Sporadic endocrine tumours and their relationship to the hereditary endocrine neoplasia syndromes

In the last years of the previous century the genes involved in the aetiology of five endocrine tumour syndromes have been identified. The tumour-suppressor gene that is responsible for Von Hippel-Lindau Disease was cloned in 1993; multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma were found to be caused by activating mutations in the ret proto-oncogene in 1993 and 1994, and most recently the menin-gene, another tumour-suppressor gene, was shown to be associated with MEN-1. As usual, the answer to one question leads to innumerable new questions. And so, now we want to know the extent to which germ-line mutations (de novo, or otherwise previously undetected) in these genes play a role in the occurrence of the various endocrine tumours that are associated with these syndromes in apparently sporadic cases. We also want to know if the nature of the (germ-line) mutation conveys any information about the characteristics (phenotype) of the disease. We want to know the role of somatic mutations in these genes in truly sporadic tumours. And finally we want to know the exact function of the proteins that are encoded by these genes. The paper by Roijers et al. [1] elsewhere in this issue is an example of a small but well-directed step on the way to address some of these questions with respect to the menin-gene. It addresses the problem of patient selection when looking for germ-line mutations in apparently sporadic MEN-1 patients. In this review we want to give a brief summary of the present status with regard to some of the questions mentioned above, in relation to the endocrine tumour syndromes caused by the vhl, ret and menin genes.     

Lack of MEN1 gene mutations in 27 sporadic insulinomas

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant familial cancer syndrome characterized by tumours of the parathyroids, anterior pituitary gland and endocrine pancreas. Since the cloning of the MEN1 gene (encoding menin) on chromosome 11q13 by Chandrasekharappa et al. in 1997, it has become possible to identify mutations that are responsible. We examined whether MEN1 gene mutations are present in sporadic insulinomas, a rare sporadic tumour that is seen more frequently in patients with the MEN 1 syndrome. PATIENTS AND METHODS: We sequenced the coding part of the MEN1 gene (exons 2-10) in tumour tissue of 27 patients suffering from an insulinoma (24 benign, three malignant). To validate our methods we also examined tumour tissue from five patients with primary hyperparathyroidism (HPT) at a younger age and/or multiple gland disease, with increased risk of MEN 1. RESULTS: We found no mutations in the nine coding exons of the MEN1 gene in the insulinoma tissues. We could confirm three benign polymorphisms (S145S, R171Q, D418D) reported previously. In the control patients we found two new point mutations (one mis-sense, one non-sense mutation) and one deletion. CONCLUSION: Mutations of the MEN1 gene do not play an important role in the pathogenesis of sporadic insulinomas. Therefore genetic screening is not cost effective in sporadic insulinoma patients without other indicators of MEN 1. Patients with primary HPT at a younger age and/or multiple gland disease should be screened for MEN1 gene mutations.     

Multiple endocrine neoplasia type 1 (MEN1) in Austria

Multiple endocrine neoplasia type 1 (MEN1) is a rare cancer predisposition syndrome. It results from the autosomal dominant inheritance of inactivating germ-line mutations of the MEN1 tumor suppressor gene. Mutation carriers are prone to develop tumors, preferentially, of the parathyroid and anterior pituitary glands as well as the enteropancreatic endocrine tissues. Because such tumors also occur without the MEN1 context, we have set up a molecular genetic screening program in Austria to discriminate between heritable and non-heritable tumor forms. Following the recognition of a MEN1-specific germ-line mutation in a tumor patient, we extend the screening to all first-degree relatives. To date, we have studied 42 individuals by sequencing the coding exons 2 to 10 of the MEN1 gene. A germ-line mutation was discovered in four of seven families suspected, clinically, to have MEN1, and in 3 of 22 (13.6%) patients with a presumed sporadic endocrine tumor. The respective mutations were also detected in three first-degree relatives of whom only one 6-year-old boy was asymptomatic at the time of investigation. The possibility to clearly discriminate between genetically predisposed and non-predisposed individuals has a significant impact on the diagnosis and clinical management of both patients and their relatives. Both symptomatic and asymptomatic mutation carriers can be closely monitored, thereby allowing early recognition and treatment of developing tumors. Non-affected relatives, on the other hand, do not require further controls. Finally, this approach also provides the information necessary for reliable genetic counseling.     

Metastatic insulinoma presenting after bariatric surgery in a patient diagnosed with MEN1

Insulinomas are uncommon neuroendocrine tumors and metastatic disease is extremely rare. We report a patient with metastatic insulinoma associated with multiple endocrine neoplasia type 1 presenting with hypoglycemia following sleeve gastrectomy. Potential causes of hypoglycemia include dumping syndrome, noninsulinoma pancreatogenous hypoglycemia syndrome, and rarely insulinoma. MEN1‐associated insulinomas have a higher recurrence rate.     

多发性内分泌腺瘤病2A型(MEN2A)中嗜铬细胞瘤的临床特点及治疗

目的 分析多发性内分泌腺瘤病2A型(MEN2A)家系中嗜铬细胞瘤患者的临床特点,并探讨其治疗方法 方法 收集3个MEN2A家系,共有8例MEN2A患者均患有嗜铬细胞瘤,分析这8例患者高血压特点、24 h尿VMA及肾上腺CT结果 、嗜铬细胞瘤患病情况及治疗方法 结果 8例MEN2A患者中7例有甲状腺髓样癌(87.5%),8例有嗜铬细胞瘤(100%),没有发现有HPT的发生,其中6例(75%)患者是以嗜铬细胞瘤起病,而且嗜铬细胞瘤中7例(87.5%)为双侧.8例患者中3例(37.5%)为持续性高血压,5例(62.5%)为阵发性发作高血压,6例(75%)24 h尿VMA升高,2例(25%)高血压发作时尿VMA/Cr比值明显升高.4例患者经腹腔镜切除肿瘤,4例经开腹手术切除肿瘤,随诊7例(87.5%)良性嗜铬细胞瘤患者术后随诊均未见肿瘤复发.结论本研究结果 提示MEN2A中嗜铬细胞瘤常为双侧,临床可表现为持续性高血压也常有阵发性高血压者,生化及影像学检查有助于诊断,RET基因的突1变检测能使MEN2A中嗜铬细胞瘤得到早期诊治,腹腔镜下手术是MEN2A中嗜铬细胞瘤治疗的理想方法     

多发性内分泌腺瘤病2A型家系临床特点分析及RET基因突变研究

目的检测互不相关的3个多发性内分泌腺瘤病2A型（MEN2A）家系中RET原癌基因突变情况，以探寻其发病的分子机制，同时总结其临床特点。方法收集3个MEN2A家系，共有8例MEN2A患者，3个家系有28位同意进行基因检测，提取28位外周血基因组DNA，对RET原癌基因21个外显子进行聚合酶链反应（PCR），PCR产物进行直接测序，对发现新的突变点进一步进行克隆测序。结果家系1RET原癌基因存在外显子11的C634R突变，家系2为C634Y突变，家系3的4例MEN2A患者均存在D631密码子（GAC）的杂合缺失，碱基序列由TGC∧GACGAGCTG变为TGCGAGCTG，导致代表天冬氨酸的D631的缺失，即del D631。8例MEN2A患者中7例有MTC（87．5％），8例有PCC（100％），未发现有HPT的发生，其中6例（75％）患者是以PCC起病，而且PCC中7例（87．5％）为双侧。结论本研究结果提示中国大陆MEN2A家系存在C634Y突变，也有exon11的D631杂合缺失突变，其中RET基因第11号外显子的D631缺失突变（delD631）是首例报道。D631 del临床特点为发病年龄较迟，肾上腺嗜铬细胞瘤可先于甲状腺髓样癌的发生。     

多发性内分泌腺瘤病2A型（MEN2A）中嗜铬细胞瘤的临床特点及治疗

目的分析多发性内分泌腺瘤病2A型（MEN2A）家系中嗜铬细胞瘤患者的临床特点,并探讨其治疗方法。方法收集3个MEN2A家系,共有8例MEN2A患者均患有嗜铬细胞瘤,分析这8例患者高血压特点、24h尿VMA及肾上腺CT结果、嗜铬细胞瘤患病情况及治疗方法。结果8例MEN2A患者中7例有甲状腺髓样癌（87．5％）,8例有嗜铬细胞瘤（100％）,没有发现有HPT的发生,其中6例（75％）患者是以嗜铬细胞瘤起病,而且嗜铬细胞瘤中7例（87．5％）为双侧。8例患者中3例（37．5％）为持续性高血压,5例（62．5％）为阵发性发作高血压,6例（75％）24h尿VMA升高,2例（25％）高血压发作时尿VMA／Cr比值明显升高。4例患者经腹腔镜切除肿瘤,4例经开腹手术切除肿瘤,随诊7例（87．5％）良性嗜铬细胞瘤患者术后随诊均未见肿瘤复发。结论本研究结果提示MEN2A中嗜铬细胞瘤常为双侧,临床可表现为持续性高血压也常有阵发性高血压者,生化及影像学检查有助于诊断,RET基因的突变检测能使MEN2A中嗜铬细胞瘤得到早期诊治,腹腔镜下手术是MEN2A中嗜铬细胞瘤治疗的理想方法。     

Rapid MEN 2A gene carrier identification using primer-specific PCR amplification

DNA testing is of great importance in families with multiple endocrine neoplasia (MEN) type 2A to identify non-mutant carrying family members and asymptomatic mutation carriers, and also to confirm the diagnosis in patients who already show clinical or biochemical signs of disease. Several point mutations of the RET proto-oncogene on exons 10 and 11 are associated with the disease, which is characterized by medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. The aim of the present study was to develop and evaluate a simple method, which indicates the mutational status of members of families where the site of the point mutation is known. The method is illustrated by the detection of mutation TGC-->TAC of codon 611, which is one of the well-known mutations associated with MEN 2A. The method involves the PCR technique with allele-specific primers and detection of the amplified sequences with biotinylated probes. There was a clear-cut difference between the readings from affected and unaffected subjects. The subjects had been evaluated independently and all subjects harboring the mutation also had clinical disease. The method provides a simple and reliable diagnostic tool for DNA screening of members of families with a known mutation of the RET-gene.     

血液灌流对氟乙酰胺的清除作用及TNF-α、IL-10水平的影响

目的探讨氟乙酰胺中毒对TNF-α、IL-10水平的影响及血液灌流对其清除作用。方法建立犬急性氟乙酰胺中毒模型，分为HP组和对照组，应用炭肾对HP组进行血液灌流（HP）2h，对照组只连接体外循环，对比分析两组在HP前、HP后不同时间点血浆中氟乙酰胺浓度及TNF-α、IL-10水平的动态变化。结果对照组和HP组在氟乙酰胺中毒后TNF-α、IL-10水平明显增高；HP组HP后血中氟乙酰胺浓度由（159．06±18．31）μg／ml，降至HP2h的（41．94±4．83）μg／ml，显著低于对照组（P〈0．01），HP后氟乙酰胺浓度逐渐降低；随着氟乙酰胺浓度的降低，IL-10水平也有下降趋势，但差异无统计学意义（P〉0．05）；TNF-α则在HP2h内逐渐下降，而HP后又轻微回升并维持在一定的水平，差异均无显著意义（P〉0．05）。结论氟乙酰胺中毒后可引起TNF-α、IL-10水平升高；HP可显著降低血中氟乙酰胺浓度；HP前后血清中TNF-α、IL-10的水平变化不明显。     

慢性阻塞性肺疾病和阻塞性睡眠呼吸暂停低通气综合征患者外周血单个核细胞TNF—α、IL-8mRNA表达的研究

目的分析慢性阻塞性肺疾病（COPD）、阻塞性睡眠呼吸暂停低通气综合征（OSAHS）及重叠综合征（overlap syndrome）患者单个核细胞TNF-α和IL-8mRNA表达的特点,从炎症反应方面探讨重叠综合征的发病机制。方法选取已确诊为COPD11例、OSAHS15例和重叠综合征4例各为一组,所有研究对象均行夜间多导睡眠图监测和肺功能检查,用半定量RT-PCR法检测外周血单个核细胞TNF-α、IL-8的mRNA水平。结果外周血单个核细胞在TNF-α的mRNA表达水平中,OSAHS组〈COPD组〈重叠组,差异均具有统计学意义（P均〈0．05）;在IL-8的mRNA表达水平中,COPD组和重叠组均高于OSAHS组,差异具有统计学意义（P均〈0．05）,而COPD组和重叠组之间无显著性差异（P〉0．05）。COPD患者单个核细胞TNF—αmRNA表达水平与第一秒用力呼气容积（FEVI／Pre％）呈负相关（r=-0．894,P〈0．01）,与低氧时间呈正相关（r=0．781,P〈0．01）;IL-8mRNA表达水平与FEVI／Pre％呈负相关（r=-0．859,P〈0．01）,与低氧时间呈正相关（r=0．862,P〈0．01）。OSAHS患者单个核细胞TNF-αmRNA表达水平与呼吸暂停和低通气指数（AHI）、低氧时间均呈正相关（r=0．833、0．742,P均〈0．01）;IL-8mRNA表达水平与AHI、低氧时间均呈正相关（r=0．825、0．882,P均〈0．01）。结论COPD患者和重叠综合征患者的IL-8和TNF-α的mRNA表达高于OSAHS患者,且IL-8和TNF-α的mRNA表达与FEVI／Pre％、AHI和低氧时间均有较好的相关性,提示炎症反应也可能在重叠综合征的发病机制和发展中起着较为重要的作用。     

Multiple endocrine neoplasia 1 (MEN 1)

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant familial cancer syndrome characterized by tumors in parathyroids, enteropancreatic endocrine tissues, and anterior pituitary. In 1997, the MEN 1 gene was identified and cloned. It is on chromosome 11q13 and has 10 exons. It encodes a 610 amino acid protein called MENIN. However, many different germline mutations in MEN 1 families have reported, there were no hotspot of mutation. The correlation between MEN 1 mutation and clinical datas has not been established yet. Recently, the possible function of MENIN protein has reported. The identification of MEN 1 mutation by employing DNA test, will facilitate early diagnosis and treatment.     

Multiple endocrine neoplasia type 2; MEN 2

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited disorder as an autosomal dominant trait, characterized by medullary thyroid carcinoma (MTC). MEN 2 is classified with associated diseases into three subtypes: MEN 2A, MEN 2B and familial MTC. It has recently been shown to be associated with germline mutation in the RET proto-oncogene. Genetic testing allows easily for accurate diagnosis of presymptomatic gene carriers and surgical treatment at an early stage of the disease. In this review we delivered the classification, clinical feature, mutation in RET, mutation analysis, and management of MEN 2, and we discuss recent progress of research on the molecular basis and how genetic testing could be used for clinical management of affected patients or individuals in at-risk families.     

多发性内分泌腺瘤1型的妊娠期管理：家系临床和基因分析并文献回顾

目的 探讨多发性内分泌腺瘤1型（MEN1）的妊娠期临床特点和管理策略。方法 收集1例MEN1先证者的性别、年龄、详细病史、临床症状、体征、实验室检查、影像学检查和病理学检查数据,并收集该MEN1家系中20名成员的人口学特征、临床特征和辅助检查。为回顾MEN1妊娠期病例,以“Multiple Endocrine Neoplasia Type 1”和“Pregnant”为关键词在PubMed搜索,以“多发性内分泌腺瘤病”和“妊娠”在万方数据知识服务平台搜索。结果 本例MEN1先证者以垂体微腺瘤（溢乳、催乳素升高）、胰腺内分泌肿瘤（低血糖）及甲状旁腺腺瘤（无症状、甲状旁腺素和血钙升高）为主要临床表现。基因分析证实MEN1基因9号外显子（CGA>TGA,Arg415Term）突变为先证者致病基因。先证者的父亲和女儿携带该致病基因并有甲状旁腺功能亢进。先证者在药物治疗垂体微腺瘤和手术治疗胰腺内分泌肿瘤、甲状旁腺腺瘤后顺利妊娠并成功分娩1名女婴,其间无再次出现溢乳和低血糖发作,血PTH和血钙水平稳定,胎儿生长发育正常。共检索到相关英文病例报道7例,中文病例1例。总结既往文献报道的8例MEN1妊娠期病例,所有MEN1患者均于育龄期起病。甲状旁腺、胰腺和垂体是最常出现临床症状的内分泌腺体,多数患者存在家族史和相应的MEN1基因突变,其中7例患者在严密病情监测和治疗下成功分娩。结论 临床医师对妊娠期MEN1患者的积极检测和诊疗,将有助于改善MEN1患者及其子代的预后。     

肾上腺皮质肿瘤与MEN1基因的相关性研究

目的 从分子水平上揭爪散发性肾上腺皮质肿瘤的发病与MEN1基因突变的相互关系,为今后开展症状前诊断和产前基因诊断创造前提条件.方法 在对先证者进行临床诊断的基础上,用微量快提法制备模板DNA,用自行设计的9对引物对先证者MEN1基因的所有编码区以及外显子与内含子的交界部位进行PCR扩增和DNA序列分析.结果 先证者MEN1基因第4内含子存在隐蔽性拼接位点ⅣS4as（-9）G〉A的杂合突变,而正常对照无此突变.结论 所用检测方法快速简便、微量经济,可用于肾上腺皮质肿瘤的快速确诊.所发现的MEN1基因的ⅣS4 as（-9）G〉A隐蔽性拼接位点突变为国内首报的病理性突变.     

The RET gene in multiple endocrine neoplasia type 2 (MEN 2)

Multiple endocrine neoplasia types 2A and 2B(MEN 2A and MEN 2B), and familial medullary thyroid carcinoma(FMTC) are autosomal, dominantly inherited syndromes involving endocrine tumors. MEN 2A is characterized by medullary thyroid carcinoma(MTC), pheochromocytoma(pheo), and parathyroid hyperplasia; MEN 2B is characterized by MTC, pheo, mucosal ganglioneuroma, and marfanoid habitus. Affected individuals in FMTC families develop MTC without any other abnormalities. MEN 2A and MEN 2B and FMTC are caused by germline mutations in the RET proto-oncogene. To investigate the spectrum of RET mutations among Japanese patients, we analyzed the RET gene 118 patients with MEN 2 or FMTC.     

Early diagnosis of the multiple endocrine neoplasia type 2 syndrome: consensus statement

The diagnosis of medullary thyroid carcinoma by biochemical and genetic testing is possible in families with multiple endocrine neoplasia type 2. At an early stage total thyroidectomy usually cures the patient. As the clinical penetrance of the autosomal dominant, transmitted, multiple endocrine neoplasia type 2 gene is not complete, family screening is indicated for every new patient who presents with apparently sporadic medullary thyroid carcinoma. Problems related to a screening programme and early diagnosis have led the members of the European Community Concerted Action: Medullary Thyroid Carcinoma group to formulate a consensus on biochemical and genetic screening. For biochemical screening, measurement of basal and pentagastrin and/or calcium stimulated serum levels of calcitonin by radioimmunoassay are essential starting at the age of three and continuing annually until 35 years of age. Furthermore, annual screening for pheochromocytoma by measuring the urinary excretion of catecholamines and for hyperparathyroidism by serum calcium determination is indicated. Genetic screening using linked markers can be done with a 95% accuracy in informative families when DNA is available from at least two family members proven to be affected. Biochemical screening can thus be reserved for gene carriers, while those at low risk can be reassured. Combined biochemical and genetic screening for multiple endocrine neoplasia type 2 is important and effective for the cure of medullary thyroid carcinoma.     

Role of positron emission tomography imaging in Multiple Endocrine Neoplasia syndromes

The aim of this review was to summarize the recent developments on the role of positron emission tomography (PET) imaging using different radiopharmaceuticals in patients with multiple endocrine neoplasia (MEN) syndromes. Although most guidelines do not mention the use of PET imaging in patients with MEN syndromes, recent data seem to suggest a relevant diagnostic role of PET imaging in this setting. In particular, latest evidence has shown that somatostatin receptor PET provides a diagnostic accuracy in detecting MEN syndromes‐related neuroendocrine tumours (NETs) higher than that of somatostatin receptor scintigraphy, thus influencing patient management in a significant percentage of cases. ¹⁸F‐DOPA PET seems to have a potential role in detecting MEN‐2‐related NETs, whereas ¹⁸F‐FDG PET is potentially useful in identifying aggressive NETs with poorer outcomes. More studies are needed to better define the role of different radiotracer‐based PET imaging in patients with MEN syndromes.     

Composite paraganglioma‐ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2B: A case report

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal‐dominant cancer syndrome with major components of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. MEN2B is the most aggressive and rarest of the MEN2 variants. Pheochromocytoma in MEN2 is virtually always located in the adrenal medulla, but MEN2‐associated extra‐adrenal pheochromocytomas (paraganglioma) are rare. A 59‐year‐old man who has been diagnosed with MEN2B consulted our hospital for surgical treatment of a 10‐mm left adrenal mass and a 30‐mm retroperitoneal mass. He had paroxysmal elevations in blood pressure and in urinary metanephrine and vanillylmandelic acid values. Laparoscopic excision of the left adrenal gland and retroperitoneal mass was performed. We experienced an extremely rare case of composite paraganglioma‐ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with MEN2B.     

Intrathyroidal parathyroid carcinoma mimicking a thyroid nodule in a MEN type 1 patient

A 59‐year‐old woman with classic manifestations of hyperparathyroidism associated with multiple endocrine neoplasia type 1 presented with a right adrenal mass and two pituitary microadenomas on imaging studies. For evaluation of hypercalcemia, ^99mTc‐MIBI scintigraphy was done and showed focal uptake at the thyroid level of the right anterior neck. Subsequent neck sonography showed several thyroid nodules, but there was no parathyroid tumor. Percutaneous fine‐needle aspiration of the dominant thyroid nodule indicated a follicular nodule. After surgery, final histopathology revealed intrathyroidal parathyroid carcinoma. This case illustrates the difficulty in diagnosing parathyroid carcinoma via fine‐needle aspiration. © 2013 Wiley Periodicals, Inc. J Clin Ultrasound 42:212–214, 2014     

Novel SDHD germ-line mutations in pheochromocytoma patients

BACKGROUND: SDHD germ-line mutations predispose to pheochromocytoma (PCC) and paraganglioma (PGL). MATERIAL AND METHODS: The incidence and types of SDHD germ-line mutations are determined in 70 patients with apparently sporadic adrenal and extra-adrenal PCC. RESULTS: SDHD sequence variants were identified in the germ line of five patients. Two of three novel mutations were in exon 1 and one in exon 3. One patient had a codon 1 missense mutation (M1K) and a concurrent 3-bp deletion in intron 1. Three of 10 family members had only the exon 1 mutation, whereas one had only the intron 1 mutation. The other exon 1 mutation resulted from a deletion of nucleotides 28-33 with a 12-bp in-frame insertion (c.28_33 del ins TAGGAGGCCCTA). This mutation generated a premature stop codon after codon 9 and was also present in the brother who had a bilateral PCC. The third patient with a carotid body tumour, with an abdominal and a thoracic PGL had a 12-bp deletion in exon 3 (codons 91-94, c.271_282 del). Her father carried the same mutation and had bilateral carotid body tumours. Two further patients, one with six PGL, carried a previously described H50R polymorphism, whose disease-specific relevance is currently unclear. The three patients with bona fide SDHD mutations were younger than those without germ-line mutations. CONCLUSION: SDHD germ-line mutations are rare in patients with PCC, but their identification is an important prerequisite for the clinical care and appropriate management of affected individuals and their families.