Phenotypic expression of a family with multiple endocrine neoplasia type 2A due to a <i>RET</i> mutation at codon 618

Lindskog, Sven; Nilsson, Ola; Jansson, Svante; Nilsson, Bengt; Illerskog, A.; Ysander, L; Ahlman, Håkan; Tisell, Lars‐Erik

doi:10.1002/bjs.4457

Cited by 21 publications

(16 citation statements)

References 18 publications

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“…)Current series(Ref. )918 RL 31.130.75 [9]112.7 [15]634 RL 21.251.1 [15]75 [15]611 RL 263 [9]–28 [21]620 RL 265 [10]–22 [15]618 RL 2127 [9]–11 [10, 22, 23]804 RL 1–6 [24]–6 [24] MTC medullary thyroid carcinoma, LN lymph node metastasis; -, not observed, RL risk level of MTC based on the 1999 consensus statement from the Seventh International Workshop on Multiple Endocrine Neoplasia [11, 15]…”

Section: Resultsmentioning

confidence: 99%

Factors Predicting Outcome of Total Thyroidectomy in Young Patients with Multiple Endocrine Neoplasia Type 2: A Nationwide Long‐Term Follow‐up Study

et al. 2010

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BackgroundMultiple endocrine neoplasia type 2 (MEN 2) is caused by a RET mutation in chromosome 10. All MEN 2 patients develop medullary thyroid carcinoma (MTC). The age-related risk of MTC is associated with the type of RET mutation. Our aim was to identify prognostic factors associated with recurrent MTC in MEN 2 patients.MethodsIn a nationwide case–control study, all patients who underwent total thyroidectomy in the Netherlands under the age of 20 years were classified into standard (1), high (2), or very high risk (3) for MTC based on RET-mutation type. Disease-free patients were compared with those with recurrent disease.ResultsA total of 93 patients were included in the study. Sixty-six percent had MTC on histology, the youngest being 1 year old. Codon 634 was most affected. Sixteen (18%) patients had persistent or recurrent disease, one of whom died. Significantly associated determinants of outcome in univariate analysis were higher age at surgery, no age-appropriate prophylactic surgery according to risk level, elevated preoperative calcitonin levels, affected codon, and the presence of lymph node metastases at surgery. On multivariate analysis only age of surgery was the single independent factor associated with persistent disease.ConclusionsProphylactic thyroidectomy beyond the recommended age is associated with persistent/recurrent disease. In addition, codon 634 mutation is associated with a high risk of recurrence requiring early surgery for all these patients.

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Section: Resultsmentioning

confidence: 99%

Factors Predicting Outcome of Total Thyroidectomy in Young Patients with Multiple Endocrine Neoplasia Type 2: A Nationwide Long‐Term Follow‐up Study

et al. 2010

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“…diagnosis at age 27 and 26 (36); both are still alive with MTC 27 and 28 years later. Preoperative calcitonin levels were not reported.…”

Section: Fig 1 Study Schemamentioning

confidence: 99%

Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk GermlineRETProto-Oncogene Mutations

Rich

Feng

Busaidy

et al. 2014

Thyroid

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Background: Age-related risk of medullary thyroid carcinoma (MTC) development in presymptomatic carriers of lower risk germline RET mutations is uncertain; such data may aid counseling patients regarding timing of thyroidectomy. Methods: From an institutional database and an exhaustive literature review, we identified 679 patients with American Thyroid Association (ATA) level A or B mutations who were identified because of family screening (index cases of MTC were excluded to minimize selection bias). We evaluated age at thyroidectomy or last evaluation if no thyroidectomy, preoperative calcitonin level (elevated or not), the mutated codon, and outcome (MTC vs. no MTC after thyroidectomy or no clinical evidence of MTC if thyroid intact). Data were used to estimate the cumulative prevalence of MTC and/or assess likelihood of MTC stratified by codon. After exclusion of cases with missing data or small representation, 503 patients with mutations in codons 533, 609, 611, 618, 620, 791, and 804 were analyzed. Results: 236 patients had MTC. Cumulative prevalence and median time to MTC varied by codon and within ATA risk levels ( p < 0.0001). Patients with a codon 620 mutation were 2.8-6.9 times more likely to have MTC than other level B mutation carriers, and 5.1-21.7 times more likely than level A mutation carriers included in our focus population. The youngest median time to MTC was 19 years for codon 620 and the oldest was 56 years for codon 611. Cumulative prevalence of MTC by age 20 was 10% or lower for codons 533, 609, 611, 791, and 804. By age 50, it ranged from 18% for codon 791 to 95% for codon 620. An elevated preoperative calcitonin level strongly predicted MTC on final pathology, though false-negative rates varied by codon ( p < 0.0001). Positive predictive values ranged from 76% to 100% by codon with an overall positive predictive value of 87% across codons. Conclusions: This study offers a better understanding of the age-related development of MTC in lower risk RET mutation carriers, provides evidence of further distinctions between lower risk mutations within ATA subgroups, and clarifies the clinical significance of codon 791 mutations. The data support individualized ''codon-based'' management approaches coupled with clinical data such as calcitonin levels.

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“…Such mutations are explicitly located in cysteines within this extracellular cysteine-rich domain and give rise to the subtype of MEN2A [12]. Codon 618 with p.Cys618Arg, p.Cys618Gly and p.Cys618Ser and to a lesser extent with codons p.Cys618Phe and p.Cys618Tyr, have been associated with the greatest rates of pheo [13][14][15]. Some studies revealed that the severity of pheo due to mutations in codons 609, 618 and 620 can be as aggressive as the one that is usually shown by the five amino acid substitutions at codon 634.…”

Section: Introductionmentioning

confidence: 99%

“…Some studies revealed that the severity of pheo due to mutations in codons 609, 618 and 620 can be as aggressive as the one that is usually shown by the five amino acid substitutions at codon 634. However, the majority of the cases, demonstrated greatest expression for 634, followed in decreasing order by codons 618, 620 and 609 [13,16,17]. In recent reports, the spectrum of mutations identified in the RET proto-oncogene in patients with MTC has shifted from the 'classical' and most prevalent worldwide mutation at codon 634 in exon 11 to clinically less aggressive forms with mutations in exons 13-15 [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

The use of nutraceuticals in male sexual and reproductive disturbances: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS)

Calogero

Aversa

Vignera

et al. 2017

J Endocrinol Invest

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Purpose Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017. Methods and patients Forty patients underwent RET testing by Sanger sequencing of exons 10-11 and 13-16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed. Results RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8 ± 14.2 years. The age of pheo diagnosis ranged from 26 to 43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation. Conclusions The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect.

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Phenotypic expression of a family with multiple endocrine neoplasia type 2A due to a RET mutation at codon 618

Cited by 21 publications

References 18 publications

Factors Predicting Outcome of Total Thyroidectomy in Young Patients with Multiple Endocrine Neoplasia Type 2: A Nationwide Long‐Term Follow‐up Study

Factors Predicting Outcome of Total Thyroidectomy in Young Patients with Multiple Endocrine Neoplasia Type 2: A Nationwide Long‐Term Follow‐up Study

Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk GermlineRETProto-Oncogene Mutations

The use of nutraceuticals in male sexual and reproductive disturbances: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS)

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