Multiple endocrine neoplasia

The MEN syndromes continue to be the focus of considerable interest and research. Since successful treatment requires early diagnosis, proper screening and follow-up of patients at risk is important. In the individual at risk for developing MEN IIa, annual screening should include measurement of the basal and stimulated plasma CT levels, and determination of plasma levels of calcium, PTH, and CEA. Twenty-four hour urine excretion rates of norepinephrine, epinephrine, metanephrine, dopamine, and VMA should also be obtained. It is our recommendation that this screening be continued through the third decade of life. Patients having thyroidectomy for MTC need to be tested annually for recurrent MTC and the development of adrenal medullary disease. All patients at risk for developing MEN IIb should be evaluated in a similar fashion. Recently, several groups using DNA linkage analysis have mapped the gene for MEN IIa to chromosome 10, although the exact location of the gene is yet to be determined. Preliminary linkage studies have mapped the gene for MEN I to chromosome 11. The identification of the genes for MEN I and MEN II will greatly simplify the diagnosis of the disease and perhaps also the therapy of affected patients.     

Multiple endocrine neoplasia

Summary The MEN syndromes continue to be the focus of considerable interest and research. Since successful treatment requires early diagnosis, proper screening and follow-up of patients at risk is important. In the individual at risk for developing MEN IIa, annual screening should include measurement of the basal and stimulated plasma CT levels, and determination of plasma levels of calcium, PTH, and CEA. Twenty-four hour urine excretion rates of norepinephrine, epinephrine, metanephrine, dopamine, and VMA should also be obtained. It is our recommendation that this screening be continued through the third decade of life. Patients having thyroidectomy for MTC need to be tested annually for recurrent MTC and the development of adrenal medullary disease. All patients at risk for developing MEN IIb should be evaluated in a similar fashion. Recently, several groups using DNA linkage analysis have mapped the gene for MEN IIa to chromosome 10, althought the exact location of the gene is yet to be determined.^50,51 Preliminary linkage studies have mapped the gene for MEN I to chromosome 11.⁵² The identification of the genes for MEN I and MEN II will greatly simplify the diagnosis of the disease and perhaps also the therapy of affected patients. This report is the gist of a paper read by S.A. Wells, Jr. at the 87th Annual Meeting of the Japan Surgical Society, Tokyo, Japan, 1989     

Ⅱ型多发性内分泌腺瘤病

目的 提高对Ⅱ型多发性内分泌腺瘤内（ＭＥＮⅡ）的认识。方法 总结３例ＭＥＮⅡ的诊治经验,结合文献进行讨论。结果 ３例均为ＭＥＮⅡａ,Ｂ超及ＣＴ检查同时发现双侧多病灶的甲状腺髓样癌及嗜铬细胞瘤,予以手术切除。结论 此病罕见,甲状腺髓样癌及嗜铬细胞瘤双侧多病灶发病是其主要临床特点,Ｂ超及ＣＴ是术前诊断的主要手段,甲状腺髓样癌根治术和及时发现并切除嗜铬细胞瘤是治疗关键。     

Multiple endocrine neoplasia type I

During the 13-year period 1970-1983 only 7 cases of multiple endocrine neoplasia type I (MEN I) were seen at Groote Schuur Hospital, suggesting that the associated gene is rare in this area. Only 1 of these patients was black. Endocrine associations were as follows: hyperparathyroidism--6 cases, pituitary hypersecretion--6 cases (3 each involving growth hormone and prolactin), and pancreatic hypersecretion--3 cases (2 of gastrinoma and 1 of insulinoma). The presenting features were predictably diverse and depended on the component which manifested first. There was little difficulty in reaching a diagnosis on routine investigation. All patients with hyperparathyroidism underwent a 3 1/2-gland parathyroidectomy as the first treatment procedure, normocalcaemia being achieved in 5 cases, but persistent hypercalcaemia in the 6th suggested a supernumerary gland. A pituitary adenoma was removed in 4 cases, but persistent prolactinaemia necessitated bromocriptine therapy in 3. Successful distal pancreatectomy was undertaken in a patient with insulinoma and a patient with gastrinoma, and a further patient with gastrinoma awaits surgery. The overall prognosis in cases of MEN I appears to depend on the most aggressive component, often the pancreatic lesion; our patients have run a surprisingly benign course with only 1 late death, from hypertensive heart disease.     

Carcinoids associated with multiple endocrine neoplasia syndromes

Carcinoids occur in association with MEN types 1 and 2. To determine the relationship between carcinoids and MEN, we reviewed nine patients with carcinoids and other endocrine tumors. Analyzing these 9 patients and 56 other patients previously described in the literature, we found several clinically important relationships. In contrast to the usual midgut and hindgut origin, most carcinoids associated with MEN (69 percent) are of foregut origin (thymus 24 percent, bronchus 27 percent, stomach 3 percent, and duodenum 14 percent). Carcinoids are more commonly associated with MEN type 1 than MEN type 2 (59 patients and 6 patients, respectively). Thymic carcinoids associated with MEN are more common in men (15 versus 2), and most (82 percent) are malignant. Bronchial carcinoids associated with MEN are more common in women (15 versus 4), and most (74 percent) are benign. There is a strong association between thymic carcinoids and parathyroid tumors and between bronchial carcinoids and pituitary tumors. Most patients with carcinoids and hyperparathyroidism (82 percent) have had parathyroid hyperplasia or multiple parathyroid adenomas. Thus, carcinoids may occur in association with both MEN type I and MEN type II. MEN should be suspected in patients with foregut carcinoids. Patients with MEN and ectopic ACTH production should be considered to have bronchial carcinoids if they are female and thymic carcinoid if they are male. The thymus should be routinely removed in patients with MEN type I because of the possible presence of an ectopic parathyroid gland in this tissue and to prevent subsequent development of a carcinoid tumor.     

Multiple endocrine neoplasia with skeletal manifestations

There are three types of familial multiple endocrine neoplasia, but type 2b, which is characterized by medullary thyroid carcinoma, pheochromocytoma, and ganglioneuromatosis, is the only one in which patients also have skeletal anomalies. These musculoskeletal abnormalities include marfanoid habitus, pes cavus, talipes equinovarus, slipped capital femoral epiphysis, kyphosis, scoliosis, lordosis, increased joint laxity, and weakness of the proximal muscles of the extremities. Affected patients have several facial abnormalities as well, the most striking being enlargement of the lips. Therefore, when a patient is seen with one or more of these musculoskeletal defects, the diagnosis of type-2b multiple endocrine neoplasia should be considered. If the characteristic facial features of the disorder are present, the patient should have a prompt examination for medullary thyroid carcinoma and pheochromocytoma.     

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.     

Multiple endocrine neoplasia type 2: Surgical management

Aim-Background

Multiple endocrine neoplasia type 2 (MEN-2) occurs as a result of germline mutation in a 21-exon proto-oncogene located on chromosome 10q11.2, which encodes a tyrosine kinase receptor (RET). Patients with MEN-2 face a lifetime risk of developing medullary thyroid carcinoma (MTC); this risk exceeds 95% in untreated patients. Three clinical subtypes have been defined: MEN-2A, MEN-2B, and familial MTC (FMTC). The type depends on the specific codon mutation, the risk of developing pheochromocytoma, hyperparathyroidism, and the presence of specific physical features. The therapeutic approaches in patients with germline mutation of an RET proto-oncogene are reviewed herein.

Methods

A Medline search was conducted using the terms MEN-2A syndrome, surgical management of MEN-2A, prophylactic thyroidectomy, lymph node dissection and thyroidectomy in MEN-2A, adrenalectomy and parathyroidectomy in MEN-2A patients.

Results

Once diagnosis for MEN-2 is suspected, patients should undergo genetic screening for RET mutations and a careful family history check. In almost 99% of cases, a mutation can be identified by a DNA test. The results of the DNA test affect the surgical management. Given the potential risk of disease and metastases development, all patients presenting a RET mutation without evidence of MTC should undergo early prophylactic thyroidectomy, preferably during childhood. Evidence of MTC demands total thyroidectomy with central lymph node dissection. If an adrenal pheocromocytoma is diagnosed in patients, this should be managed first. The optimal approach for a localized unilateral tumour is a laparoscopic unilateral adrenalectomy. In bilateral disease, bilateral excision of adrenal glands is required. If feasible, cortical sparing adrenalectomy may be considered to reduce the risk of an Addisonian crisis. Any enlarged parathyroid glands found during therapeutic or prophylactic thyroidectomy must be excised, even in those patients who are eucalcemic. If hyperparathyroidism is evident, all parathyroid can be identified by bilateral neck exploration; those with pathological morphology should be removed. In four-gland disease, subtotal or total parathyroidectomy with autotransplantation in the forearm are the optimal options.

Conclusions

MEN-2A syndrome is a rare genetic disease in which early detection of mutation can facilitate prevention and cure of cancer. There are variable expressions of phenotypes, and the therapeutic approach depends on the clinical presentation of the disease. Given the risk of recurrence and different clinical pathologies that can emerge years after the initial disease, all patients must be followed up closely.     

以嗜铬细胞瘤为主要表现的多发性内分泌腺瘤

目的：探讨以嗜铬细胞瘤为主要表现的多发性内分泌腺瘤（MEN）的诊治。方法：3例以嗜铬细胞瘤为主要表现的MEN,均行单侧肾上腺切除术,其中例1 、例2为同胞组妹均诊断为嗜铬细胞瘤并发甲状腺髓样癌,属MRN－Ⅱa型,行甲状腺全切加同侧淋巴结清扫术;例3为嗜铬细胞瘤并发胰岛素瘤,属MEN混合型,同时行嗜铬细胞瘤、胰岛素瘤切除术。结果：3例手术切除效果良好。例1术后6年死于其他疾病,例2术后已生存23年无复发,例3术后血压、血糖、血胰岛素恢复正常,随访6个月无复发。结论：提高对本病的认识,选择适当的内分泌和影像学等检查手段,是早期诊断的关键。MEN中嗜铬细胞并发其他肿;且先行嗜铬细胞瘤切除术,是否全切双侧肾上腺应依具有体情况而定,然后再处理其他肿瘤。     

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.     

Multiple endocrine neoplasia type 1 in end-stage renal failure

A 59-year-old woman with chronic renal failure due to type 2 diabetes mellitus (DM) is presented. Her father and a brother had a history of brain tumor. Her blood urea nitrogen and serum creatinine levels were 102mg/dl and 4.5mg/dl, respectively. Her serum Ca²⁺ and Pi were within the normal range (9.4mg/dl and 5.4mg/dl, respectively). Her intact parathyroid hormone (PTH) level was 1730000pg/ml. A ^99mTc-methoxy-isobutylisonitrile scintigraphy showed high uptake in three parathyroid glands. A magnetic resonance image showed microadenoma in the pituitary gland. The serum gastrin level was high. Genetic examination revealed a mutation of the MEN1 gene (894–9 G A). From these findings, she was diagnosed with multiple endocrine neoplasia (MEN) type 1. Subsequently, a parathyroidectomy was performed successfully, a parathyroid gland was transplanted to her right forearm, and her serum Ca²⁺ level was controlled at 8.5–9.0mg/dl. It is very important to identify MEN1 if an end-stage renal disease (ESRD) patient has hyperparathyroidism with multigland involvement. Examination of the MEN1 gene may be valuable to make an accurate diagnosis and choose the appropriate therapy in some ESRD patients with hyperparathyroidism.     

Multiple endocrine neoplasia 2A syndrome: Surgical management

Background/Purpose: Currently, molecular genetic diagnostics allow familial types of medullary thyroid carcinoma to be detected at an asymptomatic stage and surgery thus to be performed at a time when prognosis is good. The current report aims to determine the appropriate age for safe prophylactic thyroidectomy in children with multiple endocrine neoplasia (MEN) 2A and mutations at codon 609 according to genotype-phenotype correlations and will discuss surgical procedures. Methods: The authors describe the case of a family with hereditary MEN 2A syndrome. A DNA analysis of 7 family members confirmed the diagnosis by a mutation at codon 609 of the RET proto-oncogene. Results: A phaeochromocytoma developed in 2 family members. Four had medullary thyroid carcinoma. A grandson underwent a prophylactic thyroidectomy at the age of 5 on account of genetic evidence. Despite the negative preoperative and intraoperative findings he already had an invasive medullary thyroid carcinoma. Conclusions: Few genotype-phenotype correlations have been established for MEN 2A disease. According to the natural history of the disease, families with the genotype RET cys609gly should have a more benign disease than high-risk families (mutations at codon 634, 618). From this report the authors conclude that prophylactic thyroidectomy in [ldquo ]609[rdquo ] families should be performed earlier than actually recommended, favorably at the age of 2 to 4 years. Further multicenter studies are needed to provide more clinical and prognostic data for less frequent (codon 609, 630, 791, and 891) RET genotypes. J Pediatr Surg 37:897-900.     

Multiple endocrine neoplasia: Part II. Sipple's syndrome

Multiple endocrine neoplasia (MEN) type II is a genetically inherited disorder characterized by a combination of medullary carcinoma of the thyroid, phaeochromocytomas and, more rarely, hyperparathyroidism. A subgroup of patients who do not have the same genetic inheritance pattern have in addition a Marfanoid habitus and multiple mucosal neuromas. The phaeochromocytomas cause paroxysmal hypertensive crises due to catecholamine surges, and are diagnosed most easily by elevated levels of urinary vanillylmandelic acid. Medullary carcinoma presents as a thyroid nodule and is often associated with flushing or diarrhoea. Measurement of plasma thyrocalcitonin levels permits diagnosis and detection of affected members of the family. It is unusual for hyperparathyroidism to be asymptomatic or to require treatment. Bilateral adrenalectomy should always be performed since both adrenals are involved, even if an overt tumour is only apparent in one. Total thyroidectomy for medullary carcinoma is indicated once the phaeochromocytomas have been removed. Affected families should be regularly screened to detect overt cases.     

多内分泌功能性嗜铬细胞瘤的临床诊治(附3例报告)

目的:探讨多内分泌功能性嗜铬细胞瘤的临床、病理、组织化学特性和诊治方法及预后。方法:回顾性分析3例多内分泌功能性嗜铬细胞瘤患者的临床资料,并结合文献复习就其诊治方法予以讨论。结果:1例行开放性右肾上腺肿瘤切除术,术后血压恢复正常,Cushing综合征表现明显减轻;1例行后腹腔镜下右肾上腺区肿物切除术,术后患者腹泻消失,定期复查血钾正常;另1例死于高血压危象。结论:多内分泌功能性嗜铬细胞瘤病因尚不明确,其中分泌促皮质激素表现为Cushing综合征者相对较多,但临床易漏诊误诊。正确的诊断思路和充分的实验室检查及术前准备是诊疗的关键;治疗方式上以后腹腔镜下或开放切除肾上腺肿瘤为主。