- Email: [email protected]
The practical management of multiple endocrine neoplasia
with primary aldosteronism. J Biol Chem 266:10,731-10,734. Ogishima T, Suzuki H, Hata J, Mitani F, Ishimura Y: 1992. Zone-specific expression of aldostexone synthase cytochrome P-450 and cytochrome P-450, tg in rat adrenal cortex: histochemical basis for the functional zonation. Endocrinology 130:2971-2977. Ohnishi T, Wada A, Nonaka Y, Sugiyama T, Yamano T, Okamoto M: 1986. Effect of calmodulin on aldosterone synthesis by a cytochrome P-450 , , a-reconstituted system from bovine adrenocortical mitochondria. J Biochem 100:1065-1076. Ohnishi T, Wada A, Lauber M, Yamano T, Okamoto M: 1988. Aldosterone biosynthesis in mitochondria of isolated zones of adrenal cortex. J Steroid Biochem Mol Biol 31:73-81. Rapp JP, Dahl LK: 1976. Mutant forms of cytochrome P-450 controlling both 18-and 11 g-steroid hydroxylation in the rat. Biochemistry 15:1235-1242. Seybert DW: 1990. Lipid regulation of bovine cytochrome P-450,,, activity. Arch Biothem Biophys 279:188-194. Sun T, Zhao Y, Nonaka Y, Okamoto M: 1995. Cloning and expression of cytochrome P-450, ,a of porcine adrenal cortex. J Steroid Biochem Mol Biol 52:227-232
Takemori S, Kominami S, Ikushiro S, Yamazaki T, Harada D: 1994. Reaction mechanism of P-450 dependent steroidogenesis: regulation of catalytic activity of bovine adrenal P-45O,,e. In Lechner MC, ed. Cytochrome P-450: Biochemistry, Biophysics and Molecular Biology. Paris, John Libbey Eurotext, pp 365-371. Wada A, Ohnishi T, Nonaka Y, Okamoto M, Yamano T: 1985. Synthesis of aldosterone by a reconstituted system of cytochrome P-450, rp from bovine adrenocortical mitochondria. J Biochem 98:245-256. White PC, Pascoe L: 1992. Disorders of steroid 11 g-hydroxylase isozymes. Trends Endocrinol Metab 3:229-234. Yanagibashi K, Haniu M, Shively JE, Shen WH, Hall P: 1986. The synthesis of aldosterone by the adrenal cortex: two zones (fasciculata and glomentlosa) possess one enzyme for 1 III-, 18-hydroxylation and aldehyde synthesis. J Biol Chem 261:35563562. Yanagibashi K, Kobayashi Y, Hall PF: 1990. Ascorbate as a source of reducing equivalents for the synthesis of aldosterone. Biothem Biophys Res Commun 170: 1256 1262.
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Diana L. Learoyd, Stephen M. Twigg, Debbie J. Marsh, and Bruce G. Robinson
Advances in the identification and localization of the abnormal genes in the multiple endocrine nwplasia syndromes have provided new methods of identifying “at risk” individuals in these families. Genetic testing using linkage analysis in multiple endocrine neoplasia (MEN) 1 and direct mutation analysis of the RET protooncogene in MEN 2 is now available for these disorders. New management issues for these disorders have resulted, and a practical approach to these issues is discussed. (Trends Endocrinol Metab 1995;6:273-278). The authors are at the Kolling Institute of Medical Research (D.L.L., S.M.T., D.J.M., B&R.), and the Department of Endocrinology (D.L.L., S.M.T., B.G.R.), at Royal North Shore Hospital, St. Leonards, New South Wales 2065, and the University of Sydney (D.L.L., S.M.T., D.J.M., B.G.R.), Sydney, New South Wales 2006, Australia.
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tification of disease gene carriers in these syndromes. A number of new management issues have resulted and new guidelines are being formulated to monitor the expression of the disease phenotype. In this review, we present a practical approach to the investigation and management of families with MEN type 1 or 2. Earlier reviews of MEN 1 and MEN 2 in this journal preceded recent genetic advances in both of these conditions (Marx 1989, Gage1 1991).
*
Multiple Endocrine Neoplasia Type 1
MEN 1 is an autosomal dominant syndrome characteristically involving tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary. The propensity for specific organ involvement tends to be consistent in any one family (Skogseid et al. 1991). In contrast to sporadic (nonfamilial) endocrine tumors in these involved tissues, tumors in MEN 1 are more often multicentric, are commonly associated with hyperplasia, and have a higher rate of recurrence following treatment. Genetic Screening in Multiple Endocrine Neoplasia Type 1
The Practical Management of Multiple Endocrine Neoplasia
TEM Vol. 6,No. 8,1995
There have been several recent advances in the understanding of the pathogenesis of the multiple endocrine neoplasia (MEN) syndromes. These new findings have subsequently been applied to iden-
The gene segregating with the clinical defects found in MEN 1 is believed to be a tumor suppressor gene that maps to a 900-kb region on the long arm of chromosome 11 at 1 lq13 (Weber et al. 1994). Loss of heterozygosity at this site has been detected in 70% of tumor tissue samples studied in MEN 1. The disorder is autosomal dominant, and offspring of an affected individual have a 50% chance of inheriting the disease phenotype. Genetic screening for this disease is performed by linkage analysis. In a family in which at least two individuals are affected and there are informative markers flanking the MEN1 locus, risk
estimates of greater than 99.5% for carrying the defective gene can be given (Larsson et al. 1992). Following identification of a gene carrier, specific organ screening should follow in an attempt to detect and treat tumors at their earliest stage. The com-
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Zollinger-Ellison syndrome, which is characterized by elevated serum gastrin, gastric acid hypersecretion, diarrhea, and severe esophagitis, with recurrent Genetic screening of f$ly by linkage analysis allows and multiple peptic ulcers. Duodenal >99.5% risk estimation with gastrinomas occur more commonly in MEN 1 than in sporadic disease. Techniques traditionally used to localize gasScreening investigations trinomas include transabdominal and for specific organ disease intraoperative ultrasound, CT scanning, parathyroid ( calcium & parathyroid hormone), pituitary and portal venous sampling. Recently, (prolactin), pancreas (fasting sequential injection of secretin into the gastrin). Commence at age 15 celiac axis with subsequent hepatic vein sampling for gastrin has been shown to localize pancreatic gastrinomas better Repeat screening than angiography alone and to have less Define, localise & Reassure ‘linkage every 3 years. treat specific organ negative’ family morbidity than transhepatic portal disease. members. venous sampling (Fraker and Norton 1993). If possible, distal pancreatectomy Figure 1. Familial multiple endocrine neoplasia type 1. Management algorithm. is performed for gastrinomas in the tail or body of the pancreas, and lesions in with mild hypercalcemia and a clear diag- the pancreatic head or duodenum are bined use of genetic and specific organ nosis of hyperparathyroidism because screening (Figure 1) has reduced the age enucleated. Total pancreatectomy has hypercalcemia is progressive and may po- been used in some cases when an aggresof detecting clinical organ involvement tentiate pituitary and pancreatic disease, in MEN 1 to the late teens rather than sive tumor course has occurred in family including hypergastrinemia (Fraker and the fourth decade, as was previously the members. Recurrent and/or metastatic Norton 1989). Other units delay initial case (Vasen et al. 1989). Specific organ disease occurs in 50% of patients (Grasurgery because of high rates of permascreening is performed by measurement ma et al. 1992). Palliative medical thernent hypoparathyroidism or recurrent hy- apies to control hyperacidity include of serum ionized calcium, PTH, PRL, and basal serum gastrin. Compliance is percalcemia postoperatively. high-dose proton pump inhibitors and Three and a half gland parathyroidecgreatest if screening is kept simple and the somatostatin analogue octreotide. regular. Occasionally, further tests in- tomy and cervical thymectomy should Partial hepatectomy and hepatic transbe performed by an experienced survolving a specific organ may be indiplantation are palliative options in all geon. More limited surgery results in types of islet cell cancer with hepatic cated if a particular tumor type has been rapid recurrence of hypercalcemia. A involvement. present in a family. Some groups recommend more extensive screening for all 40-60-mg parathyroid remnant from Insulinoma occurs in up to 35% of one gland may be relocated in the neck families (Skogseid et al. 1991). MEN 1 patients, with metastases in 5% or placed into the forearm and clipped to 10% of cases (Rasbach et al. 1985). Parathyroid Disease for ease of future identification. In the Fasting endogenous hyperinsulinemia common case of recurrent disease, localduring symptomatic hypoglycemia and Hyperparathyroidism is the most comization procedures preoperatively may elevated ratio of serum proinsulin to inmon abnormality in MEN 1 and usually sulin are diagnostic. In addition to prethe first to be detected on screening. On- have a role. 99mTc sestamibi scanning may improve sensitivity in localizing viously described localizing procedures, set is described in the teens and, by age parathyroid disease over other comselective arterial catheterization with 40, greater than 95% of MEN 1 patients bined modalities, such as computerized calcium injection as an insulin secretahave hypercalcemia (Eberle and Grun tomography (CT), magnetic resonance gogue may be helpful (Fraker and 1981). Multiple gland hyperplasia, imaging (MRI), ultrasound, and Norton 1993). Intraoperative ultrasound which may lead to one or more parathythallium-technetium scanning (Mitchell may localize disease not determined by roid adenomas, is characteristic. other methods, including palpation at Diagnosis is made by detection of si- et al. 1995). surgery (Zeiger et al. 1993). Patients multaneously elevated serum calcium and Pancreatic Disease with insulinoma are usually cured by PTH levels with an elevated urinary ca.lPalliative Pancreatic islet cell tumors occur in 30% subtotal pancreatectomy. cium to creatinine ratio. Measuring ionto 80% of patients (Vasen et al. 1989). medical therapy for inoperable metaized serum calcium and PTH may detect Multicentric disease is common, and static or recurrent disease includes diadisease at an earlier stage than total serum zoxide and chemotherapy with streptocalcium corrected for albumin (Benson et slowly growing metastases occur in approximately 50% of cases. Multiple pepzotocin, dacarbazine and 5-fluorouracil, al. 1987). We have not found preoperative localizing studies to be helpful unless hy- tides may be secreted by a tumor, alalone or in combination. Octreotide is generally not beneficial and can exacerperpamthyroidism recurs and repeat sur- though usually one predominates. Gastrinomas occur in up to 60% of gery is being considered. We favor early bate hypoglycemia. For hepatic disease, MEN 1 patients, and may cause the parathyroidectomy in MEN 1 patients the options are as for gastrinoma.
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Rare
islet cell tumors
in MEN
1 in-
vasointestinal clude glucagonomas, polypeptide (VIP)omas, and those prepancreatic dominantly secreting polypeptide. Plasma glucagon is nonspecifically elevated in the majority of MEN 1 patients. True glucagonomas cause a clinical syndrome with a characteristic rash (necrolytic migratory erythema) and hyperglycemia. Pancreatic polypeptide is also commonly elevated in MEN 1, but does not cause a specific clinical syndrome. Markedly elevated levels following a stimulatory meal can identify patients with pancreatic lesions. VIPomas may produce the Verner-Morrison syndrome, with watery diarrhea, achlorhydria, and hypokalemia. Treatment of these rare tumors is surgical. Chemotherapy and octreotide are palliative options to control symptoms of hormonal excess. There is no evidence that octreotide clearly reduces the bulk of any islet cell tumors. Pituitary Adenomas in Multiple Endocrine Neoplasia Type 1 Pituitary adenomas occur in 15%42% of MEN 1 patients (Skogseid et al. 1994). Prolactinomas are the most common pituitary lesion. Acromegaly is usually caused by a pituitary tumor, although rare pancreatic tumors may release GHRH ectopically, and measurement of this hormone in peripheral blood is indicated in the workup of MEN 1 patients with acromegaly. Cushing’s syndrome in MEN 1 may also rarely be due to ectopic ACTH and/or CRH production. Diagnosis and management of pituitary adenoma in MEN 1 is equivalent to that in sporadic disease, with the added awareness of potential associated ectopic releasing hormone production. The recurrence rate of pituitary tumors exceeds that in sporadic disease, probably owing to the propensity to multicentric disease in MEN 1. Hypophysectomy (complete anterior pituitary resection), and external beam radiotherapy are indicated in recurrent disease. Subcutaneous octreotide therapy can reduce pituitary tumor size and control hormonal excess in acromegaly
not cured by initial surgery.
Other Clinical Manifestations Multiple Endocrine
in
Neoplasia Type 1
Other tissue manifestations include carcinoid tumors, which in MEN 1 are usually in the thymus or lungs. Surgical
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Familial MEN 2 / FMTC + Identify germline mutation in family (blood DNA) - codons 609,611,618,620,634,768,
Mutation identified identified
in family.
Assess patient for presence of pheochromocytoma - 24 hour urinary catecholamines & metanephriies.
v
Reassure patient. No further testing.
Remove pheochromocytoma prior to further surgery.
Reassure and repeat annually up to age of 30 years.
2. Familial multiple endocrine neoplasia type 2. Management algorithm. FMTC, familial medullary thyroid carcinoma.
Figure
cure for carcinoid tumor is attempted as first line therapy, but palliative chemotherapy with combinations of methotrexate and cyclophosphamide or streptozotocin and 5-fluorouracil, plus octreotide or interferon, may be used in incurable cases to control associated hormonal features. Adrenocortical adenomas, bilateral or unilateral, are reported in up to one-third of patients; primary hyperaldosteronism may occasionally be present (Becker-s et al. 1992), and adrenocortical carcinoma has been reported (Skogseid et al. 1992). Impaired fertility has been reported in siblings with germline deletions of both alleles of the MENJ locus (Brandi et al. 1993).
??
Multiple Endocrine Neoplasia Type 2
Previously known as Sipple’s syndrome, MEN 2 is characterized by three endocrine tumors in different combinations. In MEN 2A, medullary thyroid carcinoma (MTC) occurs in combination with pheochromocytoma in up to 50% of cases and hyperparathyroidism in 15% 30% (Schimke 1990). In MEN 2B, the features of MEN 2A occur together with mucosal neuromas, Marfanoid body habitus, and ganglioneuromatosis of the gastrointestinal tract. In addition, MTC
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may also occur in families without other manifestations (familial MTC, or FMTC). As with MEN 1, these syndromes exhibit autosomal dominant inheritance, although some MEN 2B cases occur de novo (Carlson et al. 1994a). An approach to the investigation and management of familial MEN 2 is illustrated in Figure 2. Genetic Screening in Multiple Endocrine Neoplasia Type 2 Germline point mutations have been identified in the RET protooncogene on chromosome 10 segregating with the disease phenotype in MEN 2 and FMTC (Mulligan et al. 1993, Donis-Keller et al. 1993, Hofstra et al. 1994, Marsh et al. 1994, Eng et al. 1995, Bolino et al. 1995). The majority of the mutations segregating with MEN 2A and FMTC are clustered in five cysteine (TGC) codons, in exon 10 (codon 609, 611, 618, and 620) in the extracellular domain, and in exon 11 (codon 634) in the transmembrane domain of RET. A germline mutation in codon 9 18 in exon 16 in the tyrosine kinase domain of RET has been found in both familial and de novo MEN 2B (Carlson et al. 1994b). This mutation causes the substitution of a methionine (ATG) by a threonine (ACG). Currently, data from 12 centers worldwide are being collected by the RET Mutation Con-
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sortium and analyzed for confirmation of predicted genotype-phenotype correlations, including the suggestion that the codon 634 mutations correlate with the presence of pheochromocytoma (Mulligan et al. 1994 and 1995). Genetic screening of individuals with the clinical presentations of MEN 2 or FMTC, or those individuals at risk of inheriting one of these syndromes, is now readily available and is performed on DNA extracted from peripheral blood leukocytes. Rapid screening methods have been described (Marsh et al. 1994, Wells et al. 1994b, Xue et al. 1994), and these should always be performed on two blood samples collected for genetic analysis at different times to minimize the chance of a sample mix-up. Management of a New Multiple Endocrine Neophzsia Type 2 Family Accurate history taking and careful review of histopathological data are essential to confirm that one is dealing with a MEN 2 family. There are a number of families that have been incorrectly given this diagnostic label on the basis of one family member with documented MTC and one or two others with alleged C cell hyperplasia (CCH) or family members who have died of the complications of hypertension (unpublished observations). Once adequate phenotypic evidence of MEN 2 is present, it is appropriate to begin screening the RET protooncogene for the described mutations in these syndromes. Mutations are present in approximately 86% of FMTC families, in 97% of MEN 2A families (Mulligan et al. 1994), and in greater than 93% of MEN 2B families (Mulligan et al. 1995). The identification of a mutation in a family enables rapid determination of those family members who carry the mutation and those who do not. Noncarriers do not require further investigation and can be reassured that their risk of developing thyroid carcinoma is not different from that of the normal population. Investigation of RET Mutation Carriers The most appropriate management of RET mutation carriers has not been clearly established, although at the Fifth International Workshop on Multiple Endocrine Neoplasia in Stockholm there was general agreement that thyroidectomy should be performed in mutation
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carriers aged 6 years or older (Wells et al. 1994a). A more conservative approach would involve performing annual pentagastrin stimulation tests on RET mutation carriers and performing thyroidectomy when the test becomes abnormal. There is evidence that individuals found to have CCH rather than MTC would have a good prognosis (Gagel et al. 1988). The major problem with this approach is that the pentagastrin test is unpleasant and annual compliance rates are likely to be low. Ninetyfive percent of gene carriers will have a positive pentagastrin test by the age of 30 years (Ponder et al. 1988). Annual assessment for the presence of pheochromocytoma should include obtaining a careful history and physical examination, including measurement of supine and erect blood pressure and measurement of urinary catecholamines Pheochromocyand metanephrines. toma usually presents several years after MTC (Camey et al. 1976), but formal assessment for its presence should be performed in RET mutation carriers prior to any operation. The anesthesiologist should be made aware of the possibility of pheochromocytoma in these patients even if catecholamines are normal. Hyperparathyroidism is relatively uncommon and can be readily excluded by measurement of serum calcium at the annual assessment. Management of Medullary Thyroid Carcinoma MTC can be multicentric and bilateral and, in 50% of cases, has metastasized to cervical lymph nodes at the time of diagnosis (Wells et al. 1978). Primary surgery should include total thyroidectomy and removal of all lymph nodes in the central neck compartment. Macroscopitally abnormal nodes in the lateral neck compartment and upper mediastinum should also be removed (Duh et al. 1989). Several groups are performing studies of extensive initial surgery such as radical neck dissection (Buhr et al. 1993). An improvement in long-term outcome is, however, yet to be demonstrated with these approaches. Postoperatively, patients are screened for recurrence with calcitonin and/or carcinoembryonic antigen (CEA) measurements. The number of techniques described for localization of recurrence,
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including radionuclide scanning with 201 thallium, 99mTc DMSA, 99mTc sesta1311 metaiodobenzylguanidine mibi, (MIBG), radiolabeled monoclonal antibodies, and labeled somatostatin receptors, indicates that each has limitations (Hoefnagel et al. 1988). Ultrasound, CT, and MRI scans are commonly used, but sensitivity is only about 50% (Abdelmoumene et al. 1994). Selective venous catheterization is the most sensitive method of localizing recurrence, especially when combined with pentagastrin stimulation (Abdelmoumene et al. 1994), but it is both invasive and unpleasant. Therapy for Recurrent Disease Surgery aimed at debulking macroscopic tumor offers the best option, although biochemical cures appear difficult to achieve even with extensive surgery (Van Heerden et al. 1990), and data on long-term outcome are scarce. Other therapies have little place for recurrent or metastatic disease. Radiotherapy may have a role in palliation, such as for bone pain, but studies have shown no survival benefit either when it is given perioperatively or separately (Samaan et al. chemotherapeutic 1988). Multiple agents have been used both alone and in combination. Doxorubicin is the most effective single agent, giving partial response rates of about 30%, but in general the studies are very small and results disappointing. The long-acting somatostatin analogue octreotide may be used for symptom control, and there are case reports of diarrhea being controlled by its use and calcitonin levels declining (Mahler et al. 1990). Pheochromocytoma Pheochromocytoma in MEN 2 may be bilateral and often presents years after MTC. Screening should always be performed prior to any surgery in RET mutation carriers by measurement of 24-h urine catecholamine and metanephrine levels. Repeated measurements are often required and patients may be given bottles for the collection to be used on a day that symptoms are experienced. Once catecholamine excess is proven, imaging of the adrenals with 1311-or ‘231-labeled MIBG should be performed because of the high frequency of multiple tumors. Preoperative preparation with (r receptor blockade and the subsequent intro-
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duction of p blockade is well described (Ross et al. 1971). Surgery is generally performed 2-3 weeks after the institution of (r and/or g receptor blockade and with an experienced anesthesiologist. The affected adrenal is removed and the opposite adrenal inspected for enlargement or nodularity. This necessitates an anterior surgical approach. Some authors have proposed that bilateral adrenalectomy be performed initially because of the 50% likelihood that the unaffected adrenal will develop a pheochromocytoma within 10 years (Van Heerden 1984). This area remains controversial because of the problems associated with rendering a patient adrenally insufficient. Hyperparathyroidism
Parathyroid disease in MEN 2 is investigated and managed as in MEN 1 (see earlier discussion here).
??
Multiple Endocrine Neoplasia Type 2b
The features of this syndrome have already been mentioned. Investigations and management are as for MEN 2A; however, it should be noted that the MTC occurs in a more aggressive form than in MEN 2A or sporadic MTC, and thyroidectomy should be performed as early as possible. The neuromas may require surgical removal if they cause local obstruction, and gastrointestinal tract involvement may lead to intestinal obstruction. Parathyroid disease is less common in MEN 2B than in MEN 2A.
??
Acknowledgment
The authors acknowledge all the investigators who contributed to the findings discussed in this review but whose work could not be referenced, owing to space limitations.
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screening for multiple endocrine neoplasia type 2a: an 18-year experience. N Engl J Med 3 18:478-484.
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Bolino A, Schuffenecker I, Luo Y, et al.: 1995. RET mutations in exons 13 and 14 of FMTC patients. Oncogene l&2415-2419.
Hoefnagel CA, Delprat CC, Zanin D, van der Schoot JB: 1988. New mdionuclide tracers for the diagnosis and therapy of medullary thyroid carcinoma. Clin Nucl Med 13:159165.
Brandi ML, Weber G, Svensson A, et al.: 1993. Homozygotes for the autosomal dominant neoplasia syndrome (MENl). Am J Hum Genet 53: 1167-l 172. Buhr HJ, Kallinowski F, Raue F, Frank Raue K, Herfarth C: 1993. Microsurgical neck dissection for occultly metastasizing medullary thyroid carcinoma: three-year results. Cancer 72:3685-3693. Carlson KM, Bracamontes J, Jackson CE, et al.: 1994a. Parent of origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 551076-1082. Carlson KM, Dou S, Chi D, et al.: 1994b. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Nat1 Acad Sci USA 91:1579-1583. Camey JA, Sizemore GW, Sheps SG: 1976. Adrenal medullary disease in multiple endocrine neoplasia, type 2: pheochromocytoma and its precursors. Am J Clin Path01 66~279-290. Donis-Keller Mutations associated Mol Genet
H, Dou S, Chi D, et al.: 1993. in the RET proto-oncogene are with MEN 2A and FMTC. Hum 2:851-856.
Duh QY, Sancho JJ, Greenspan FS, et al.: 1989. Medullary thyroid carcinoma: the need for early diagnosis and total thyroidectomy. Arch Surg 124: 1206-1210. Eberle F, Gnm R: 1981. Multiple endocrine neoplasia, type I (MEN I). Ergeb Inn Med Kinderheilkd 46:76-149. Eng C, Smith DP, Mulligan LM, et al.: 1995. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene 10:509-S 13. Fraker DL, Norton JA: 1989. The role of surgery in the management of islet cell tumors. Gastroenterol Clin North Am 18:805-830. Fraker DL, Norton JA: 1993. Controversies in surgical therapy for APUDomas. Semin Surg Oncol9z437-442. Gage1 RF: 1991. The impact of gene mapping techniques in the management of multiple endocrine neoplasia type 2. Trends Endocrinol Metab 2: 19-25. Gage1 RF, Tashjian AH Jr, Cummings T, et al.: 1988. The clinical outcome of prospective
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Ross EJ, Prichard BNC, Kaufman L: 1971. Preoperative and operative management of patients with pheochromocytoma. BMJ 1:191-198. Samaan NA, Schultz PN, Hickey RC: 1988. Medullaty thyroid carcinoma: prognosis of familial versus sporadic disease and the role of radiotherapy. J Clin Endocrinol Metab 67801-805. Schimke RN: 1990. Multiple endocrine neoplasia: how many syndromes? [comments]. Am J Med Genet 37:375-383. Skogseid B, Eriksson B, Lundqvist G, et al.: 1991. Multiple endocrine neoplasia type 1: a IO-year prospective screening study in four kindreds. J Clin Endocrinol Metab 73: 281-287. Skogseid B, Larsson C, Lindgren PC, et al.: 1992. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 75:76-81. Skogseid B, Rastad J, Oberg K: 1994. Multiple endocrine neoplasia type 1: clinical fea-
tures and screening. Endocrinol Metab Clin North Am 23:1-18. Van Heerden JA, Sizemore GW, Carney JA, Grant CS, ReMine WH, Sheps SC: 1984. Surgical management of the adrenal glands in the multiple endocrine neoplasia type II syndrome. World J Surg 8:612-621. Van Heerden JA, Grant CS, Gharib H, Hay ID, Ilstrup DM: 1990. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 212:395-400. Vasen HF, LanternCB, Lips CJ: 1989. Screening for the multiple endocrine neoplasia syndrome type I: a study of 11 kindreds in The Netherlands. Arch Intern Med 149:27172722. Weber G, Friedman E, Grimmond S, et al.: 1994. The phospholipase C beta 3 gene located in the MEN1 region shows loss of expression in endocrine tumors. Hum Mol Genet 3:1775-1781.
Wells SA Jr, Baylin SB, Linehan WM. Farrell RE, Cox EB, Cooper CW: 1978 Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 188: 139-141. Wells SA, Chi D, Toshima K, Norton JA, Moley JF, Donis-Keller H: 1994a. Prophylactic thyroidectomy for Multiple Endocrine Neoplasia Type 2A [abst 841. In Proceedings of the Fifth International Workshop on MEN, Stockholm. Wells SA, Chi DD, Toshima K, et al.: 1994b. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 220:237-250. Xue F, Yu H, Maurer LH, et al.: 1994. Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. Hum Mol Genet 3:635-638. Zeiger MA, Shawker TH, Norton JA: 1993. Use of intraoperative ultrasonography to localize islet cell tumors. World J Surg TEM 17:448-454.
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Takemori S, Kominami S, Ikushiro S, Yamazaki T, Harada D: 1994. Reaction mechanism of P-450 dependent steroidogenesis: regulation of catalytic activity of bovine adrenal P-45O,,e. In Lechner MC, ed. Cytochrome P-450: Biochemistry, Biophysics and Molecular Biology. Paris, John Libbey Eurotext, pp 365-371. Wada A, Ohnishi T, Nonaka Y, Okamoto M, Yamano T: 1985. Synthesis of aldosterone by a reconstituted system of cytochrome P-450, rp from bovine adrenocortical mitochondria. J Biochem 98:245-256. White PC, Pascoe L: 1992. Disorders of steroid 11 g-hydroxylase isozymes. Trends Endocrinol Metab 3:229-234. Yanagibashi K, Haniu M, Shively JE, Shen WH, Hall P: 1986. The synthesis of aldosterone by the adrenal cortex: two zones (fasciculata and glomentlosa) possess one enzyme for 1 III-, 18-hydroxylation and aldehyde synthesis. J Biol Chem 261:35563562. Yanagibashi K, Kobayashi Y, Hall PF: 1990. Ascorbate as a source of reducing equivalents for the synthesis of aldosterone. Biothem Biophys Res Commun 170: 1256 1262.
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Diana L. Learoyd, Stephen M. Twigg, Debbie J. Marsh, and Bruce G. Robinson
Advances in the identification and localization of the abnormal genes in the multiple endocrine nwplasia syndromes have provided new methods of identifying “at risk” individuals in these families. Genetic testing using linkage analysis in multiple endocrine neoplasia (MEN) 1 and direct mutation analysis of the RET protooncogene in MEN 2 is now available for these disorders. New management issues for these disorders have resulted, and a practical approach to these issues is discussed. (Trends Endocrinol Metab 1995;6:273-278). The authors are at the Kolling Institute of Medical Research (D.L.L., S.M.T., D.J.M., B&R.), and the Department of Endocrinology (D.L.L., S.M.T., B.G.R.), at Royal North Shore Hospital, St. Leonards, New South Wales 2065, and the University of Sydney (D.L.L., S.M.T., D.J.M., B.G.R.), Sydney, New South Wales 2006, Australia.
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tification of disease gene carriers in these syndromes. A number of new management issues have resulted and new guidelines are being formulated to monitor the expression of the disease phenotype. In this review, we present a practical approach to the investigation and management of families with MEN type 1 or 2. Earlier reviews of MEN 1 and MEN 2 in this journal preceded recent genetic advances in both of these conditions (Marx 1989, Gage1 1991).
*
Multiple Endocrine Neoplasia Type 1
MEN 1 is an autosomal dominant syndrome characteristically involving tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary. The propensity for specific organ involvement tends to be consistent in any one family (Skogseid et al. 1991). In contrast to sporadic (nonfamilial) endocrine tumors in these involved tissues, tumors in MEN 1 are more often multicentric, are commonly associated with hyperplasia, and have a higher rate of recurrence following treatment. Genetic Screening in Multiple Endocrine Neoplasia Type 1
The Practical Management of Multiple Endocrine Neoplasia
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There have been several recent advances in the understanding of the pathogenesis of the multiple endocrine neoplasia (MEN) syndromes. These new findings have subsequently been applied to iden-
The gene segregating with the clinical defects found in MEN 1 is believed to be a tumor suppressor gene that maps to a 900-kb region on the long arm of chromosome 11 at 1 lq13 (Weber et al. 1994). Loss of heterozygosity at this site has been detected in 70% of tumor tissue samples studied in MEN 1. The disorder is autosomal dominant, and offspring of an affected individual have a 50% chance of inheriting the disease phenotype. Genetic screening for this disease is performed by linkage analysis. In a family in which at least two individuals are affected and there are informative markers flanking the MEN1 locus, risk
estimates of greater than 99.5% for carrying the defective gene can be given (Larsson et al. 1992). Following identification of a gene carrier, specific organ screening should follow in an attempt to detect and treat tumors at their earliest stage. The com-
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Zollinger-Ellison syndrome, which is characterized by elevated serum gastrin, gastric acid hypersecretion, diarrhea, and severe esophagitis, with recurrent Genetic screening of f$ly by linkage analysis allows and multiple peptic ulcers. Duodenal >99.5% risk estimation with gastrinomas occur more commonly in MEN 1 than in sporadic disease. Techniques traditionally used to localize gasScreening investigations trinomas include transabdominal and for specific organ disease intraoperative ultrasound, CT scanning, parathyroid ( calcium & parathyroid hormone), pituitary and portal venous sampling. Recently, (prolactin), pancreas (fasting sequential injection of secretin into the gastrin). Commence at age 15 celiac axis with subsequent hepatic vein sampling for gastrin has been shown to localize pancreatic gastrinomas better Repeat screening than angiography alone and to have less Define, localise & Reassure ‘linkage every 3 years. treat specific organ negative’ family morbidity than transhepatic portal disease. members. venous sampling (Fraker and Norton 1993). If possible, distal pancreatectomy Figure 1. Familial multiple endocrine neoplasia type 1. Management algorithm. is performed for gastrinomas in the tail or body of the pancreas, and lesions in with mild hypercalcemia and a clear diag- the pancreatic head or duodenum are bined use of genetic and specific organ nosis of hyperparathyroidism because screening (Figure 1) has reduced the age enucleated. Total pancreatectomy has hypercalcemia is progressive and may po- been used in some cases when an aggresof detecting clinical organ involvement tentiate pituitary and pancreatic disease, in MEN 1 to the late teens rather than sive tumor course has occurred in family including hypergastrinemia (Fraker and the fourth decade, as was previously the members. Recurrent and/or metastatic Norton 1989). Other units delay initial case (Vasen et al. 1989). Specific organ disease occurs in 50% of patients (Grasurgery because of high rates of permascreening is performed by measurement ma et al. 1992). Palliative medical thernent hypoparathyroidism or recurrent hy- apies to control hyperacidity include of serum ionized calcium, PTH, PRL, and basal serum gastrin. Compliance is percalcemia postoperatively. high-dose proton pump inhibitors and Three and a half gland parathyroidecgreatest if screening is kept simple and the somatostatin analogue octreotide. regular. Occasionally, further tests in- tomy and cervical thymectomy should Partial hepatectomy and hepatic transbe performed by an experienced survolving a specific organ may be indiplantation are palliative options in all geon. More limited surgery results in types of islet cell cancer with hepatic cated if a particular tumor type has been rapid recurrence of hypercalcemia. A involvement. present in a family. Some groups recommend more extensive screening for all 40-60-mg parathyroid remnant from Insulinoma occurs in up to 35% of one gland may be relocated in the neck families (Skogseid et al. 1991). MEN 1 patients, with metastases in 5% or placed into the forearm and clipped to 10% of cases (Rasbach et al. 1985). Parathyroid Disease for ease of future identification. In the Fasting endogenous hyperinsulinemia common case of recurrent disease, localduring symptomatic hypoglycemia and Hyperparathyroidism is the most comization procedures preoperatively may elevated ratio of serum proinsulin to inmon abnormality in MEN 1 and usually sulin are diagnostic. In addition to prethe first to be detected on screening. On- have a role. 99mTc sestamibi scanning may improve sensitivity in localizing viously described localizing procedures, set is described in the teens and, by age parathyroid disease over other comselective arterial catheterization with 40, greater than 95% of MEN 1 patients bined modalities, such as computerized calcium injection as an insulin secretahave hypercalcemia (Eberle and Grun tomography (CT), magnetic resonance gogue may be helpful (Fraker and 1981). Multiple gland hyperplasia, imaging (MRI), ultrasound, and Norton 1993). Intraoperative ultrasound which may lead to one or more parathythallium-technetium scanning (Mitchell may localize disease not determined by roid adenomas, is characteristic. other methods, including palpation at Diagnosis is made by detection of si- et al. 1995). surgery (Zeiger et al. 1993). Patients multaneously elevated serum calcium and Pancreatic Disease with insulinoma are usually cured by PTH levels with an elevated urinary ca.lPalliative Pancreatic islet cell tumors occur in 30% subtotal pancreatectomy. cium to creatinine ratio. Measuring ionto 80% of patients (Vasen et al. 1989). medical therapy for inoperable metaized serum calcium and PTH may detect Multicentric disease is common, and static or recurrent disease includes diadisease at an earlier stage than total serum zoxide and chemotherapy with streptocalcium corrected for albumin (Benson et slowly growing metastases occur in approximately 50% of cases. Multiple pepzotocin, dacarbazine and 5-fluorouracil, al. 1987). We have not found preoperative localizing studies to be helpful unless hy- tides may be secreted by a tumor, alalone or in combination. Octreotide is generally not beneficial and can exacerperpamthyroidism recurs and repeat sur- though usually one predominates. Gastrinomas occur in up to 60% of gery is being considered. We favor early bate hypoglycemia. For hepatic disease, MEN 1 patients, and may cause the parathyroidectomy in MEN 1 patients the options are as for gastrinoma.
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Rare
islet cell tumors
in MEN
1 in-
vasointestinal clude glucagonomas, polypeptide (VIP)omas, and those prepancreatic dominantly secreting polypeptide. Plasma glucagon is nonspecifically elevated in the majority of MEN 1 patients. True glucagonomas cause a clinical syndrome with a characteristic rash (necrolytic migratory erythema) and hyperglycemia. Pancreatic polypeptide is also commonly elevated in MEN 1, but does not cause a specific clinical syndrome. Markedly elevated levels following a stimulatory meal can identify patients with pancreatic lesions. VIPomas may produce the Verner-Morrison syndrome, with watery diarrhea, achlorhydria, and hypokalemia. Treatment of these rare tumors is surgical. Chemotherapy and octreotide are palliative options to control symptoms of hormonal excess. There is no evidence that octreotide clearly reduces the bulk of any islet cell tumors. Pituitary Adenomas in Multiple Endocrine Neoplasia Type 1 Pituitary adenomas occur in 15%42% of MEN 1 patients (Skogseid et al. 1994). Prolactinomas are the most common pituitary lesion. Acromegaly is usually caused by a pituitary tumor, although rare pancreatic tumors may release GHRH ectopically, and measurement of this hormone in peripheral blood is indicated in the workup of MEN 1 patients with acromegaly. Cushing’s syndrome in MEN 1 may also rarely be due to ectopic ACTH and/or CRH production. Diagnosis and management of pituitary adenoma in MEN 1 is equivalent to that in sporadic disease, with the added awareness of potential associated ectopic releasing hormone production. The recurrence rate of pituitary tumors exceeds that in sporadic disease, probably owing to the propensity to multicentric disease in MEN 1. Hypophysectomy (complete anterior pituitary resection), and external beam radiotherapy are indicated in recurrent disease. Subcutaneous octreotide therapy can reduce pituitary tumor size and control hormonal excess in acromegaly
not cured by initial surgery.
Other Clinical Manifestations Multiple Endocrine
in
Neoplasia Type 1
Other tissue manifestations include carcinoid tumors, which in MEN 1 are usually in the thymus or lungs. Surgical
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Familial MEN 2 / FMTC + Identify germline mutation in family (blood DNA) - codons 609,611,618,620,634,768,
Mutation identified identified
in family.
Assess patient for presence of pheochromocytoma - 24 hour urinary catecholamines & metanephriies.
v
Reassure patient. No further testing.
Remove pheochromocytoma prior to further surgery.
Reassure and repeat annually up to age of 30 years.
2. Familial multiple endocrine neoplasia type 2. Management algorithm. FMTC, familial medullary thyroid carcinoma.
Figure
cure for carcinoid tumor is attempted as first line therapy, but palliative chemotherapy with combinations of methotrexate and cyclophosphamide or streptozotocin and 5-fluorouracil, plus octreotide or interferon, may be used in incurable cases to control associated hormonal features. Adrenocortical adenomas, bilateral or unilateral, are reported in up to one-third of patients; primary hyperaldosteronism may occasionally be present (Becker-s et al. 1992), and adrenocortical carcinoma has been reported (Skogseid et al. 1992). Impaired fertility has been reported in siblings with germline deletions of both alleles of the MENJ locus (Brandi et al. 1993).
??
Multiple Endocrine Neoplasia Type 2
Previously known as Sipple’s syndrome, MEN 2 is characterized by three endocrine tumors in different combinations. In MEN 2A, medullary thyroid carcinoma (MTC) occurs in combination with pheochromocytoma in up to 50% of cases and hyperparathyroidism in 15% 30% (Schimke 1990). In MEN 2B, the features of MEN 2A occur together with mucosal neuromas, Marfanoid body habitus, and ganglioneuromatosis of the gastrointestinal tract. In addition, MTC
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may also occur in families without other manifestations (familial MTC, or FMTC). As with MEN 1, these syndromes exhibit autosomal dominant inheritance, although some MEN 2B cases occur de novo (Carlson et al. 1994a). An approach to the investigation and management of familial MEN 2 is illustrated in Figure 2. Genetic Screening in Multiple Endocrine Neoplasia Type 2 Germline point mutations have been identified in the RET protooncogene on chromosome 10 segregating with the disease phenotype in MEN 2 and FMTC (Mulligan et al. 1993, Donis-Keller et al. 1993, Hofstra et al. 1994, Marsh et al. 1994, Eng et al. 1995, Bolino et al. 1995). The majority of the mutations segregating with MEN 2A and FMTC are clustered in five cysteine (TGC) codons, in exon 10 (codon 609, 611, 618, and 620) in the extracellular domain, and in exon 11 (codon 634) in the transmembrane domain of RET. A germline mutation in codon 9 18 in exon 16 in the tyrosine kinase domain of RET has been found in both familial and de novo MEN 2B (Carlson et al. 1994b). This mutation causes the substitution of a methionine (ATG) by a threonine (ACG). Currently, data from 12 centers worldwide are being collected by the RET Mutation Con-
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sortium and analyzed for confirmation of predicted genotype-phenotype correlations, including the suggestion that the codon 634 mutations correlate with the presence of pheochromocytoma (Mulligan et al. 1994 and 1995). Genetic screening of individuals with the clinical presentations of MEN 2 or FMTC, or those individuals at risk of inheriting one of these syndromes, is now readily available and is performed on DNA extracted from peripheral blood leukocytes. Rapid screening methods have been described (Marsh et al. 1994, Wells et al. 1994b, Xue et al. 1994), and these should always be performed on two blood samples collected for genetic analysis at different times to minimize the chance of a sample mix-up. Management of a New Multiple Endocrine Neophzsia Type 2 Family Accurate history taking and careful review of histopathological data are essential to confirm that one is dealing with a MEN 2 family. There are a number of families that have been incorrectly given this diagnostic label on the basis of one family member with documented MTC and one or two others with alleged C cell hyperplasia (CCH) or family members who have died of the complications of hypertension (unpublished observations). Once adequate phenotypic evidence of MEN 2 is present, it is appropriate to begin screening the RET protooncogene for the described mutations in these syndromes. Mutations are present in approximately 86% of FMTC families, in 97% of MEN 2A families (Mulligan et al. 1994), and in greater than 93% of MEN 2B families (Mulligan et al. 1995). The identification of a mutation in a family enables rapid determination of those family members who carry the mutation and those who do not. Noncarriers do not require further investigation and can be reassured that their risk of developing thyroid carcinoma is not different from that of the normal population. Investigation of RET Mutation Carriers The most appropriate management of RET mutation carriers has not been clearly established, although at the Fifth International Workshop on Multiple Endocrine Neoplasia in Stockholm there was general agreement that thyroidectomy should be performed in mutation
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carriers aged 6 years or older (Wells et al. 1994a). A more conservative approach would involve performing annual pentagastrin stimulation tests on RET mutation carriers and performing thyroidectomy when the test becomes abnormal. There is evidence that individuals found to have CCH rather than MTC would have a good prognosis (Gagel et al. 1988). The major problem with this approach is that the pentagastrin test is unpleasant and annual compliance rates are likely to be low. Ninetyfive percent of gene carriers will have a positive pentagastrin test by the age of 30 years (Ponder et al. 1988). Annual assessment for the presence of pheochromocytoma should include obtaining a careful history and physical examination, including measurement of supine and erect blood pressure and measurement of urinary catecholamines Pheochromocyand metanephrines. toma usually presents several years after MTC (Camey et al. 1976), but formal assessment for its presence should be performed in RET mutation carriers prior to any operation. The anesthesiologist should be made aware of the possibility of pheochromocytoma in these patients even if catecholamines are normal. Hyperparathyroidism is relatively uncommon and can be readily excluded by measurement of serum calcium at the annual assessment. Management of Medullary Thyroid Carcinoma MTC can be multicentric and bilateral and, in 50% of cases, has metastasized to cervical lymph nodes at the time of diagnosis (Wells et al. 1978). Primary surgery should include total thyroidectomy and removal of all lymph nodes in the central neck compartment. Macroscopitally abnormal nodes in the lateral neck compartment and upper mediastinum should also be removed (Duh et al. 1989). Several groups are performing studies of extensive initial surgery such as radical neck dissection (Buhr et al. 1993). An improvement in long-term outcome is, however, yet to be demonstrated with these approaches. Postoperatively, patients are screened for recurrence with calcitonin and/or carcinoembryonic antigen (CEA) measurements. The number of techniques described for localization of recurrence,
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including radionuclide scanning with 201 thallium, 99mTc DMSA, 99mTc sesta1311 metaiodobenzylguanidine mibi, (MIBG), radiolabeled monoclonal antibodies, and labeled somatostatin receptors, indicates that each has limitations (Hoefnagel et al. 1988). Ultrasound, CT, and MRI scans are commonly used, but sensitivity is only about 50% (Abdelmoumene et al. 1994). Selective venous catheterization is the most sensitive method of localizing recurrence, especially when combined with pentagastrin stimulation (Abdelmoumene et al. 1994), but it is both invasive and unpleasant. Therapy for Recurrent Disease Surgery aimed at debulking macroscopic tumor offers the best option, although biochemical cures appear difficult to achieve even with extensive surgery (Van Heerden et al. 1990), and data on long-term outcome are scarce. Other therapies have little place for recurrent or metastatic disease. Radiotherapy may have a role in palliation, such as for bone pain, but studies have shown no survival benefit either when it is given perioperatively or separately (Samaan et al. chemotherapeutic 1988). Multiple agents have been used both alone and in combination. Doxorubicin is the most effective single agent, giving partial response rates of about 30%, but in general the studies are very small and results disappointing. The long-acting somatostatin analogue octreotide may be used for symptom control, and there are case reports of diarrhea being controlled by its use and calcitonin levels declining (Mahler et al. 1990). Pheochromocytoma Pheochromocytoma in MEN 2 may be bilateral and often presents years after MTC. Screening should always be performed prior to any surgery in RET mutation carriers by measurement of 24-h urine catecholamine and metanephrine levels. Repeated measurements are often required and patients may be given bottles for the collection to be used on a day that symptoms are experienced. Once catecholamine excess is proven, imaging of the adrenals with 1311-or ‘231-labeled MIBG should be performed because of the high frequency of multiple tumors. Preoperative preparation with (r receptor blockade and the subsequent intro-
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duction of p blockade is well described (Ross et al. 1971). Surgery is generally performed 2-3 weeks after the institution of (r and/or g receptor blockade and with an experienced anesthesiologist. The affected adrenal is removed and the opposite adrenal inspected for enlargement or nodularity. This necessitates an anterior surgical approach. Some authors have proposed that bilateral adrenalectomy be performed initially because of the 50% likelihood that the unaffected adrenal will develop a pheochromocytoma within 10 years (Van Heerden 1984). This area remains controversial because of the problems associated with rendering a patient adrenally insufficient. Hyperparathyroidism
Parathyroid disease in MEN 2 is investigated and managed as in MEN 1 (see earlier discussion here).
??
Multiple Endocrine Neoplasia Type 2b
The features of this syndrome have already been mentioned. Investigations and management are as for MEN 2A; however, it should be noted that the MTC occurs in a more aggressive form than in MEN 2A or sporadic MTC, and thyroidectomy should be performed as early as possible. The neuromas may require surgical removal if they cause local obstruction, and gastrointestinal tract involvement may lead to intestinal obstruction. Parathyroid disease is less common in MEN 2B than in MEN 2A.
??
Acknowledgment
The authors acknowledge all the investigators who contributed to the findings discussed in this review but whose work could not be referenced, owing to space limitations.
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Benson L, Ljunghall S, Groth T, et al.: 1987. Optimal discrimination of mild hyperparathyroidism with total serum calcium, ionized calcium and parathyroid hormone measurements. Ups J Med Sci 92:147-176.
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Bolino A, Schuffenecker I, Luo Y, et al.: 1995. RET mutations in exons 13 and 14 of FMTC patients. Oncogene l&2415-2419.
Hoefnagel CA, Delprat CC, Zanin D, van der Schoot JB: 1988. New mdionuclide tracers for the diagnosis and therapy of medullary thyroid carcinoma. Clin Nucl Med 13:159165.
Brandi ML, Weber G, Svensson A, et al.: 1993. Homozygotes for the autosomal dominant neoplasia syndrome (MENl). Am J Hum Genet 53: 1167-l 172. Buhr HJ, Kallinowski F, Raue F, Frank Raue K, Herfarth C: 1993. Microsurgical neck dissection for occultly metastasizing medullary thyroid carcinoma: three-year results. Cancer 72:3685-3693. Carlson KM, Bracamontes J, Jackson CE, et al.: 1994a. Parent of origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 551076-1082. Carlson KM, Dou S, Chi D, et al.: 1994b. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Nat1 Acad Sci USA 91:1579-1583. Camey JA, Sizemore GW, Sheps SG: 1976. Adrenal medullary disease in multiple endocrine neoplasia, type 2: pheochromocytoma and its precursors. Am J Clin Path01 66~279-290. Donis-Keller Mutations associated Mol Genet
H, Dou S, Chi D, et al.: 1993. in the RET proto-oncogene are with MEN 2A and FMTC. Hum 2:851-856.
Duh QY, Sancho JJ, Greenspan FS, et al.: 1989. Medullary thyroid carcinoma: the need for early diagnosis and total thyroidectomy. Arch Surg 124: 1206-1210. Eberle F, Gnm R: 1981. Multiple endocrine neoplasia, type I (MEN I). Ergeb Inn Med Kinderheilkd 46:76-149. Eng C, Smith DP, Mulligan LM, et al.: 1995. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene 10:509-S 13. Fraker DL, Norton JA: 1989. The role of surgery in the management of islet cell tumors. Gastroenterol Clin North Am 18:805-830. Fraker DL, Norton JA: 1993. Controversies in surgical therapy for APUDomas. Semin Surg Oncol9z437-442. Gage1 RF: 1991. The impact of gene mapping techniques in the management of multiple endocrine neoplasia type 2. Trends Endocrinol Metab 2: 19-25. Gage1 RF, Tashjian AH Jr, Cummings T, et al.: 1988. The clinical outcome of prospective
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Ross EJ, Prichard BNC, Kaufman L: 1971. Preoperative and operative management of patients with pheochromocytoma. BMJ 1:191-198. Samaan NA, Schultz PN, Hickey RC: 1988. Medullaty thyroid carcinoma: prognosis of familial versus sporadic disease and the role of radiotherapy. J Clin Endocrinol Metab 67801-805. Schimke RN: 1990. Multiple endocrine neoplasia: how many syndromes? [comments]. Am J Med Genet 37:375-383. Skogseid B, Eriksson B, Lundqvist G, et al.: 1991. Multiple endocrine neoplasia type 1: a IO-year prospective screening study in four kindreds. J Clin Endocrinol Metab 73: 281-287. Skogseid B, Larsson C, Lindgren PC, et al.: 1992. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 75:76-81. Skogseid B, Rastad J, Oberg K: 1994. Multiple endocrine neoplasia type 1: clinical fea-
tures and screening. Endocrinol Metab Clin North Am 23:1-18. Van Heerden JA, Sizemore GW, Carney JA, Grant CS, ReMine WH, Sheps SC: 1984. Surgical management of the adrenal glands in the multiple endocrine neoplasia type II syndrome. World J Surg 8:612-621. Van Heerden JA, Grant CS, Gharib H, Hay ID, Ilstrup DM: 1990. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 212:395-400. Vasen HF, LanternCB, Lips CJ: 1989. Screening for the multiple endocrine neoplasia syndrome type I: a study of 11 kindreds in The Netherlands. Arch Intern Med 149:27172722. Weber G, Friedman E, Grimmond S, et al.: 1994. The phospholipase C beta 3 gene located in the MEN1 region shows loss of expression in endocrine tumors. Hum Mol Genet 3:1775-1781.
Wells SA Jr, Baylin SB, Linehan WM. Farrell RE, Cox EB, Cooper CW: 1978 Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 188: 139-141. Wells SA, Chi D, Toshima K, Norton JA, Moley JF, Donis-Keller H: 1994a. Prophylactic thyroidectomy for Multiple Endocrine Neoplasia Type 2A [abst 841. In Proceedings of the Fifth International Workshop on MEN, Stockholm. Wells SA, Chi DD, Toshima K, et al.: 1994b. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 220:237-250. Xue F, Yu H, Maurer LH, et al.: 1994. Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. Hum Mol Genet 3:635-638. Zeiger MA, Shawker TH, Norton JA: 1993. Use of intraoperative ultrasonography to localize islet cell tumors. World J Surg TEM 17:448-454.
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