel variant p.Tyr826Ser seems to be low with careful clinical surveillance. For individualized and patient-related decision making, our data emphasize the importance of combined clinical and genetic assessment of novel RET variants in patients with familial medullary thyroid cancer and their relatives. zygous for both mutations, and five further relatives were heterozygous for only one of both sequence variants. Prophylactic thyroidectomy was recommended for the two carriers of the RET mutation p.Val804Met, revealing a C-cell hyperplasia for one of them at the age of 19 years. Medical surveillance of 6 heterozygous carriers including repeated neck ultrasound examination as well as basal and calcium (pentagastrin)-stimulated calcitonin levels were recommended. Conclusion: Our data emphasize the importance of an interdisciplinary approach to assess the functional and clinical significance of novel RET variants. In the absence of functional studies, the plausibility of the pathologic significance of a detected endocrine genetic variant can be estimated by in silico methods such as computational analysis of protein structure and biophysical differences or comparative database search for evolutionary conservation.

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Section: Discussion Of the Available Literature In The Absence Of Funmentioning

confidence: 99%

How to Assess the Clinical Relevance of Novel RET Missense Variants in the Absence of Functional Studies?

et al. 2016

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“…Phenotypes associated with the V804M RET mutation have been reported almost exclusively in FMTC. Only several cases of V804M mutations associated with MEN 2A (MTC plus hyperparathyroidism) have been reported in the literature (10-12). …”

Section: Discussionmentioning

confidence: 99%

“…Pinna et al (10) reported the prevalence of V804M in up to 48% of index cases (3/7 families) and 59% of overall family members (17/19 relatives) in Sardinia, possibly as a consequence of founder effect in this population. Shifrin et al (12) also reported 107 members of an Italian family (origin from Florence/Calabria) with RET V804M proto-oncogene mutations. With exception of Italian, RET V804M protooncogene mutations are very rare in other races.…”

Section: Discussionmentioning

confidence: 99%

A Case of Medullary Thyroid Carcinoma with de novo V804M RET Germline Mutation

et al. 2013

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Many cases of RET proto-oncogene mutations of hereditary medullary thyroid carcinoma (MTC) have been reported in Korea. However, MTC with V804M RET proto-oncogene germline mutations have not been reported in Korea. A 33-yr-old man was diagnosed with a 0.7-cm sized thyroid nodule. Laboratory testing revealed serum calcitonin was elevated. The patient underwent total thyroidectomy with central compartment neck dissection for the thyroid tumor. RET gene analysis was performed in both the index patient and his family. There were no V804M RET mutation and abnormal laboratory findings within his family except the index patient. Therefore, this patient was a de novo V804M RET germline mutation.

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“…Interestingly, it was suggested that in addition to their association with MTC, mutations in codons 790 or 804 may be associated with PTC [ 185 ].…”

Section: Men2 Genotype-phenotype Correlationmentioning

confidence: 99%

The Multiple Endocrine Neoplasia Syndromes

Grozinsky‐Glasberg

Gross

2015

Neuroendocrine Tumours

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The term multiple endocrine neoplasia (MEN) refers to hereditary neoplastic disorder involving more than one endocrine organ and includes the MEN type 1 (MEN1), the MEN type 2 (MEN2), and the familial medullary thyroid carcinoma (FMTC). The estimated frequency of each of these syndromes is around 1 in 30,000 and is characterized by complete penetrance with variable expression [ 1 , 2 ]. The recent progress in our knowledge of both the molecular and the clinical genetics of these syndromes has improved the clinical management of the patients [ 3 ]. On the one hand, the MEN1 gene, a tumor suppressor gene responsible of MEN1 syndrome, is involved in the regulation of several cell functions (e.g., DNA replication and repair and transcriptional machinery). On the other hand, the RET proto-oncogene encodes for a receptor tyrosine kinase protein whose expression is fundamental for appropriate migration, development, and differentiation of neuroendocrine cells originating from neural crest [ 4 ]. Currently, DNA testing allows the early identifi cation of germline mutations in presymptomatic mutant gene carriers in the MEN syndromes [ 5 ]. Consequently, an early identifi cation of the MEN-associated neoplasms and the genotype-phenotype correlation improve the outcome and the quality of life for affected subjects [ 6 ].

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One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: Is this a new syndrome—MEN 2C?

Cited by 33 publications

References 25 publications

How to Assess the Clinical Relevance of Novel RET Missense Variants in the Absence of Functional Studies?

How to Assess the Clinical Relevance of Novel RET Missense Variants in the Absence of Functional Studies?

A Case of Medullary Thyroid Carcinoma with de novo V804M RET Germline Mutation

The Multiple Endocrine Neoplasia Syndromes

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