Prophylactic thyroidectomy in pediatric carriers of multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma: mutation in C620 is associated with Hirschsprung's disease

Bütter, Andreana; Gagné, Julie; Al‐Jazaeri, Ayman; Emran, Mohammad A.; Deal, Cheri; St-Vil, Dickens

doi:10.1016/j.jpedsurg.2006.09.019

Cited by 29 publications

(16 citation statements)

References 17 publications

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“…Butter et al [17] reported a 50% incidence of HSCR in 20 patients with a RET C620 mutation, undergoing a prophylactic thyroidectomy for RET-associated MTC risk, In one further reported case of familial MTC [18] with a C620S point mutation, the MTC developed 12 years after surgical correction of HSCR in the child plus a maternal MTC 7 years after the child's birth. This was also observed in family 1 of this series where MTC onset in the parent followed the birth of the affected child.…”

Section: Discussionmentioning

confidence: 99%

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

Moore

Zaahl

2010

Journal of Pediatric Surgery

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Section: Discussionmentioning

confidence: 99%

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

Moore

Zaahl

2010

Journal of Pediatric Surgery

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“…Some earlier studies have recommended mutation analysis of the RET gene in HD (De Groot et al 2005, Skába et al 2006, Fialkowski et al 2008. MEN2A/FMTC has been found to co-occur with HD in few patients worldwide (Borst et al 1995, Borrego et al 1999, Eng 1999, Fernández et al 2003, Nishikawa et al 2003, De Groot et al 2005, Dvoráková et al 2005, Bütter et al 2007, Fialkowski et al 2008. The main focus of these studies has been in the genetic screening of certain RET germline mutations (Pasini et al 2002, Nishikawa et al 2003, Dvoráková et al 2005.…”

Section: Discussionmentioning

confidence: 99%

“…In other studies, smaller and younger selected patient cohorts have undergone genetic screening after the diagnosis of HD followed by prophylactic thyroidectomy in patients with high-risk RET mutations (Dvoráková et al 2005, Fialkowski et al 2008. Genetic screening of MTC patients has also revealed RET mutations co-occurring with HD in some cases (Bütter et al 2007). To our best knowledge, there are no previous studies on unselected population-based cohort of adult HD patients screened for thyroid malignancies both genetically and clinically.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have focused on genetic screening of certain germline RET mutations in non-population-based cohorts of selected HD and/or MTC patients or their families (Nishikawa et al 2003, De Groot et al 2005, Bütter et al 2007, Fialkowski et al 2008. Taking into account that genetics of HD is still incompletely understood, this approach may lead to biased conclusions regarding the risk of thyroid malignancies or co-occurring RET mutations among HD patients in general.…”

Section: Introductionmentioning

confidence: 99%

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Thyroid cancer and co-occurring RET mutations in Hirschsprung disease

Virtanen

Pukkala

Kivisaari

et al. 2013

Endocrine-Related Cancer

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The objective of this study was to assess the occurrence of thyroid cancer and co-occurring RET mutations in a population-based cohort of adult Hirschsprung disease (HD) patients. All 156 patients operated for HD in a tertiary center during 1950-1986 were followed for thyroid malignancies up to 2010 through the nationwide Finnish Cancer Registry. Ninety-one individuals participated in clinical and genetic screening, which included serum calcitonin and thyroid ultrasound (US) with cytology. Exons 10, 11, 13, and 16 were sequenced in all, and all exons of RET in 43 of the subjects, including those with thyroid cancer, RET mutations, suspicious clinical findings, and familial or long-segment disease. Through the cancer registry, two cases (aged 35 and 37 years) of medullary thyroid cancer (MTC) were observed; the incidence for MTC was 340-fold (95% CI 52-1600) compared with average population. These individuals had C611R and C620R mutations in exon 10. One papillary thyroid cancer without RET mutations was detected by clinical screening. Four subjects (aged 31-50 years) with co-occurring RET mutations in exons 10 (C609R; nZ1) and 13 (Y791F, nZ3) had sporadic short-segment HD with normal thyroid US and serum calcitonin. Three novel mutations and five single-nucleotide polymorphisms were found outside exons 10 and 13 without associated signs of thyroid cancer. MTC-associated RET mutations were restricted to exons 10 and 13 affecting w5% of unselected adults with HD. Clinical thyroid assessment did not improve accuracy of genetic screening, which should not be limited to patients with familial or long-segment disease.

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“…In 7 out of the 13 patients (54%), the aganglionic segment was long (L-HSCR) [30] and it would appear that patients with long segment HSCR and a C620 mutation carry the highest risk. In assessing 20 patients undergoing a prophylactic thyroidectomy for RET-associated MTC risk, Butter et al [21] reported a 50% incidence of HSCR in those with a C620 mutation. A case of familial medullary thyroid carcinoma was also reported in a C620S patient, 12 years after surgical corection of HSCR, the maternal MTC developing 7 years after the child's birth.…”

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

confidence: 99%

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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Prophylactic thyroidectomy in pediatric carriers of multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma: mutation in C620 is associated with Hirschsprung's disease

Cited by 29 publications

References 17 publications

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

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

Thyroid cancer and co-occurring RET mutations in Hirschsprung disease

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

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