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1.
Zhou Y  Zhao Y  Cui B  Gu L  Zhu S  Li J  Liu J  Yin M  Zhao T  Yin Z  Yu C  Chen C  Wang L  Xiao B  Hong J  Zhang Y  Tang Z  Wang S  Li X  Ning G 《Clinical endocrinology》2007,67(4):570-576
OBJECTIVE: Multiple endocrine neoplasia type 2 is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene, which includes multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC). In this paper we present the phenotype-genotype correlation of 20 unrelated Chinese families with 15 cases of MEN2A and five cases of MEN2B. DESIGN: Cross-sectional study. PATIENTS: A total of 147 members from the 20 families were included. Among them, 119 family members were from MEN2A pedigrees (including 15 MEN2A probands) and 28 members from MEN2B pedigrees (including five MEN2B probands). MEASUREMENTS: Genomic DNA was isolated from peripheral blood leucocytes and was amplified using polymerase chain reaction (PCR). DNA analysis for RET mutations in exons 8, 10, 11, 13, 14, 15 and 16 was performed with specific primers. RESULTS: Thirty-seven MEN2A and five MEN2B patients were identified as having RET mutations. The incidence of medullary thyroid carcinoma (MTC), pheochromocytoma (PCC) and hyperparathyroidism (HPT) in the 37 MEN2A patients was 91.9, 56.8 and 10.8%, respectively; the onset of MTC in MEN2A patients was earlier than that of PCC and HPT. Five germline mutations, all located at codon 634 of exon11 in the RET proto-oncogene, were detected in all of the 37 MEN2A patients. The highest frequency of the five germline mutations was C634Y (46.7%), followed by C634R (26.7%), C634W (13.3%), C634F (6.7%) and C634S (6.7%). No statistical significance was found between the incidence of PCC and different genotypes of codon 634 in MEN2A patients, whereas the incidence of HPT was closely associated with C634R and C634Y. The gene mutation (M918T) at exon16 of the RET proto-oncogene was present in five MEN2B probands. CONCLUSIONS: RET proto-oncogene mutations were restricted to codon 634 and 918 in Chinese families with MEN2A and MEN2B. In general the genetic characteristics of these patients with MEN2A and MEN2B reflect the general pattern around the world and it remains to be determined with larger studies in China whether Chinese patients have a different genetic pattern of mutations.  相似文献   

2.
OBJECTIVE The pentagastrin stimulation test is the traditional test used for the identification of asymptomatic individuals in multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC). The identification of mutations in the RET proto-oncogene segregating with the disease phenotype in MEN 2A and FMTC families has made it possible to re-examine the validity of using this test for the identification of affected family members. DESIGN Sequential and single pentagastrin stimulation test data were collected following the identification of RET mutation positive and RET mutation negative members of families with MEN 2A or FMTC. PATIENTS RET mutations were identified in 16 Australian and New Zealand MEN 2A or FMTC families. An analysis of 39 individuals from these families was included in this study. Thirty-two individuals (14 males, 18 females) had previously been determined as RET mutation negative. Seven individuals (6 males, 1 female) had previously been determined as RET mutation positive. Two RET mutation negative males had thyroidectomy based on prior pentagastrin test results. MEASUREMENTS Serum calcitonin levels in response to stimulation with pentagastrin were measured at 0, 1, 2, 5 and 10 minutes post injection. Mutation analysis of the RET proto-oncogene was performed in all individuals. In two RET mutation negative individuals from two MEN 2A families, thyroidectomy was performed and C-cells were quantitated in order to determine the diagnosis of C-cell hyperplasia. RESULTS There was a statistically significant difference (P < 0.013) between RET mutation negative male and female mean peak calcitonin responses of 282 ± 236 and 96 ± 62 (mean ±SD) ng/l respectively. False positive responses to pentagastrin stimulation were identified in seven individuals who were RET mutation negative in two of the 16 families. Histologic examination of the thyroid glands in the two RET mutation negative individuals who had thyroidectomy demonstrated C-cell hyperplasia in one but not in the other. CONCLUSIONS There is considerable overlap between pentagastrin test results in individuals who are RET mutation positive and those who are RET mutation negative. These results indicate a need for routine performance of RET proto-oncogene analysis on all individuals at risk of developing MEN 2A or FMTC and a coupling of pentagastrin test results and RET proto-oncogene analysis in the decision to proceed with thyroidectomy.  相似文献   

3.
15个多发性内分泌腺瘤2A型家系的临床和RET基因突变研究   总被引:1,自引:1,他引:0  
Zhou YL  Zhu SX  Li JJ  Liu JB  Yin M  Xiao BY  Yu CL  Wang LM  Gu LQ  Cui B  Ning G  Li XY  Zhao YJ 《中华内科杂志》2007,46(6):466-470
目的 研究15例多发性内分泌腺瘤2A型(MEN2A)先证者及其家系成员的临床表型和RET原癌基因突变情况。方法 收集15例MEN2A先证者家系的共119名家系成员,提取其外周血基因组DNA,分别对RET原癌基因第8、10、11、13、14、15、16外显子进行PCR产物直接测序。结果 在15个MEN2A家系中,共有49例检出RET原癌基因突变。其中37例有MEN2A临床表型,另12例为基因携带者,前者诊断MEN2A的年龄显著晚于后者[(43.0±13.9)岁比(9.8±7.4)岁,P〈0.01];37例MEN2A患者中甲状腺髓样癌(MTC)、嗜铬细胞瘤(PCC)和甲状旁腺增生或腺瘤(HPT)的发生率分别为91.9%,56.8%和10.8%;在15个MEN2A家系中,共检出5种基因突变类型,均位于RET原癌基因第11外显子634位点,分别为:C634W(13.3%),C634Y(46.7%),C634R(26.7%),C634F(6.7%),C634S(6.7%)。结论 15个MEN2A家系中,37例有临床表型的MEN2A患者平均确诊年龄高于国外相关报道;MEN2A患者MTC和PCC的发病率和国外文献报道的基本一致,而HPT则较低;所有MEN2A患者的RET原癌基因突变均位于634位点,较国外文献报道的单一。  相似文献   

4.
Abstract. One hundred and ninety-seven members of 28 kindreds with multiple endocrine neoplasia type 2A (MEN 2A) were screened for RET proto-oncogene exon 10 and 11 mutations. Seventy-one known affected individuals had mutations of codons 609, 618, 620 or 634, whereas 53 unaffected individuals had no abnormalities. Nineteen out of 54 individuals of unknown status, mostly children, had RET mutations. Four of these children had thyroidectomy based on this analysis and were found to have C-cell abnormalities. We identified one false negative mutation analysis because of a codon 691 polymorphism. We conclude that RET mutational analysis is a cost-effective and accurate method for determination of gene carrier status in MEN 2A.  相似文献   

5.
OBJECTIVE: Both multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are caused by germline mutations of the RET proto-oncogene. A broad spectrum of malignancy within and between families has been described with no clear genotype-phenotype correlation due to a scarcity of available data of large kindreds. DESIGN: Here we present the only known family with a germline mutation of codon 611 TGC to TTC (exon 10) in the RET proto-oncogene leading to a replacement of cysteine by phenylalanine (Cys611Phe or C611F). RESULTS: Twenty family members of this large kindred are gene carriers (GCs) and seven (5-13 years old) are potential carriers but have yet to be analysed. The clinical course of medullary thyroid carcinoma (MTC) in this family is characterized by a very slow evolution and progression of the tumour with no MTC-related death to date. Of 11 patients (30-69 years old) having undergone thyroidectomy six were classified as pT1, four as pT2 and one as C-cell hyperplasia according to the TNM system of the International Union Against Cancer. Due to cervical and mediastinal lymph node metastasis one patient (44 years old) had to be operated on a second time. The seven non-operated GCs of the fourth and fifth generation (17-26 years old) are yearly monitored with pentagastrin stimulation tests; one non-operated GC (43 years old) has refused any further investigations. Screening for primary hyperparathyroidism and phaeochromocytoma was negative in all cases. CONCLUSION: We suggest from these experiences that the general advice for thyroidectomy in early childhood should be modified in certain families, depending on genotype.  相似文献   

6.
目的 探讨一个多发性内分泌腺瘤病2A型(MEN2A)家系的临床表现和RET原癌基因突变方式.方法 对一个MEN2A家系成员进行临床调查,提取其中3例具有典型临床表现的患者及15个家庭成员的外周血淋巴细胞DNA,对RET原癌基因的第8、10、11、13~16外显子进行DNA测序分析,并对发现突变的PCR产物进行亚克隆测序.结果 该家系先证者系30岁起先后确诊为嗜铬细胞瘤和甲状腺髓样癌的男性,其一姐患有嗜铬细胞瘤、一弟患有甲状腺髓样癌.在这3例患者及另外2例未发病的家庭成员中,发现了RET原癌基因第11号外显子存在相同的杂合突变,即1893-1895delCGA,系一种新的突变类型.结论 RET原癌基因第11号外显子1893-1895delCGA杂合突变,是一种新突变,可能为该MEN2A家系的致病基因.  相似文献   

7.
甲状腺髓样癌患者RET原癌基因突变的研究   总被引:5,自引:3,他引:5  
目的研究甲状腺髓样癌(MTC)的RET原癌基因突变情况。方法从12例病理诊断的MTC患者和2例临床上怀疑MTC患者提取外周血基因组DNA,对RET原癌基因第10、11、16外显子进行PCR产物直接测序。结果发现8例患者存在基因突变。1例是第10外显子618密码子TGC/CGC突变;2例是第11外显子634密码子TGC/TAC突变;3例是634密码子TGC/CGC突变;2例是第16外显子918密码子ATG/ACG突变。结论直接基因测序分析能在基因水平诊断MTC,分子遗传学分析使术前诊断该疾病成为可能。  相似文献   

8.
Cancers connected with mutations in RET proto-oncogene   总被引:3,自引:0,他引:3  
Altanerová V 《Neoplasma》2001,48(5):325-331
Germline mutations of RET proto-oncogene are connected with inherited cancer syndrome multiple endocrine neoplasia type 2. The syndrome is characterized by incidence of medullary thyroid carcinoma frequently associated with pheochromocytoma and hyperparathyroidism. Genetic testing of family members at risk significantly contributed to diagnosis and management of MEN 2. Early genetic screening for RET mutations allow to detect people who have inherited the MEN2 specific RET mutation with subsequent possibility to of prophylactic thyroidectomy. On the other hand those family members at risk of MEN 2 who had not inherited the mutation do not require further testing. The involvement of RET proto-oncogene in tumorigenesis is reviewed.  相似文献   

9.
Yao B  Liu X  Chen X  Dong TT  Liang H  Weng JP 《中华内科杂志》2007,46(11):914-918
目的 检测两个2A型多发性内分泌腺瘤(MEN2A)家系中RET原癌基因突变情况,初步探讨两个家系发病的分子机制及了解五肽胃泌素激发试验在MEN2A诊疗中的意义。方法 提取两个MEN2A家系共6名成员外周血基因组DNA,对RET原癌基因21个外显子进行PCR,PCR产物进行直接测序,对4例患者测定血降钙素并行五肽胃泌素激发试验。结果 两个家系中各有2例患者分别携带RET原癌基因外显子11的C634R突变和C634Y突变。初诊及复发的MEN2A患者血清降钙素明显升高(400.5~13 510.7ng/L,正常值16.6~132.8ng/L),五肽胃泌素激发后升高更显著(494.1~33 901.9ng/L)。结论 本研究中临床诊断为MEN2A的家系存在RET原癌基因外显子11的C634位点突变。血降钙素水平及五肽胃泌素激发试验有助于临床诊断和疗效随访。  相似文献   

10.
目的 检测一个多发性内分泌腺瘤病(MEN)2A型家系中RET原癌基因的突变情况.方法 观察一个MEN2A家系成员的表型,并对与MEN相关的且点突变率较高的RET原癌基因第10和11外显子进行PCR产物直接DNA测序以了解其杂合性.结果 家系中4名家族成员均存在RET原癌基因第11外显子Cys(TGC)634Arg(CGC)错义突变和Gly(GGT)691Ser(AGT)的单核苷酸多态性,另有1名成员仅存在RET原癌基因Gly(GGT)691Set(AGT)的单核苷酸多态性.经B超检查发现其中2名成员双侧甲状腺及一侧肾上腺和一侧甲状旁腺有实性占位病变,1名成员双侧甲状腺及一侧肾上腺有实性占位病变,1名成员双侧甲状腺、双侧肾上腺和一侧甲状旁腺有实性占位病变,1名成员仅有甲状腺多发性小结节.另外有3名成员B超检查有异常,但无基因突变.结论 对MEN2A家系的基因分析证实RET原癌基因第11外显子634位密码子存在突变和(或)691位密码子存在单核苷酸多态性,对MEN2A能在基因水平作出诊断.  相似文献   

11.
OBJECTIVE: Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are genetic diseases due to activating mutations of the RET proto-oncogene. Affected patients develop medullary thyroid carcinoma (100%), in an isolated form (FMTC) or in association with phaeochromocytoma (30-50%), and primary hyperparathyroidism (10-20%) (MEN 2A). The presence of cutaneous lichen amyloidosis (CLA) has been anecdotally described in few families harbouring RET proto-oncogene mutation in codon 634. The aim of the study was to evaluate the incidence of CLA in MEN 2A/FMTC families. PATIENTS AND DESIGN: Ten MEN 2A/FMTC families were studied and RET gene mutations identified in all. Complete dermatological assessment was carried out in each family member. Skin biopsy for histological studies was performed in patients with CLA. RESULTS: Among 10 MEN 2A/FMTC families, the presence of CLA was found only in patients belonging to the three families with MEN 2A and RET mutation in codon 634. Nine of 25 patients (36%) with codon 634 mutation presented CLA, though two of them did not show CLA skin lesions but the typical neurological pruritus in the upper back. In all patients, neurological pruritus was present since infancy as a precocious marker of the disorder. The dermatological study of patients with CLA skin lesions added further evidence that pruritus has a pivotal role in the development of CLA, the amyloid deposition being the consequence of repeated scratching. Light microscopy revealed orthokeratotic hyperkeratosis, with elongation of the rete ridges, rare intramalpighian apoptic keratinocytes and deposits of amorphous material in the superficial dermis. Examination under ultraviolet light showed thioflavin T-positive staining, confirming the presence of amyloid in the papillary dermis. The use of Capsaicin at the dilution of 0.025% had a mild efficacy on the cutaneous symptoms. CONCLUSIONS: Among the members of the three families with MEN 2A and RET 634 mutation, the incidence of CLA was 36%, a figure similar to that reported in the literature for phaeochromocytoma (30-50%) and even higher than that for hyperparathyroidism (10-20%). The present data confirm that CLA is linked to codon 634 RET mutations and is a precocious marker of the disorder.  相似文献   

12.
OBJECTIVE AND DESIGN: Genetic screening in multiple endocrine neoplasia type 2 (MEN 2) has led to specific management guidelines based on genotype-phenotype analysis. However, there is controversy regarding the appropriate age for prophylactic thyroidectomy in families with mutations in codon 804 in exon 14 of the RET proto-oncogene, where medullary thyroid cancer (MTC) may not develop until adulthood. We prospectively studied two MEN 2A families, one with the V804L and the other with the V804M RET mutation, to report our experience of genetic and biochemical screening and prophylactic thyroidectomy. Family 1 is one of the largest MEN 2A families in the literature, where 22 prophylactic thyroidectomies have been performed. PATIENTS AND RESULTS: C-cell hyperplasia (CCH) was found in 23 out of 25 thyroidectomy specimens from family members of ages 5 years and upwards. MTC was found in 10 out of 18 adults of age 25 years upwards, including the family 2 proband, who was found to have MTC with lymph node metastases at age 28. Phaeochromocytoma was only observed in one patient, but six cases of histologically confirmed hyperparathyroidism were seen in family 1. CONCLUSION: We suggest that prophylactic thyroidectomy should not be delayed until adulthood in MEN 2A families carrying codon 804 RET mutations, but should be performed when there is CCH, before the development of MTC, as close as possible to age 6 years, which is the age of the youngest reported case of MTC in '804' families.  相似文献   

13.
Abstract. The RET proto-oncogene, a receptor tyrosine kinase, has been evaluated as a candidate gene for multiple endocrine neoplasia type 2A and type 2B (MEN 2A and MEN 2B), for familial medullary thyroid carcinoma (FMTC), and for sporadic cases of medullary thyroid carcinoma (MTC) and pheochromocytomas. We determined the genomic structure of RET and used single-strand conformational polymorphism (SSCP) analysis to identify sequence variants in genomic DNA from families segregating MEN 2 and FMTC. In addition, we examined paired tumour and lymphocyte genomic DNAs from individuals with sporadic cases of MTC and pheochromocytoma. Altogether, we and others found 21 missense mutations in five cysteines clustered in the extra cellular domain of RET (exons 10 and 11) associated with 111 MEN 2 A and FMTC families. In contrast, a single point mutation that results in the substitution of threonine for methionine within the catalytic core of the tyrosine kinase domain (codon 918, exon 16) is responsible for all 66 reported cases of MEN 2B. Two missense mutations and a six base-pair deletion were identified in MTC tumour DNA, but no mutations were identified from pheochromocytoma tumour DNAs. A predictive DNA test for MEN 2A-associated mutations in RET has been developed that is based on detection of missense mutations by polymerase chain reaction (PCR) amplification and restriction endonuclease cleavage. A dominant oncogene model for the action of the RET gene product is proposed as a mechanism of action in MEN 2A, MEN 2B, FMTC and for at least some cases of sporadic MTC.  相似文献   

14.
15.
16.
Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung's disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and the extent of surgery are based upon a model that utilizes genotype- phenotype correlations to stratify mutations into three risk levels.  相似文献   

17.
Germline mutations in specific hot spot-codons of the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (MEN 2). Clinical RET gene testing has been routine for the last 10 years in some countries. In Argentina, RET testing excluding MEN 2B was always reported with a mutation at codon 634, with one exception: we described a novel mutation T > C transition at codon 630 (C630R), the family to which we extend the study in the present report. This family comprised 29 members in four generations including 6 individuals affected with medullary thyroid cancer (MTC), positive for the C630R mutation and normal adrenaline/ noradrenaline and ionized calcium/parathyroid hormone levels. Two asymptomatic mutation carriers aged 5 and 11 years underwent total thyroidectomy. The histopathologic examination showed C-cell hyperplasia and microcarcinoma foci, while preoperative basal calcitonins were normal for both. Our report emphasizes the importance of testing for non-hot spot RET mutations in apparently mutation negative MEN 2 families. Furthermore, it would appear that C630R mirrors C634R in penetrance (100% in this family) and in early age of onset of MTC, although paradoxically, no pheochromocytomas and hyperparathyroidism have developed. In addition to recommending RET testing before 5 years of age; we also can postulate that codon 630 may be the key point along the extracellular domain, important in the tissue-specific penetrance.  相似文献   

18.
Multiple endocrine neoplasia type 28 (MEN 28) is a rare cancer syndrome which is inherited in an autosomal dominant manner. The molecular basis of this condition has recently been defined as a mutation of codon 918 of exon 16 of the RET proto-oncogene. The mutation in codon 918 has been described in 69 out of 72 families with MEN 28. We have studied a brother and sister who undoubtedly have the features of MEN 28 as evidenced by medullary thyroid carcinoma, phaeochromocytoma, mucosal neuromas and skeletal abnormalities. Neither of these patients has the classic gene mutation at codon 918 of exon 16 of the RET proto-oncogene, and although exons 2–20 have also been sequenced, no abnormality has been found DNA analysis is a sensitive method of screening families for the MEN 2 syndromes. The absence of the mutation at codon 918 in a phenotypically normal individual would refute the diagnosis of MEN 28, but in an individual with some of the features of MEN 28 would make the clinician reconsider the diagnosis. This family demonstrates that, although it is rare, the absence of the mutation in codon 918 of exon 16 of the RET proto-oncogene does not always exclude the diagnosis of MEN 28. In such families routine biochemical screening for medullary thyroid carcinoma and phaeochromocytoma must be maintained for all individuals at genetic risk.  相似文献   

19.
Identification of the germline mutation in the RET proto-oncogene is important for the diagnosis of hereditary medullary thyroid carcinoma (MTC). Hereditary forms account for approximately 25%-30% of all cases of MTC. The objective of this study was to evaluate the prevalence of the RET mutation and the genotype-phenotype relation in Korean patients with MTC. Genomic DNAs were obtained from 33 patients with MTC (M:F = 10:23, 39.8 +/- 12.0 years) who underwent total thyroidectomy between 1997 and 2003 at the Samsung Medical Center. Exons 10, 11, 13, 14, 15 and 16 of the RET proto-oncogene were amplified with specific primers using polymerase chain reaction (PCR). Sequence analysis was performed on the polymerase chain reaction (PCR) product using an automatic sequence analyzer. Nine of the 33 patients (M:F = 3:6, 33.3 +/- 10.0 years) were identified as having RET mutations. Six patients had multiple endocrine neoplasia (MEN) 2A and one had familial medullary thyroid carcinoma (FMTC). The remaining two patients were thought to have sporadic MTC. Five of the patients with MEN 2A had RET mutations in codon 634 of exon 11 (3 patients, C634Y; 2 patients, C634R) and the other patient with MEN 2A had a RET mutation in codon 618 of exon 10 (C618R). The patient with FMTC had a mutation in codon 634 (C634W). The two patients with sporadic MTC had RET mutations in codon 634 (1 patient, C634Y; 1 patient, C634S). We were not able to identify any genotype-phenotype relations because of the limited number of patients. Twenty-seven percent (9/33) of the patients with MTC in this study had RET mutations. Taking other studies into account, 77% (10/13) of Korean families with MEN 2A, including 7 other families in three reports from Korea, had RET mutations in codon 634 (5 families, C634Y; 4 families, C634R; 1 family, C634W), and 23% (3/13) had RET mutations in codon 618 (2 families, C618R; 1 family, C618S). RET proto-oncogene mutations were restricted to codon 634 and 618 in Korean families with MEN 2A.  相似文献   

20.
INTRODUCTION: Calcitonin measurement is advised in the diagnosis of thyroid nodules, as it is an accurate marker of medullary thyroid carcinoma (MTC). C-cell hyperplasia (CCH)-induced hypercalcitoninemia cannot be distinguished from that induced by MTC, unless surgery is performed. CASE: We report the clinical and biological features of a patient with a family history of cancer, including melanoma and pancreatic cancer, who had previously undergone surgery for melanoma. He presented the unusual association of papillary thyroid carcinoma (PTC), normocalcemic hyperparathyroidism, and hypercalcitoninemia with a pathological response to pentagastrin, which was histologically deemed secondary to CCH. Multiple endocrine neoplasia (MEN) 2A was diagnosed. RET gene analysis showed a p.V804M missense mutation in exon 14, a low- but variably penetrant defect found in both sporadic and MEN2A-associated MTC/CCH, and a p.G691S polymorphism in exon 11. Furthermore, the germline P48T mutation was found in the CDKN2A gene exon 1, which is known to be associated with melanoma and pancreatic cancer. The patient showed the uncommon coexistence of a germline mutation in two suppressor genes, RET and CDKN2A; this finding, deemed to be a mere coincidence, did not modify the phenotype expected by each single mutation. CCH associated with V804M RET mutation is a precancerous condition and surgery is recommended. In order to exclude MTC, surgery is advised in patients with a pathological calcitonin response to pentagastrin, in the absence of thyroid autoimmunity. CCH-induced hypercalcitoninemia can be associated with thyroid cancers other than MTC (e.g., PTC). Family history is important in scheduling specific genetic screening in high-risk patients and their relatives.  相似文献   

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