Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 “Janus” genetic variation

Moore, Sam; Zaahl, Monique G.

doi:10.1016/j.jpedsurg.2009.10.080

Cited by 32 publications

(15 citation statements)

References 30 publications

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“…In contrast to gain-of-function activating RET mutations that cause MTC, the loss-of-function RET mutations in Hirschprung disease result in inactivation of the mutant ret protein. However, some activating RET mutations, which are almost exclusively localized in exon 10, have been found in patients with both Hirschsprung disease and MTC; such dual function mutations are known as ‘ RET Janus mutations’ [80,81]. In one recent series, Hirschsprung disease was present in 20/267 informative carriers (7.5%), 2/37 (5.4%) in those with mutations in codon 609, 0/44 in codon 611, 1/56 (1.8%) in codon 618, and 17/130 (13.1%) in codon 620 [82].…”

Section: Other Phenotypes That Require Germline Ret Mutation Screeningmentioning

confidence: 99%

2012 European Thyroid Association Guidelines for Genetic Testing and Its Clinical Consequences in Medullary Thyroid Cancer

Elisei¹,

Alevizaki²,

Conte-Devolx³

et al. 2012

Eur Thyroid J

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Twenty-five percent of medullary thyroid cancers (MTC) are familial and inherited as an autosomal dominant trait. Three different phenotypes can be distinguished: multiple endocrine neoplasia (MEN) types 2A and 2B, in which the MTC is associated with other endocrine neoplasias, and familial MTC (FMTC), which occurs in isolation. The discovery that germline RET oncogene activating mutations are associated with 95–98% of MEN 2/FMTC syndromes and the availability of genotyping to identify mutations in affected patients and their relatives has revolutionized the diagnostic and therapeutic strategies available for the management of these patients. All patients with MTC, both those with a positive familial history and those apparently sporadic, should be submitted to RET genetic screening. Once an RET mutation has been confirmed in an index patient, first-degree relatives should be screened rapidly to identify the 50% who inherited the mutation and are therefore at risk for development of MTC. Relatives in whom no RET mutation is identified can be reassured and discharged from further follow-up, whereas RET-positive subjects (i.e. gene carriers) must be investigated and a therapeutic strategy initiated. These guideline recommendations are derived from the most recent studies identifying phenotype-genotype correlations following the discovery of causative RET gene mutations in MEN 2 eighteen years ago. Three major points will be discussed: (a) identification of patients and relatives who should have genetic screening for RET mutations, (b) management of asymptomatic gene carriers, and (c) ethics.

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Section: Other Phenotypes That Require Germline Ret Mutation Screeningmentioning

confidence: 99%

2012 European Thyroid Association Guidelines for Genetic Testing and Its Clinical Consequences in Medullary Thyroid Cancer

Elisei¹,

Alevizaki²,

Conte-Devolx³

et al. 2012

Eur Thyroid J

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“…This indicates that a particular RET mutation apparently can have a loss-of-function effect during embryonal development as well as a gain-of-function effect in postnatal life [53].…”

Section: Study (Year) Resultsmentioning

confidence: 97%

Standards of Care Intended for Multiple Endocrine Neoplasia Families

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Höppener

et al. 2014

Int. J. Endo. Oncol.

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In the past, the medical expenditure for multiple endocrine neoplasia families was high and the course of their disease not predictable. In a couple of decades, the prospects changed completely. The genetic origin of the diseases is well known and prevention is possible, whereas in advanced stages target-directed treatment is coming within reach. The most important change is the responsibility for these families. Initially, this was completely the task of the attending physician, whereas at this moment patients and disease gene carriers themselves have the central responsibility with respect to these diseases. Unfortunately, for them information about the disease is insufficiently available.

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“…A null mutation of the Ednrb gene in animal models although essential for normal enteric neuron development, has been found to be insufficient to alone cause HSCR when bred onto a different genetic background in rats carrying Ednrb(sl) mutations [33]. These same studies suggested a novel noncoding sequence mutation in GDNF that modifies the penetrance and severity of the aganglionosis phenotype in EDNRB-deficient rats [34].…”

Section: Discussionmentioning

confidence: 98%

“…In one significant 6 generation association, the risk of Hirschsprung's disease and MEN was associated with the non-coding Cysteine mutation at C620R (the so called "Janus" gene) [34].…”

Section: Discussionmentioning

confidence: 99%