Screening for multiple endocrine neoplasia type I

Background Multiple endocrine neoplasia type I (MEN I) is a familial condition inherited in autosomal dominant manner, characterized by primary hyperparathyroidism (multiple gland hyperplasia 95%), pancreatic islet cell tumours (65%) and pituitary adenomata (prolactinoma 5%). Screening of family members permits the identification of affected relatives and allows early treatment of the condition before the onset of complications. Methods We have employed a new sensitive immunochemiluminometric assay (ICMA) specific for intact parathyroid hormone together with measurement of serum calcium and prolactin to screen 102 relatives of patients with proven MEN (11 families) and 25 relatives of patients with non-MEN I familial hyperparathyroidism or multiple parathyroid gland hyperplasia. Results 7 MEN I relatives with abnormal biochemical results had significant clinical symptoms (renal calculi 3, duodenal ulcer 3, secondary amenorrhea 1). 15 MEN I relatives had clinical or biochemical evidence of MEN I syndrome. Conclusion We conclude that biochemical screening of MEN I kindred is worthwhile and the intact parathormone assay (ICMA) may increase diagnostic sensitivity.      

Multiple endocrine neoplasia type 1 with pyonephrosis.

A case of multiple endocrine neoplasia type 1 (MEN 1) with a clinical manifestation of pyonephrosis is reported. A 47-year-old woman with a 14-year history of renal stones was initially seen with pyonephrosis. The patient was found to have elevated serum levels of parathyroid hormone and growth hormone. Radiologic examinations demonstrated an ectopic parathyroid tumor and a pituitary tumor. She was diagnosed as having MEN 1.     

Unusual multiple endocrine neoplasia

An unusual case of multiple endocrine neoplasia (MEN) is reported. A 64‐year old male was found on investigation to have neoplastic lesions involving thyroid, parathyroid, pituitary and adrenal glands. The adrenal neoplasm shared features of a biochemically silent phaeochromocytoma and an oestrogen‐secreting cortical tumour. This association in the same neoplastic mass has not previously been described in conjunction with MEN syndrome.      

Multiple carcinoids of the duodenum accompanied by type I familial multiple endocrine neoplasia

2 lymph node dissection was performed. The macroscopic findings of the resected specimen showed multiple polypoid lesions with delles on the top, measuring 3 to 15 mm in size throughout the duodenum. A microscopic examination revealed the tumor to have infiltrated into the submucosa extensively, and an immunohistochemical analysis also demonstrated the tumor cells to be positive for somatostatin, but not for pancreatic polypeptide. After surgery, the serum level of somatostatin returned to normal but the pancreatic polypeptide remained high. The post-operative course was uneventful, and the patient remains in good health. (Received for publication on Dec. 24, 1996; accepted on July 8, 1997)     

Resected invasive thymoma with multiple endocrine neoplasia type 1

We report a rare case of multiple endocrine neoplasia (MEN) type 1 with thymoma. A 57-year-old woman with a chronic duodenal ulcer and hypoglycemia had been seen at a nearby clinic. Abdominal echogram revealed two nodules in the pancreas and she was referred to our hospital for evaluation. Her diagnosis was MEN type 1, gastrinoma and hyperparathyroidism with anterior mediastinal tumor. There were high calcium levels in the blood and urine. Gastrin was quite high. A chest X-ray revealed a retrosternal tumor. Computed tomography revealed an anterior mediastinal tumor without sign of invasion to the surrounding organs, and two small masses in the pancreas. Cervical echogram revealed a few masses in both sides behind the thyroid. From these findings, her preoperative diagnosis was MEN type 1 with thymic carcinoid or thymoma. We performed thymectomy and parathyroidectomy concomitantly. The mediastinal tumor was diagnosed as invasive thymoma. (Jpn J Thorac Cardiovasc Surg 2006; 54:171-173)     

Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening

Background Adrenal tumors are a common manifestation of the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Prevalence in recent studies varies between 9 and 45%. A genotype–phenotype correlation has been described as well as the development of adrenocortical carcinomas. Long-term prospective data are still lacking. Materials and methods Thirty-eight MEN-1 patients with proven germline mutations have been prospectively observed in a regular screening program in our hospital. Adrenal glands have been screened by biochemical analysis and either by endoscopic ultrasound (EUS) or computed tomography (CT) or both. Median follow-up was 48 months (12–108 months). Age at diagnosis of MEN-1, type of adrenal tumor, genotype, therapy, and clinical characteristics have been analyzed. Results In 21 (55%) patients, adrenal involvement of the disease was detected. Adrenal lesions were detected in average 6.9 years after the initial diagnosis of MEN-1. Median tumor size was 12 mm (5–40 mm). Tumor size smaller than 10 mm was observed in 11 patients. Twelve patients had unilateral while nine had bilateral adrenal lesions. EUS detected all adrenal tumors, whereas CT failed in seven cases. In three patients, functioning tumors (one pheochromocytoma, one bilateral Cushing adenoma, and one adrenocortical carcinoma) and one nonfunctioning adenoma were diagnosed by histology and biochemical assessment. Two laparoscopic adrenalectomies and one laparoscopic subtotal resection were performed. Nonfunctioning adrenal lesions, not characterized by histology yet, were found in 18 patients. There was no statistical difference with regard to adrenal involvement between patients with germline mutations in exons 2 and 10 (12/21) and those with mutations in exons 3–9 (6/11). Conclusion MEN-1-associated adrenal tumors are mostly small, benign, and nonfunctioning and much more common than previously reported. EUS was the most sensitive imaging procedure. The genotype–pheotype correlation previously suggested by our group could not be confirmed. This work was presented at the 2nd Biennial Congress of the ESES, May 2006, in Krakow, Poland.     

Familial hyperparathyroidism: Report of a case

(Received for publication on Aug. 18, 1997; accepted on May 15, 1998)     

多发性内分泌肿瘤1型的诊断和外科处理

目的探讨多发性内分泌肿瘤1型（multiple endocrine neoplasia type 1，MEN1）的诊断和外科处理。方法回顾性分析1974年至2005年我院诊断和治疗的MEN1患者的临床资料。结果本组MEN1患者17例，其中11例分属4个家系。1997年后的14例均发现MEN1基因突变。17例患者中甲状旁腺受累11例，并发胰岛素瘤6例，垂体腺瘤8例，肾上腺受累6例，胸腺类癌2例，皮肤纤维瘤样增生合并皮下脂肪瘤2例。2例4种腺体受累，3例3种腺体受累，7例2种腺体受累，4例1种腺体受累，1例12岁携带者尚未检出临床症状及生化改变。6例以肾结石、6例以胰腺内分泌功能障碍为首发症状，2例无明显自觉症状。17例患者中4例行甲状旁腺次全切除，1例行甲状旁腺腺瘤摘除，4例行胰岛素瘤切除手术，2例胸腺类癌行胸腺肿瘤摘除术。结论MEN1临床表现多样，即使同一家系病例亦可有不同表型。基因检查有助明确诊断。手术主要针对甲状旁腺增生、胰岛素瘤和胸腺类癌，在治疗肿瘤同时可改善患者的生存质量。     

多发性内分泌肿瘤-1型相关胰腺内分泌肿瘤的诊断与治疗

目的 总结多发性内分泌肿瘤-1型(MEN-1)相关胰腺内分泌肿瘤(PET)的诊治经验.方法 2004年1月至2007年12月上海交通大学医学院附属瑞金医院外科共收治MEN-1相关PET患者10例,其中男性2例,女性8例.来院时均未诊断为MEN-1,首次出现PET相关症状年龄为11～49岁,平均(32±11)岁.通过对患者进行定性、定位检查和基因测序明确诊断.并对患者进行药物治疗、手术干预和随访观察.结果 10例患者中诊断胰岛素瘤9例,其中多发性胰岛素瘤2例,单发胰岛素瘤合并多发无功能性胰岛细胞瘤及十二指肠恶性胃泌素瘤肝转移1例;胰高血糖素瘤1例.10例患者中,有家族史5例,检出MEN1基因突变9例.所有患者中,7例患者经过9次手术治疗,发现胰岛素瘤12个、无功能胰岛细胞瘤4个、十二指肠胃泌素瘤1个;2例患者接受饮食和药物治疗;1例患者放弃治疗.随访1个月～11年,除1例患者放弃治疗死亡外,其余9例患者病情稳定,血糖均在正常范围之内.结论 加强对PET及MEN-1的认识,及时诊断MEN-1相关的PET,进行合理积极的手术治疗,能够改善患者生活质量,并有望延长患者的生存期.     

Menin mutations in the diagnosis and prediction of multiple endocrine neoplasia type 1

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the development of multiple endocrine adenomas, typically in the pancreas, anterior pituitary, and parathyroid glands. The disease is associated with germ-line mutations of the menin gene, a putative tumor-suppressor gene located on human chromosome 11q13. Methods: To facilitate the diagnosis and prediction of MEN1 in patients and their relatives, we developed a molecular two-step strategy to screen for menin gene mutations. DNA fragments covering the entire menin coding sequence are generated from patient cDNA by polymerase reaction (PCR) and subsequently analyzed by single-strand conformational polymorphism electrophoresis (SSCP). Fragments with aberrant SSCP migration are DNA-sequenced to directly characterize menin mutations. In a second diagnostic step, genomic DNA of healthy relatives of the corresponding MEN1 index patient is analyzed by PCR, with only the specific exon amplified harboring the family-specific mutation. Mutation-specific restriction enzyme digestion of this PCR product finally allows the identification of mutation carriers through pathological restriction fragment patterns. Results: Using this approach, we identified an in-frame deletion mutation (Δ Tyr Met) located in menin exon 4 (codon 227 – 228) that co-segregates with the disease phenotype in a large MEN1 family from Southern Germany. Conclusion: It is likely that the direct molecular analysis of menin gene mutations will replace the genetic and biochemical screening tests currently used in the clinical management of MEN1 families. In addition, these studies may provide clues to the tumor biology of both sporadic and MEN1-associated endocrine adenomas. Received: 2 January 1998     

Multiple endocrine neoplasia type 2B

We report a case of multiple endocrine neoplasia type 2B (MEN 2B) in a 30-year-old woman. There was no family history of MEN 2B in her family. DNA testing was carried out and a point mutation was found in exon 16, codon 918 (ATG to ACG) in the RET proto-oncogene. The woman died of medullary thyroid carcinoma, 13 years after a total thyroidectomy.     

多发性内分泌肿瘤2型的诊断和外科处理

目的 探讨多发性内分泌肿瘤2型（multiple endocrine neoplasia,MEN2）的诊断和外科处理方法.方法 回顾性研究1997年6月至2006年6月我院诊断和治疗的MEN2患者28例的临床资料.结果 MEN2a型25例,其中23例分属7个家系,均有RET基因11外显子634编码子突变;MEN2b型3例,无家族史,为RET基因16外显子918编码子突变.MEN2a型中22例有甲状腺肿物伴降钙素升高,其中17例经病理证实为甲状腺髓样癌;12例合并嗜铬细胞瘤,其中5例为多发性,2例恶性;5例合并甲状旁腺功能亢进症,3例无临床症状及生化改变.3例MEN2b型均为甲状腺髓样癌合并黏膜神经瘤病和马凡样体形,其中1例伴双侧肾上腺嗜铬细胞瘤.MEN2a型中12例接受双侧甲状腺全切除＋双侧颈淋巴清扫,5例行甲状腺肿物切除;甲状旁腺病变在甲状腺手术时一并处理;9例接受11次肾上腺肿瘤摘除术,3例为双侧肾上腺手术.3例MEN2b型均行双侧甲状腺全切除＋双侧颈淋巴清扫.结论 MEN2型以甲状腺髓样癌为主要病变,基因筛查可帮助早期诊断.根治性甲状腺切除能预防和治疗甲状腺髓样癌.     

Cervical metastases of glucagonoma in a patient with multiple endocrine neoplasia type 1: Report of a case

Multiple endocrine neoplasia type 1 (MEN 1) is a syndrome characterized by tumors of the parathyroid glands, pancreatic islet cells, duodenum, and pituitary gland. We report a case of cervical metastases of glucagonoma with MEN 1. The patient was a 34-year-old woman admitted to our hospital with epigastric pain. Her medical history included two resections of prolactinoma and two upper GI hemorrhages secondary to duodenal ulcers. Computed tomography (CT) showed two hypervascular lesions in the tail of the pancreas and cervical ultrasound showed multiple hypoechogenic ovoid images in the neck. A cervical CT scan confirmed two 15-mm lymph nodes in the left cervical region and 111In-DOTATOC imaging showed focal abnormal somatostatin expression in the pancreatic tail and the cervical nodes. The patient had asymptomatic hypoglycemic episodes, with blood sugar levels as low as 30 mg/dl, which raised our suspicion of MEN 1 associated with pancreatic insulinoma. Thus, we performed a distal pancreatectomy with bilateral cervical dissection and parathyroid gland resection. Histopathological examination revealed 12 pancreatic tumors as well as metastases in four cervical lymph nodes. The resected parathyroid glands had normal structure, suggesting parathyroid hyperplasia. A follow-up CT scan, 18 months after surgery, showed new tumors in the head of the pancreas and in the duodenal wall. A pancreatoduodenectomy was performed and histopathological examination revealed nine nonfunctioning endocrine tumors in the pancreas, one tumor in the duodenal wall, and metastases in two peripancreatic lymph nodes. The patient recovered well and remains asymptomatic.     

多发性内分泌腺瘤2A的诊治(附2例报告)

目的　提高对多发性内分泌腺瘤2A(MEN2A)的认识及诊治水平。方法　总结 2 例 MEN2A的诊治经验,并结合文献进行讨论。结果　B超、CT、MRI及131I 间 碘苄胍(MIBG)检查发现甲状腺肿块及嗜铬细胞瘤,血清降钙素及血、尿儿茶酚胺测定异常;例1 行嗜铬细胞瘤切除及甲状腺全切并淋巴结清扫术,随诊至今无复发;例 2 行双侧嗜铬细胞瘤切除及甲状腺穿刺活检术,术后随访9个月,效果良好。结论　行内分泌及影像学检查可诊断此病,肾上腺嗜铬细胞瘤切除及甲状腺全切并淋巴结清扫术是治疗的主要手段,高危家族的基因检测筛选及早期手术是治愈本病的关键。     

The natural history of multiple endocrine neoplasia type 2A—A clinical analysis

The records of 18 patients with multiple endocrine neoplasia (MEN) type 2A in a family consisting of 87 members in 5 generations, were reviewed with respect to age at onset and length of survival in a study of the natural history of this syndrome. Of these 18 patients, 8 were alive following surgical treatment, while 10 had died without treatment. The clinical onset of medullary thyroid carcinoma was noticed as a nodule in the neck at between 17 and 34 years of age (mean 24 years); the onset of pheochromocytoma was characterized by palpitation, hypertensive attacks or recurrent headache at between 17 and 42 years of age (mean 27 years); and death occurred in 10 patients at between 23 and 67 years of age (mean 40.6 years). This information on the age at onset of individual clinical manifestations, and on the length of survival of gene carriers, may be useful for clinicians who are asked to assess the risk of the development of this syndrome in a genetically predisposed asymptomatic individual, because screening tests are often refused by members of Japanese families with MEN type 2A.     

Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism

Background

Primary hyperparathyroidism (PHPT) is uncommon in children. The surgical management of PHPT in children has evolved over the past two decades.

Methods

A retrospective study of patients who underwent parathyroidectomy for PHPT diagnosed at age < 18 years and managed at a tertiary referral center for endocrine and familial disorders.

Results

Thirty-eight patients met eligibility criteria (1981–2012). Median age at PHPT diagnosis was 15 years. Two-thirds of patients were symptomatic (68%, n = 26), most commonly from nephrolithiasis. Twenty-six (68%) patients underwent a standard cervical exploration while 32% underwent a focused unilateral parathyroidectomy. Multiple endocrine neoplasia type 1 (MEN1) was diagnosed preoperatively in 22/26 patients. Patients with a preoperative diagnosis of MEN1 were more likely to undergo a complete initial operation (≥ 3 gland parathyroidectomy with transcervical thymectomy, 13/22, 59% vs. 0/4, 0%; P = 0.03) and less likely to have recurrent disease (10/22, 45% vs. 3/4, 75%; P < 0.001) during follow up than patients diagnosed postoperatively.

Conclusions

Children with PHPT should raise suspicion for MEN1. Preoperative MEN1 evaluation helped guide the extent of initial parathyroidectomy and was associated with lower rates of recurrence in sporadic and familial PHPT in pediatric patients. Management should occur at a high volume center with experienced clinicians and genetic counseling services.     

Familial non-multiple endocrine neoplasia medullary thyroid carcinoma: Report of a case confirming a new clinical entity in Japan

Most hereditary medullary thyroid carcinomas (MTC) occur in association with multiple endocrine neoplasia (MEN) type 2 syndromes. Since Farndon et al. reported two kindreds, that is collections of relatives, with familial non-MEN MTC in 1986, only five kindreds with this disorder have been reported in the English literature. In this paper, we describe a rare Japanese kindred with familial non-MEN MTC, confirming the existence of this distinct clinical entity in Japan. A 42-year-old woman underwent a left hemithyroidectomy with modified neck dissection (MND) under a diagnosis of sporadic MTC at 28 years of age. She developed lymph node metastasis in the right neck region 7 years after the initial surgery, and underwent MND and right hemithyroidectomy. Although no findings of MTC were histologically confirmed in the resected right thyroid lobe, C-cell hyperplasia was observed. Hereditary MTC was strongly suspected, but we could not confirm specific manifestations associated with MEN type 2 in any family members. However, 7 years later, a paternal aunt and cousin were diagnosed with MTC. Other family members were evaluated by ultrasonography and calcium-pentagastrin provocation testing, and three additional patients with MTC across two generations were found. None of these patients had any extrathyroidal manifestations associated with MEN type 2, and the entity of familial non-MEN MTC was confirmed.     

German medullary thyroid carcinoma/multiple endocrine neoplasia registry

Introduction: A national registry for medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2 (MEN2) was set up to evaluate epidemiological, clinical and prognostic factors of the sporadic and hereditary forms of MTC. Patients and methods: Coded data from 1217 patients with MTC from 57 participating centers in Germany were registered and statistically analyzed. The series included 515 (42%) males (mean age 43.1±16.1 years) and 702 (58%) females (mean age 44.4±17.6 years), with a mean follow-up of 5.2 years; 865 (71%) exhibited the sporadic form and 352 (29%) the familial form (244 MEN2a, 32 MEN2b, 76 FMTC). The mean age at diagnosis was 49 years for sporadic and 30 years for the familial form. Results: Of the patients, 17% presented at stage I, according to the UICC, and 30%, 45%, and 8% presented at stages II, III, and IV, respectively. There were 12% of patients who died of the disease. The overall adjusted survival rate was 87% at 5 years, and 76% at 10 years. In a univariate analysis, the stage of disease at diagnosis, age, gender, and form were relevant prognostic factors. In a multivariate proportional-hazards analysis, the difference between patients with sporadic and familial disease disappeared. Conclusion: As the tumor stage at presentation is the major prognostic factor, early diagnosis and surgical intervention before cervical lymph node metastases appear is necessary to improve survival especially in sporadic cases. Received: 28 January 1998 / Accepted: 3 July 1998     

Medullary thyroid carcinoma and pheochromocytoma accompanied with nodular hyperplasia in multiple endocrine neoplasia type 2

Three patients with familial multiple endocrine neoplasia type 2 underwent total adrenalectomy and subsequently near-total or total thyroidectomy. The overt pheochromocytomas were present bilaterally in two patients and unilaterally in another patient. In addition, multiple nodules measuring a few mm in diameter were demonstrated in all adrenal medullas examined. All patients exhibited bilateral medullary thyroid carcinomas which varied in size from a few minute nodules accompanied by the microscopic C-cell hyperplasia to distinct large tumors. The thyroid C-cell hyperplasia appeared to be confined to the upper and middle thirds of the lateral lobe, and micronodules of the C-cell hyperplasia enlarged to coalesce, forming one large carcinoma mass. On the other hand, nodular hyperplasia of the chromaffin cells was distributed diffusely throughout the adrenal medulla and each nodule appeared to develop individually into a large pheochromocytoma. These findings suggested that, at least in the family members at a high risk for multiple endocrine neoplasia type 2, the development of both medullary thyroid carcinoma and pheochromocytoma was always preceded by a multicentric nodular hyperplasia. On the basis of the pathogenesis of these tumors, the most rational surgical approach was presented. Presented at the 14th Annual Congress of the Japan Society for Cancer Therapy, Sendai, September 30, 1976.