Multiple Endocrine Neoplasia Type 2B (MEN2B) delayed diagnosis: importance of opportune recognition of MEN2 Syndromes in pediatric thyroid cancer

ABSTRACT Background: RET proto-oncogene mutations are responsible for familial thyroid medullary carcinoma and multiple endocrine neoplasia (MEN) type 2A and 2B. These syndromes develop specific biomarkers and, in the case of MEN2B, clinically observable stigmas. However, the diagnosis of patients with MEN2B is usually delayed. Because of the close genotype-phenotype correlation, molecular testing is the final approach for the diagnosis to establish preventive care and therapeutic behaviors. Discussion: pM918T is classified as ''highest risk'' for medullary carcinoma with a 50% of lifetime risk for developing pheochromocytoma. Most cases of MEN2B are due to a de novo mutation. Even with the increased risk of developing pheochromocytoma, our 24-year-old patient does not yet present one. Other factors may be involved in the modulation of the phenotype in different populations. Case report: We present the case of a woman diagnosed with a thyroid nodule at the age of nine. She underwent a total thyroidectomy plus radical cervical lymph node dissection, with a diagnosis and initial management of papillary thyroid carcinoma. During the evolution of the disease, she developed pulmonary metastases. At the age of 24, after her first endocrinological evaluation, typical physical manifestations of MEN2B were observed. A re-evaluation of the original thyroidectomy revealed a medullary carcinoma, with positive manifestation CEA and calcitonin. The analysis of RET proto-oncogene identified a de novo mutation in exon 16 (pM918T). Conclusion: The timely diagnosis of MEN2B offers opportunities to make appropriate preventive and therapeutic decisions that may change the natural evolution of the disease and its complications.

The mutation site and the targeted therapy of RET proto-oncogene in medullary thyroid carcinoma / 中华内分泌外科杂志

Medullary thyroid carcinoma (MTC) is an endocrine tumor originating from the parafollicular cells of the thyroid gland.The mutation of RET gene has been considered as the molecular basis of MTC.Different types of MTC have different RET mutation sites,and the corresponding clinical manifestations and prognosis are also very different.RET gene detection is helpful for individual accurate gene diagnosis,molecular risk assessment,individual analysis and early prevention management.Nowadays,targeted therapy for RET gene mutations in MTC has developed rapidly.Some of those drugs,which have been approved for clinical application,bring new hope for advanced MTC.

A comparison of clinical characteristics between 2 pedigrees of multiple endocrine neoplasia type 2A with different RET mutations / 中华内科杂志

Multiple endocrine neoplasia type 2A (MEN2A) is a hereditary syndrome. Here, two different RET proto-oncogen mutation were identified from family members of two MEN2A pedigrees by genetic screening. One RET mutations were found at codons 1893 and 1895 in exon 11 (1893-1895delCGA) from pedigree 1, which is a novel mutation, the other occurs at codon 634 (Cys634Arg) in exon 11 from pedigree 2. However, the clinical characteristics were similar in the patients of the two pedigrees. All the patients were in middle-age at onset. Most of them were firstly diagnosed with bilateral adrenal pheochromocytoma with different degrees of thyroid abnormalities (elevated serum calcitonin with or without thyroid mass, or had been diagnosed with medullary thyroid carcinoma). Some family members were with elevated serum parathyroid hormone but with no other evidences for hyperparathyroidism.

Pheochromocytoma Developed in a Boy with Multiple Endocrine Neoplasia Type 2A Confirmed by the RET Proto-Oncogene Mutation / 임상소아혈액종양

A 9-year-old boy presented with increased sweating and abdominal pain. His mother and uncle had been diagnosed with bilateral pheochromocytoma and medullary thyroid carcinoma. Magnetic resonance imaging of the boy's abdomen revealed a 7.5 cm×7.0 cm×6.0 cm mass with a thick peripheral enhancing wall and fluid-fluid level at the right suprarenal region. His ¹²³I-meta-iodobenzylguanidine (MIBG) scan showed a large mass with increased MIBG uptake in the right adrenal gland. The levels of serum norepinephrine, urine epinephrine/norepinephrine, metanephrine, and vanillylmandelic acid were elevated. He, his mother, and two sisters tested positive for the known mutation of multiple endocrine neoplasia type 2A, Cys634Tyr in RET proto-oncogene. Laparoscopic tumor excision and right adrenalectomy were performed. Final diagnosis was pheochromocytoma with malignant behavior, based on adrenal gland scoring scale. However, there was no overt metastasis. After surgery, his symptoms resolved and abnormal laboratory tests were normalized.

Pheochromocytoma Developed in a Boy with Multiple Endocrine Neoplasia Type 2A Confirmed by the RET Proto-Oncogene Mutation / 임상소아혈액종양

A 9-year-old boy presented with increased sweating and abdominal pain. His mother and uncle had been diagnosed with bilateral pheochromocytoma and medullary thyroid carcinoma. Magnetic resonance imaging of the boy's abdomen revealed a 7.5 cm×7.0 cm×6.0 cm mass with a thick peripheral enhancing wall and fluid-fluid level at the right suprarenal region. His ¹²³I-meta-iodobenzylguanidine (MIBG) scan showed a large mass with increased MIBG uptake in the right adrenal gland. The levels of serum norepinephrine, urine epinephrine/norepinephrine, metanephrine, and vanillylmandelic acid were elevated. He, his mother, and two sisters tested positive for the known mutation of multiple endocrine neoplasia type 2A, Cys634Tyr in RET proto-oncogene. Laparoscopic tumor excision and right adrenalectomy were performed. Final diagnosis was pheochromocytoma with malignant behavior, based on adrenal gland scoring scale. However, there was no overt metastasis. After surgery, his symptoms resolved and abnormal laboratory tests were normalized.

Extraskeletal osteosarcoma of the orbit: A clinicopathologic case report and review of literature.

Primary extraskeletal osteosarcoma (EOS) is an extremely rare malignancy. In this report, the clinical course of a 32-yearold man presenting with proptoses is described. Medical history included Hirschsprung disease (HD), horseshoe kidney, azoospermia, and vertebral anomalies. Imaging of the orbit showed an oval, well-defined heterogeneous mass adjacent to the lateral wall of the orbit. The patient underwent a lateral orbitotomy and complete excision of the mass. The mass was not attached to the bone. Histopathologic and immunohistochemical examination confirmed the diagnosis of an EOS. The patient received chemotherapy and radiotherapy and is free of the disease 3 years after the diagnosis. Genetic screening showed no mutations for both the RET protooncogene for HD and the p53 tumor suppressor gene for osteosarcoma.

Diagnóstico, tratamento e seguimento do carcinoma medular de tireoide: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia / Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism

Introdução O carcinoma medular de tireoide (CMT) origina-se das células parafoliculares da tireoide e corresponde a 3-4% das neoplasias malignas da glândula. Aproximadamente 25% dos casos de CMT são hereditários e decorrentes de mutações ativadoras no proto-oncogene RET (REarranged during Transfection). O CMT é uma neoplasia de curso indolente, com taxas de sobrevida dependentes do estádio tumoral ao diagnóstico. Este artigo descreve diretrizes baseadas em evidências clínicas para o diagnóstico, tratamento e seguimento do CMT. Objetivo O presente consenso, elaborado por especialistas brasileiros e patrocinado pelo Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia, visa abordar o diagnóstico, tratamento e seguimento dos pacientes com CMT, de acordo com as evidências mais recentes da literatura. Materiais e métodos: Após estruturação das questões clínicas, foi realizada busca das evidências disponíveis na literatura, inicialmente na base de dados do MedLine-PubMed e posteriormente nas bases Embase e SciELO – Lilacs. A força das evidências, avaliada pelo sistema de classificação de Oxford, foi estabelecida a partir do desenho de estudo utilizado, considerando-se a melhor evidência disponível para cada questão. Resultados Foram definidas 11 questões sobre o diagnóstico, 8 sobre o tratamento cirúrgico e 13 questões abordando o seguimento do CMT, totalizando 32 recomendações. Como um todo, o artigo aborda o diagnóstico clínico e molecular, o tratamento cirúrgico inicial, o manejo pós-operatório e as opções terapêuticas para a doença metastática. Conclusões O diagnóstico de CMT deve ser suspeitado na presença de nódulo tireoidiano e história ...

Introduction Medullary thyroid carcinoma (MTC) originates in the thyroid parafollicular cells and represents 3-4% of the malignant neoplasms that affect this gland. Approximately 25% of these cases are hereditary due to activating mutations in the REarranged during Transfection (RET) proto-oncogene. The course of MTC is indolent, and survival rates depend on the tumor stage at diagnosis. The present article describes clinical evidence-based guidelines for the diagnosis, treatment, and follow-up of MTC. Objective The aim of the consensus described herein, which was elaborated by Brazilian experts and sponsored by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism, was to discuss the diagnosis, treatment, and follow-up of individuals with MTC in accordance with the latest evidence reported in the literature. Materials and methods: After clinical questions were elaborated, the available literature was initially surveyed for evidence in the MedLine-PubMed database, followed by the Embase and Scientific Electronic Library Online/Latin American and Caribbean Health Science Literature (SciELO/Lilacs) databases. The strength of evidence was assessed according to the Oxford classification of evidence levels, which is based on study design, and the best evidence available for each question was selected. Results Eleven questions corresponded to MTC diagnosis, 8 corresponded to its surgical treatment, and 13 corresponded to follow-up, for a total of 32 recommendations. The present article discusses the clinical and molecular diagnosis, initial surgical treatment, and postoperative management of MTC, as well as the therapeutic options for metastatic disease. Conclusions 7 .

A novel RET proto-oncogene mutation in multiple endocrine neoplasia type 2A / 中华内分泌代谢杂志

Objective To observe the mode of RET proto-oncogene mutation in a pedigree with multiple endocrine neoplasia type 2A (MEN2A).Methods Six members from a MEN2A family,including the proband,were enrolled.Genomic DNAs of these members were extracted from peripheral blood lymphocytes for polymerase chain reaction(PCR),PCR products of 21 exons of the RET proto-oncogene were purified and a direct gene sequence analysis was performed.DNA sequencing was performed on the related exon of the other family members after verifying the mutation site.Results The female proband sufferd from pheochromocytoma and medullary thyroid carcinoma since the age of 45,two missense mutations of TGC(Cys) to TCC(Ser) at codon 634 and CTG(Leu) to TTT(Phe) at codon 633 in exon 11 of the RET proto-oncogene were detected in the proband,while the other members remain unchanged.Conclusions Analysis of the RET proto-oncogene identifies a united mutation of TGC (Cys) to TCC (Ser) at codon 634 and CTG(Leu) to TTT(Phe) at codon 633 in the proband.The former is a proven mutation related to MEN2A,while the latter has never been reported before.

A Case of Medullary Thyroid Carcinoma with de novo V804M RET Germline Mutation

Many cases of RET proto-oncogene mutations of hereditary medullary thyroid carcinoma (MTC) have been reported in Korea. However, MTC with V804M RET proto-oncogene germline mutations have not been reported in Korea. A 33-yr-old man was diagnosed with a 0.7-cm sized thyroid nodule. Laboratory testing revealed serum calcitonin was elevated. The patient underwent total thyroidectomy with central compartment neck dissection for the thyroid tumor. RET gene analysis was performed in both the index patient and his family. There were no V804M RET mutation and abnormal laboratory findings within his family except the index patient. Therefore, this patient was a de novo V804M RET germline mutation.

Genotype-phenotype correlation in multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 is an autosomal-dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the rearranged during transfection proto-oncogene, which encodes the receptor tyrosine kinase, on chromosome 10. It has a strong penetrance of medullary thyroid carcinomas and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Multiple endocrine neoplasia type 2 is divided into three varieties depending on its clinical features: multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma. The specific rearranged during transfection mutation may suggest a predilection toward a particular phenotype and clinical course of medullary thyroid carcinoma, with strong genotype-phenotype correlations. Offering rearranged during transfection testing is the best practice for the clinical management of patients at risk of developing multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2 has become a classic model for the integration of molecular medicine into patient care. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on the classification of rearranged during transfection mutations into risk levels according to genotype-phenotype correlations. Earlier identification of patients with hereditary medullary thyroid carcinoma can change the presentation from clinical tumor to preclinical disease, resulting in a high cure rate of affected patients and a much better prognoses.

Over-representation of the G12S polymorphism of the SDHD gene in patients with MEN2A syndrome

OBJECTIVE: To evaluate whether germline variants of the succinate dehydrogenase genes might be phenotypic modifiers in patients with multiple endocrine neoplasia type 2. Mutations of genes encoding subunits of the succinate dehydrogenase are associated with hereditary paraganglioma/pheochromocytoma syndrome. Pheochromocytoma is one of the main manifestations of multiple endocrine neoplasia type 2 caused by germline mutation of the rearranged during transfection proto-oncogene. METHODS: Polymorphisms of the succinate dehydrogenase genes were analyzed in 77 rearranged during transfection mutation carriers, 47 patients with sporadic medullary thyroid cancer, 48 patients with sporadic Pheo, and 100 healthy individuals. Exons 10-16 of the rearranged during transfection proto-oncogene were analyzed by direct DNA sequencing, and all exons of the von Hippel-Lindau, succinate dehydrogenase B, and succinate dehydrogenase subunit D genes were tested by direct DNA sequencing and multiple ligation probe analysis. The G12S polymorphism of the succinate dehydrogenase subunit D gene was determined by restriction fragment length polymorphism. RESULTS: Of the 77 rearranged during transfection mutation carriers, 55 from 16 families had multiple endocrine neoplasia type 2A, three from three families had multiple endocrine neoplasia type 2B, and 19 from two families had familial medullary thyroid carcinoma. Eight of 55 (14.5%) patients with multiple endocrine neoplasia type 2A had this variant whereas it was absent in multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, sporadic medullary thyroid carcinoma, and sporadic pheochromocytoma groups, and its prevalence in controls was 1% (p<0.002 multiple endocrine neoplasia type 2A versus controls). No associations between G12S and age of manifestation, incidence of pheochromocytoma or hyperparathyroidism, or level of serum calcitonin were observed. CONCLUSION: The high prevalence of the G12S variant in patients with multiple endocrine neoplasia type 2A raises questions about its role as a genetic modifier, but this proposal remains to be established.

RET proto-oncogene mutation analysis in a pedigree with multiple endocrine neoplasia 2A / 中华泌尿外科杂志

ObjectiveTo discuss the clinical diagnosis and treatment of multiple endocrine neoplasia ( MEN ) 2A, and report the mutation of the RET proto-oncogene in a pedigree of three patients with MEN 2A.MethodsBilateral adrenalectomy was performed on two of the three patients with hypertension and bilateral adrenal-conserving adrenal pheochromocytoma resection was performed on the other patient. All three patients were treated by total thyroidectomy and neck lymphadenectomy. Twelve family members were recruited to the study. Peripheral blood was collected and total genomic DNA was prepared for polymerase chain reaction (PCR). PCR products of exon 10 and exon 11 of the RET proto-oncogene were purified and a direct DNA sequence analysis was performed.ResultsThe pathological diagnosis of the specimens was bilateral adrenal pheochromocytoma and medullary thyroid carcinoma in all the three patients. There was no tumor recurrence or distant metastasis after 1.5 - 5 years of follow-up. A missense mutation of TGC (Cys)to CGC (Arg) at codon 634 in exon 11 of the RET proto-oncogene was detected in all three patients. Genetic screening identified two mutation carriers in the other members of this pedigree.ConclusionGenetic mutation screening and surgical intervention may be helpful to the members of high-risk families.

A Family Presenting with Catastrophic Features due to Pheochromocytoma Associated with Multiple Endocrine Neoplasia 2A

Multiple endocrine neoplasia 2A (MEN 2A) is an autosomal dominant disease that consists of medullary thyroid carcinoma (MTC), pheochromocytoma and parathyroid hyperplasia. The activation of germ-line mutations in the RET proto-oncogene are responsible for MEN 2A. We describe here a rare case of MEN 2A in a patient who presented with an acute catecholamine-induced cardiomyopathy with cardiogenic shock and acute renal failure. The patient was diagnosed with pheochromocytoma and MTC associated with MEN 2A, which was confirmed by the detection of a RET proto-oncogene mutation at exon 11 on codon 634 (Cys634Arg). During familial screening, the patient's younger sister was found to have a benign thyroid nodule. Re-evaluation of this thyroid nodule revealed MTC with the same gene mutation. We also provide a review of the relevant literature.

Medullary Thyroid Carcinoma: 25-year Experience and the Results of the RET Proto-oncogene Screening Test / 대한내분비외과학회지

PURPOSE: Medullary thyroid carcinoma (MTC) is a rare thyroid tumor and its clinical course is quite variable. The aim of this study was to retrospectively analyze our clinical and laboratory data for 25 years to review the clinicopathologic characteristics, the operation methods, the tumor recurrence and the prognosis of medullary thyroid carcinoma. We also reevaluate the limits of the previous diagnostic and treatment modalities. The positivity for and the location of the RET mutation are also evaluated. Finally, we want to contribute to a systemic approach for the diagnosis, treatment, patient management and clinical study of medullary thyroid carcinoma. METHODS: We conducted a retrospective review of the records of 77 patients with MTC that were seen at our hospital from 1982 to 2007. The medical records were reviewed for the demographic data, the laboratory data and the clinical course, the treatment, the long-term outcome and the RET proto-oncogene mutation. The mean follow-up period was 69.6 months (range: 6~201). RESULTS: There were 50 females and 27 males. The mean patient age was 44.2 years (range: 1~80). There were 16 cases of the sporadic form (79.2%) and 16 cases of the hereditary form. At diagnosis, 73 patients (94.8%) had local disease and 4 patients (5.2%) had distant metastasis. The patients with the hereditary form were younger than the patients with the sporadic form (P=0.004), and they had more muticentric (P=0.002) and bilateral tumor (P<0.001). The initial surgery consisted of total thyroidectomy in 74 patients (96.1%), and lateral neck dissection in 41 patients (53.2%) (therapeutic: 23, prophylactic: 18), except for 3 cases with less than total thyroidectomy. Forty-four patients (57.1%) achieved a long-term remission state, 13 patients (16.9%) had biochemical persistent disease, and 20 patients (26.0%) had metastasis. The 5- and 10-year survival rates were 86.5% and 74.1% respectively. On univariate analysis, tumor size (more than 2 cm), extracapsular invasion, involvement of the neck nodes and distant metastasis at the time of diagnosis were the significant prognostic factors of persistent or recurrence disease. CONCLUSION: Patients with MTC generally have a favorable outcome. The presence of distant metastasis at the time of diagnosis is predictive of persistent or recurrence disease by multivariate analysis. In order to achieve an early diagnosis and administer prompt treatment, we suggest that optimal RET oncogene screening and counseling should be performed for medullary patients and their relatives.

A novel RET proto-oncogene mutation in a pedigree of multiple endocrine neoplasia type 2A / 中华内分泌代谢杂志

Objective To observe the clinical manifestation and the mode of RET proto-oncogene mutation in a pedigree of mutiple endocrine neoplasia type 2A (MEN2A). Methods Genomic DNA was extracted from the peripheral blood lymphocytes in 18 family members including 3 patients, then PCR was performed to amplify seven exons of the RET proto-oncogene, i. e. exon 8,10,11,13-16. The PCR products were directly sequenced to identify the RET mutation and then sequenced after subcloning to identify their heterozygosity. Results The male proband suffered from pheochromocytoma and medullary thyroid carcinoma since the age of 30; while his sibling sister was ill with pheochromocytoma, and his brother with medullary thyroid carcinoma. A novel heterozygous mutation, 1893-1895delCGA, was detected in exon 11 of the RET proto-oncogene in the 3 patients and the other 2 family members. Conclusion A novel heterozygous mutation of RET proto-oncogene, 1893-1895delCGA, seems to be the disease-causing mutation in the studied MEN2A family.

Importância da identificação das mutações do protooncogene RET e sua atuação no desenvolvimento dos diversos fenótipos das neoplasias endócrinas múltiplas tipo 2 / Importance of RET proto-oncogene mutations identification and its performance in thedevelopment of the multiples endocrines neoplasias type 2 several phenotypes

A hereditariedade autossômica dominante da neoplasia endócrina múltipla tipo 2 (NEM 2) relaciona-se à ativação do proto-oncogene RET, através de mutações missense. As mutações do RET são encontradas em 95% dos casos índices de NEM 2 e apresentam relação direta entre sua localização codon específica e os diversos fenótipos desenvolvidos, dentre eles, carcinoma medular datireóide, feocromocitoma e/ou hiperparatireoidismo. Baseando-se em análises bioquímicas e genéticas, é possível efetuar um diagnósticoprematuro, viabilizando a intervenção cirúrgica em tempo hábil. A periodicidade da monitorização bioquímica é ditada pelo fenótipopresente, pelas manifestações clínicas familiares e pelo genótipo RET. A recomendação da análise genética deve ser feita a todos indivíduos afetados e também a seus ascendentes e descendentes diretos, caso alguma mutação esteja presente; permitindo identificar os portadores de mutações RET, previamente ao início da sintomatologia. Neste trabalho, serão discutidos os aspectos molecularesdos diversos fenótipos da NEM 2, bem como a importância da identificação genotípica do proto-oncogene RET e sua interação com os testes bioquímicos visando o diagnóstico precoce, prevenção, monitorização, screening familiar e, portanto, maior sobrevidado paciente.

The dominant autossomic hereditarity of the multiple endocrine neoplasia type 2 (MEN 2) is related to RET proto-oncogene activation, through mutations missense. RET mutations are found in 95% of MEN 2 index cases and present direct relation between its specific localization codon and the diverse developed phenotypes, among them, medullary thyroid carcinoma, pheochromocytoma and/or hyperparathyroidism. Being based on biochemists and genetics analyses, it is possible to perform a premature diagnosis, making possible a surgical intervention in the right time. The biochemist monitoring regularity is determined by present phenotype, the familiar clinical manifestations and RET genotype. The recommendation of the genetic analysis must be made to all affected individuals and also their ascendants and descendants, in case some mutation is present, allowing to identify the RET mutations carriers previously to the beginning of the symptomatology. In this work, the molecular aspects of MEN 2 diverse phenotypes will be discussed, as well as the importance of the RET proto-oncogene genotypic identification and its interaction with the biochemists tests aiming the precocious diagnosis, prevention, monitoring, familiar screening e, therefore, the patient’s longer survival.

Screening of RET gene mutations in multiple endocrine neoplasia type-2 using Conformation Sensitive Gel Electrophoresis (CSGE)

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant inherited tumor syndrome caused by RET proto-oncogene germline mutations (RET). Here we tested the Conformation Sensitive Gel Electrophoresis (CSGE) as a screening method for RET hot-spot mutations. Seven MEN2 families were studied by direct sequencing analysis, CSGE and Single Strand Conformational Polymorphism (SSCP). Using CSGE/SSCP, we were able to detect four out of five types of RET mutations verified by sequencing analysis: Cys620Arg, Cys634Arg, Cys634Tyr, and Met918Thr, furthermore a missense substitution at codon 648 (Val648Ile). RET polymorphisms 691 and 769 were also verified. Data obtained using CSGE/SSCP were fully concordant. We conclude that CSGE showed to be a sensitive, fast, low-cost, and simple procedure to detect RET mutations in codons which are reported as the most prevalent RET variants (~ 95 percent) in large MEN2 series. As to the Val804Met mutation, this method still needs to be optimized.

A neoplasia endócrina múltipla tipo 2 (NEM2) é uma síndrome tumoral herdada por mutações germinativas no proto-oncogene RET (RET). Analisamos a aplicação do método Eletroforese em Gel Sensível à Conformação (CSGE) no rastreamento de mutações hot spots do RET. Sete famílias com NEM2 foram rastreadas pelo seqüenciamento gênico, CSGE e análise do Polimorfismo Conformacional de Cadeia Simples (SSCP). Usando ambas as metodologias de rastreamento, identificamos quatro dos cinco tipos de mutações verificadas pelo seqüenciamento: Cys620Arg, Cys634Arg, Cys634Tyr e Met918Thr, além da variação gênica Val648Ile. Das análises englobando mutações hot spots do RET, 90,6 por cento concordaram com o seqüenciamento genético (incluindo a variação gênica Val648Ile). Polimorfismos nos códons 691 e 769 foram documentados. Os dados obtidos por CSGE/SSCP foram totalmente concordantes. Concluímos que o CSGE revelou ser metodologia sensível, rápida, de fácil execução e baixo custo no rastreamento de mutações nos códons associados à grande maioria (~ 95 por cento) dos pacientes com NEM2.

Polimorfismos genéticos: implicações na patogênese do carcinoma medular de tireóide / Genetic polymorphisms: implications in the pathogenesis of medullary thyroid carcinoma

O carcinoma medular de tireóide (CMT) é uma neoplasia maligna rara, ocorrendo na forma esporádica ou hereditária. Mutações germinativas no proto-oncogene RET são responsáveis pelo CMT hereditário. No entanto, a maioria dos casos de CMT ocorre em indivíduos sem história familiar, na qual a patogênese da doença ainda é pouco compreendida. Os polimorfismos do gene RET são descritos na população geral assim como em pacientes com CMT. Embora estas variações alélicas aparentemente não confiram qualquer atividade transformadora no receptor RET, estudos sugerem que essas alterações genéticas podem modificar a suscetibilidade à doença e o fenótipo clínico em pacientes com CMT esporádico ou hereditário. Uma maior freqüência dos polimorfismos localizados nos exons 11 (G691S), 13 (L769L), 14 (S836S) e 15 (S904) é descrita em pacientes com CMT provenientes de países americanos e europeus. Na presente revisão, analisamos criticamente os resultados obtidos nos diferentes estudos e descrevemos a freqüência dos polimorfismos do RET em pacientes brasileiros com CMT esporádico.

Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia, which may occur on sporadic form or on a hereditary basis. Germ line mutations in the RET proto-oncogene is responsible for hereditary MTC. However, most MTC occur in individuals without family history where the pathogenesis is still unclear. Single nucleotide polymorphisms (SNPs) of the RET gene have been described in the general population as well as in patients with MTC. Even though these allelic variants do not seem to confer any transforming activity to the tyrosine kinase domain of the RET protein, cumulative studies suggest that they could modify disease susceptibility and clinical phenotype in patients with sporadic or hereditary MTC. Polymorphisms located in exons 11 (G691S), 13 (L769L), 14 (S836S), and 15 (S904S) seem to be over-represented in sporadic MTC patients from American and European countries. Here, we discuss the results obtained in different studies as well as describe the frequency of RET polymorphisms in Brazilian patients with sporadic MTC.

Mutation of the ret proto-oncogene in two Chinese families with multiple endocrine neoplasia type 2A(MEN2A) / 中国实用内科杂志

Objective To detect ret mutations in two Chinese families with multiple endocrine neoplasia type 2A(MEN2A).Methods In our study,9 members from these two families including 3 patients were recruited.Polymerase chain reaction(PCR)and direct gene sequencing of PCR products by an automated DNA sequencer were applied to scan the entire 21 exons of ret proto-oncogene in the leukocyte DNA of the subjects.Results Two missense mutations were detected in exon11 of the ret proto-oncogene.One was C634R in the 2 patients from a family and the other was C634Y in 2 subjects from another family(one was the patient).Two heterozygous variants(A45A and L769L)in these 4 subjects were revealed.Conclusion Two mutations(C634R and C634Y)are detected in two families with MEN2A.Direct DNA sequencing analysis can diagnose MEN2A at gene level,which is helpful in making clinical management of the disease and in diagnosing earlier in their offspring.

A family of multiple endocrine neoplasia type 2A associated with a C618R mutation in RET proto-oncogene / 대한내과학회지

Medullary thyroid carcinoma (MTC) is a relatively rare malignant thyroid disease that accounts for approximately 1% to 5% of all thyroid carcinomas. MTC occurs as a sporadic disease and as an inherited disease with the multiple endocrine neoplasia type 2A (MEN2A), MEN2B, and familial non-MEN medullary carcinoma (FMTC). MEN2A is characterized by MTC, pheochromocytoma, and parathyroid adenoma. The mutation of RET proto-oncogene plays an important role in MEN2A syndromes. Recently the authors diagnosed MEN2A patient and screened his family with thyroid ultrasonogram and RET proto-oncogene analysis. A genetic analysis of the peripheral leukocyte showed a codon 618 mutation (Cys618Arg) at exon 10 of the RET proto-oncogene in a family presenting third generations from age 7 to age 56 years. We report this case of MEN2A with a review of the related literatures.