Familial medullary carcinoma prevention, risk evaluation, and RET in children of families with MEN2

Moore, Samuel W.; Appfelstaedt, Justus; Zaahl, Monique G.

doi:10.1016/j.jpedsurg.2006.10.005

Cited by 39 publications

(14 citation statements)

References 51 publications

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“…There is a further group of MEN-related genetic variations, associated with non-cysteine areas of gene, which raises interesting questions as to the oncogenic mechanism. This latter group appeared to occur more frequently than expected in our series [67] in keeping with other genetic pools [82].…”

Section: The Effect Of Ret Mutation On Ret Protein Functionsupporting

confidence: 90%

“…We have experience with a further case of a C620W mutation occurring in a patient with long segment Hirschsprung's disease, who had a parent with MTC and the same mutation [68].…”

Section: Hirschsprung's Disease and Men-related Ret Mutationsmentioning

confidence: 99%

“…It is clear that RET should be screened in HSCR (particularly in L-HSCR cases) [67] Risk level and codon-directed surgery…”

Section: Genetic Screening For Inherited Mtc Riskmentioning

confidence: 99%

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Multiple endocrine neoplasia syndromes, children, Hirschsprung’s disease and RET

Moore

Zaahl

2008

Pediatr Surg Int

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Multiple endocrine neoplasia (MEN) type 2 syndromes are autosomal dominant clinical associations characterized by a common clinical feature, medullary thyroid carcinoma (MTC). The ability to accurately predict the risk by genetic RET proto-oncogene analysis has resulted in the active follow-up of children at risk for developing early metastatic tumours and which can be prevented by prophylactic thyroidectomy. The C634 and M918T mutations (associated with MEN2A and MEN2B, respectively) are particularly associated with early aggressive behavior and distant metastatic spread requiring early intervention. RET is known to be involved in cellular signalling processes during development and controls the survival, proliferation, differentiation and migration of the enteric nervous system (ENS) progenitor cells, as well as the survival and regeneration of sympathetic neural and kidney cells. The centrality of RET in the etiology of both MEN2 and HSCR is now well established with fairly consistent associations existing between RET genotype and phenotype in MEN2. The relationship between Hirschsprung's disease (HSCR) MEN2 syndromes appears to be a highly significant one, sharing a common etiological factor in the RET proto-oncogene. It is now well accepted that most HSCR arises from loss of function, RET mutations, RET haploinsufficiency or RET polymorphisms and haplotypes of the RET promotor region. MEN2 syndromes result from gene up regulation due to germline activating mutations in the RET proto-oncogene (1:500,000). MTC is mostly associated with variations in the 5 cysteine RET radicals and codon-risk management protocols are of considerable value but not infallible. Oncogenic RET mutations may, however, vary between specific population groups. RET analysis in MEN has revolutionized the management of children of MEN2 and allowed surgical prediction and prophylaxis to take place. We discuss the role of genetic testing and possible guidelines for the management of patients from MTC families. The future appears full of promise and the current evaluation of RET-targeting tyrosine kinase and other inhibitors are of considerable interest in the management of these conditions.

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Section: The Effect Of Ret Mutation On Ret Protein Functionsupporting

confidence: 90%

“…We have experience with a further case of a C620W mutation occurring in a patient with long segment Hirschsprung's disease, who had a parent with MTC and the same mutation [68].…”

Section: Hirschsprung's Disease and Men-related Ret Mutationsmentioning

confidence: 99%

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Multiple endocrine neoplasia syndromes, children, Hirschsprung’s disease and RET

Moore

Zaahl

2008

Pediatr Surg Int

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“…MTC became the first identified inherited human neoplasm to be associated with the dominant activation of a protooncogene. Recent advances in our understanding of molecular carcinogenesis of MTC have significant clinical implications and, nowadays, genetic screening is considered of key importance in the management of these patients (Moore et al 2007). Identification of a germline mutation in a patient with MTC enables classification of the tumor as being of the inherited type, regardless of the absence of family history or associated endocrinopathies (Bugalho et al 2007).…”

Section: Genetic Alterations In Hereditary Mtcmentioning

confidence: 99%

“…Operation removing the target organ (thyroidectomy), ideally before the development of MTC, remains the only effective preventive/therapeutic approach (Evans et al 1999, Gimm et al 2001, thus explaining the importance of early diagnosis of germline carriers as well as of early prophylactic thyroidectomy (Niccoli-Sire et al 1999, Machens et al 2003a,b, Skinner et al 2005. Often, prophylactic thyroidectomy in RET mutation carriers should be performed before age of 5 years or in the first decade of life (Brandi et al 2001, Moore et al 2007.…”

Section: Timing Of Prophylactic Thyroidectomymentioning

confidence: 99%

The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy

Sakorafas¹,

Friess²,

Peros³

2008

Endocrine Related Cancer

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Medullary thyroid cancer (MTC) may occur either sporadically or on a hereditary basis. Hereditary MTC may be observed with either multiple endocrine neoplasia syndromes (MEN 2A and MEN 2B) or as familial MTC (FMTC). Despite the rarity of these syndromes, early diagnosis is especially important, since MTC is a lethal disease if not promptly and appropriately treated. Recently, the development of genetic testing and direct DNA analysis allows the identification of asymptomatic patients. Surgical prophylaxis should be considered in these cases, ideally to prevent the development of MTC. During the recent decade, the concept of 'codon-directed' timing of prophylactic surgery emerged as a reasonable strategy in the management of these patients. Currently, genetic analysis offers the possibility to define genotype-phenotype correlations and to adjust the time of prophylactic surgery. Hereditary MTC is a model of genetically determined cancer in which both diagnostic and therapeutic strategies rely on the identification of specific mutations.Endocrine-Related Cancer (2008) 15 871-884

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Revisiting the genotype‐phenotype correlation in children with medullary thyroid carcinoma: A report from the GPOH‐MET registry

Kuhlen

Frühwald

Dunstheimer

et al. 2020

Pediatric Blood & Cancer

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Background Medullary thyroid carcinomas (MTC) account for 3% to 5% of all thyroid cancers. In most cases, MTC is hereditary and occurs as part of the multiple endocrine neoplasia (MEN) type 2A and 2B syndromes. There is a strong genotype‐phenotype correlation associated with the respective RET mutations, making risk‐adapted management possible. Procedure We report the prospectively collected data on children and adolescents of the multicenter nonrandomized German GPOH‐MET registry. Children and adolescents with MTC and C‐cell hyperplasia (CCH) were included. Results From 1997 to June 2019, a total of 57 patients with MTC and 17 with CCH were reported. In patients with MTC, median follow‐up was five years (range, 0‐19) and median age at diagnosis 10 years (range, 0‐17). Overall survival and event‐free survival (EFS) were 87% and 52%, respectively. In total 96.4% of patients were affected by MEN2 syndromes, which was in 37/42 MEN2A and 3/28 MEN2B (M918T mutation) inherited. EFS in MEN2A was 78%, and in MEN2B 38% (P < 0.001). In multivariate analyses, lymph node (LN) status and postoperatively elevated calcitonin were significant prognostic factors for EFS. Notably, modest‐risk mutation carriers presented with MTC at a rather young age, without raised calcitonin, and LN metastases. Conclusions Identification of children carrying de novo RET M918T mutations by means of the characteristic phenotype is crucial to detect MTC at an early stage, which will be associated with improved survival. As calcitonin levels may be false‐negative and modest‐risk mutation carriers present with a variable phenotype, particular attention should be paid to these children.

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Familial medullary carcinoma prevention, risk evaluation, and RET in children of families with MEN2

Cited by 39 publications

References 51 publications

Multiple endocrine neoplasia syndromes, children, Hirschsprung’s disease and RET

Multiple endocrine neoplasia syndromes, children, Hirschsprung’s disease and RET

The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy

Revisiting the genotype‐phenotype correlation in children with medullary thyroid carcinoma: A report from the GPOH‐MET registry

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