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      RET Gene Abnormalities and Thyroid Disease: Who Should be Screened and When

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          Abstract

          Mutations in the RET proto-oncogene have been implicated in the pathogenesis of several forms of medullary thyroid cancer (MTC). Multiple endocrine neoplasia type 2 (MEN-2) is an autosomal dominant syndrome caused by germline activating mutations of the RET proto-oncogene and has been categorized into three distinct clinical forms. MEN-2A is associated with MTC, bilateral pheochromocytoma, and primary hyperparathyroidism. MEN-2B is associated with MTC, bilateral pheochromocytoma, and mucosal neuromas. The rarest clinical form of MEN-2 is familial MTC (FMTC), which is also associated with MTC, but other endocrinopathies are characteristically not present. Each clinical form of MEN-2 results from a specific RET gene mutation, with a strong correlation of phenotype expression with regard to the onset and course of MTC and the presence of other endocrine tumors and a corresponding genotype. Recommendations for screening of RET mutations are necessary as their presence or absence will influence interventional strategies such as the timing of a prophylactic thyroidectomy and extent of surgery. Timing of screenings and development of interventional strategies are extremely important in caring for patients with certain RET mutations as evidence of metastatic MTC has been documented as early as 6 years of age. Interventional strategies should consider the risks of complications of these interventions based on certain characteristics of each individual case such as age of the patient, course of disease in affected family members, and the invasiveness of any proposed surgical procedure.

          Conflict of interest:None declared.

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          Most cited references 53

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          Guidelines for diagnosis and therapy of MEN type 1 and type 2.

          This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.
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            Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

            Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.
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              Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

              Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.
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                Author and article information

                Journal
                J Clin Res Pediatr Endocrinol
                J Clin Res Pediatr Endocrinol
                JCRPE
                Journal of Clinical Research in Pediatric Endocrinology
                Galenos Publishing
                1308-5727
                1308-5735
                March 2013
                1 March 2013
                : 5
                : Suppl 1
                : 70-78
                Affiliations
                [1 ] City of Hope, Department of Diabetes, Endocrine & Metabolism, California, USA
                Author notes
                * Address for Correspondence: Behrouz Salehian MD, City of Hope, Department of Diabetes, Endocrine & Metabolism, California, USA Phone: +1 626 2564673 / 61235 E-mail: bsalehian@ 123456coh.org
                Article
                270
                10.4274/Jcrpe.870
                3608003
                23455356
                © Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Review

                Pediatrics

                ret gene, screening, thyroid cancer

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