Multiple endocrine neoplasia type 2B — genetic basis and clinical expression

Surgical Oncology 9 (2000) 111}118

Multiple endocrine neoplasia type 2B * genetic basis and clinical expression N.C. Lee , J.A. Norton 
* Department of Surgery, University of California, San Francisco, CA 94143, USA
Department of Surgery, San Francisco Veterans Awairs Medical Center, San Francisco, CA 94121, USA

Abstract Multiple endocrine neoplasia (MEN) type 2B is a heritable endocrine disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, multiple mucosal neuromas, and a marfanoid habitus. Intestinal ganglioneuromatosis, corneal nerve thickening and skeletal abnormalities are also often present. The disease is inherited in an autosomal dominant fashion and is caused by a single mutation in the RET proto-oncogene, with a methionine to threonine substitution at codon 918. The MTC in MEN 2B presents at an earlier age and tends to be more aggressive than the MTC in MEN 2A. It is multicentric and bilateral and occurs as young as age 3, with early lymph node metastases. Pheochromocytoma is also often bilateral but is rarely malignant. If pheochromocytoma is detected, adrenalectomy should precede thyroidectomy to avoid intraoperative catecholamine crisis. Patients at risk for MEN 2B should undergo genetic screening in infancy. Total thyroidectomy should be performed on all patients positive for RET mutations even prior to the onset of clinical symptoms.  2001 Published by Elsevier Science Ltd. Keywords: Multiple endocrine neoplasia type 2B; RET proto-oncogene; Medullary thyroid carcinoma; Pheochromocytoma; Mucosal neuroma syndrome

Multiple endocrine neoplasia (MEN) type 2B belongs to a family of heritable endocrine diseases that includes MEN 1, MEN 2A, and familial medullary thyroid carcinoma (FMTC) (Table 1). The "rst description of tumors arising in multiple endocrine organs was in 1903 by Erdheim [1]. Fifty years later, Wermer reported the familial occurrence of adenomas in the pituitary, parathyroids, and pancreatic islet cells, now known as MEN 1 [2]. In 1959, Hazard et al. "rst recognized medullary thyroid carcinoma as a distinct tumor [3]. Sipple "rst described the association of medullary thyroid cancer, pheochromocytoma and parathyroid adenoma in 1961 [4], and the syndrome was later termed `multiple endocrine neoplasia type 2a by Steiner et al. [5]. The association between medullary thyroid carcinoma, pheochromocytoma, and multiple mucosal neuromas was described by Williams and Pollock in 1966 and con"rmed by others including Gorlin and Schimke [6}8]. This syndrome was named MEN 2B in 1975 by * Corresponding author at Department of Surgery, San Francisco Veterans Administration Hospital, San Francisco, CA 94121, USA. Fax: #1-415-750-2181. E-mail addresses: [email protected] (N.C. Lee), janortn@ itsa.ucsf.edu (J.A. Norton).

Chong et al. to distinguish it from Sipple syndrome (now called MEN 2A) [9]. Both MEN 2A and 2B share the presence of medullary thyroid carcinoma and pheochromocytoma. MEN 2B is further distinguished by a characteristic phenotype that includes multiple mucosal neuromas, intestinal ganglioneuromatosis, a marfanoid habitus, and musculoskeletal and ophthalmic abnormalities. Hyperparathyroidism, which occurs in up to 30% of MEN 2A patients, is not found in MEN 2B [10]. Familial medullary thyroid cancer is de"ned by the presence of medullary thyroid cancer in four or more family members without the associated endocrine abnormalities seen in MEN 2A and 2B [11]. Ninety percent of the cases of MEN 2 are of the MEN 2A subtype [12]. While MEN 2B is less common, it appears at an earlier age and tends to be more aggressive than MEN 2A [13]. The average age of onset is in the second to third decade of life for MEN 2A, but patients with MEN 2B present in the "rst to second decade of life [14]. Patients with MEN 2B also tend to have a poorer prognosis than patients with MEN 2A or FMTC [15]. Whereas 80% of MEN 2A cases are caused by genetic inheritance, 50% of MEN 2B cases are due to de novo mutations [16]. This statistic re#ects that on average,

0960-7404/01/$ - see front matter  2001 Published by Elsevier Science Ltd. PII: S 0 9 6 0 - 7 4 0 4 ( 0 0 ) 0 0 0 3 8 - 4

112

N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118

MEN 2B patients are less likely to reproduce because they die of their disease at an earlier age. MEN 2B demonstrates an autosomal dominant pattern of inheritance. There is essentially complete penetrance of the genetic defect, but with variable expressivity, as not all patients manifest all the characteristics of the syndrome [17]. Although there is an equal sex distribution in inherited cases, Carlson et al. have shown that 25 of 25 sporadic cases of MEN 2B were formed from mutations on the paternally derived chromosome, suggesting that a RET allele may be more susceptible to mutation when inherited from the father [16]. MEN 2A, 2B, and FMTC are all caused by defects in the RET proto-oncogene. The RET (rearranged during transfection) proto-oncogene was "rst cloned as a chimeric oncogene during a classic NIH3T3 transformation assay [18]. The gene is located on chromosome 10q11.2 and consists of 21 exons spanning 55 kb [19,20]. The extracellular domain consists of a cysteine-rich region close to the cellular membrane and a more distal cadherin-like domain. Beyond a transmembrane portion there is an intracellular portion with two tyrosine kinase domains [21]. The RET gene encodes a cell surface glycoprotein which is a member of the receptor tyrosine kinase family. Binding of the RET ligand, glial-derived neurotropic factor, causes dimerization and activation of the receptor [22]. The RET gene is important in

signalling for cell growth and di!erentiation of tissues derived from neural crest cells, such as the C cells of the thyroid, the adrenal medulla, the parathyroid gland, and the enteric autonomic nerve plexus [23]. Loss of RET function prevents renal organogenesis and enteric neuron formation in mice [24]. In MEN 2A, 2B, and FMTC, mutations in the RET gene lead to activation of the gene [25]. Therefore, only a single copy of the gene need be mutated in order to cause disease. Over 95% of MEN 2B cases are caused by a single point mutation in the intracellular tyrosine kinase domain of the RET gene, with a substitution of threonine for methionine at codon 918 in exon 16 [26}28]. This MEN 2B mutation induces medullary thyroid carcinoma in transgenic mice [29]. This speci"c mutation is also found in sporadic cases of MEN 2B and is associated with a poor prognosis [30,31]. There have also been a few reported cases of MEN 2B with a mutation in codon 883, with a substitution of phenylalanine for alanine [32,33]. In contrast, there are several di!erent mutations causing MEN 2A and FMTC, which are located in the cysteine-rich extracellular domain. Mutations within one of "ve cysteine codons are found in 85}95% of patients with MEN-2A and FMTC, including mutations at codons 609, 611, 618, and 620 in exon 10 and codon 634 in exon 11 of the RET gene (Fig. 1) [34].

Table 1 Clinical and genetic characteristics of the multiple endocrine neoplasias MEN 1

MEN 2A

MEN 2B

FMTC

Age of onset Clinical features

20}30 Parathyroid hyperplasia Pancreatic islet cell tumors Anterior pituitary tumors

20}30 Medullary thyroid carcinoma Pheochromocytoma Parathyroid hyperplasia

40}50 Medullary thyroid carcinoma

Inheritance A!ected gene Chromosome Codons

Autosomal dominant menin tumor suppressor gene 11q13

Autosomal dominant RET proto-oncogene 10q11.2 609, 611, 618, 620, 634

0}20 Medullary thyroid carcinoma Pheochromocytoma Mucosal neuromas Marfanoid habitus Autosomal dominant RET proto-oncogene 10q11.2 918

Autosomal dominant RET proto-oncogene 10q11.2 609, 611, 618, 620, 768, 883

MEN, multiple endocrine neoplasia; FMTC, familial medullary thyroid carcinoma.

Fig. 1. Schematic diagram of the RET proto-oncogene receptor tyrosine kinase protein. Substitution mutations in one of "ve cysteine residues in exons 10 and 11 in the extracellular domain lead to multiple endocrine neoplasia (MEN) 2A and familial medullary thyroid carcinoma (FMTC). Mutations in codons 768 and 883 in exons 13 and 14 of the intracellular tyrosine kinase 1 region are associated with FMTC alone. Methionine to threonine mutation in codon 918 in exon 16 of the intracellular tyrosine kinase 2 region results in MEN 2B.

N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118

113

Fig. 2. The characteristic phenotype of MEN 2B include mucosal neuromas present on the lips and anterior third of the tongue.

Fig. 3. Slit lamp examination in the same patient reveals corneal nerve hypertrophy.

Patients with MEN-2B have a striking phenotypic appearance which includes mucosal neuromas and musculoskeletal abnormalities [35]. Patients have mucosal neuromas on the anterior third of the tongue, buccal mucosa, lips, and inner eyelids (Fig. 2). These neuromas contribute to a facies marked by thickened irregular lips and thickened, sometimes everted eyelids. The patients exhibit a marfanoid habitus with a tall and slender build, long limbs and high arched palate, and a long thin face with prognathism. Bony abnormalities are present such as pectus excavatum, pes cavus, talipes equinovarus, slipped capital femoral epiphysis, kyphosis, scoliosis, and increased joint laxity. Ocular manifestations such as corneal nerve hypertrophy on slit lamp examination may also be seen [36] (Fig. 3).

Intestinal involvement is a prominent feature of MEN 2B, and is usually present early in life before the endocrine neoplasms are manifest. Most patients describe constipation since early infancy. Other features include abdominal pain and cramping, projectile vomiting, diverticulosis and megacolon in severe cases. In adulthood either constipation or diarrhea is usually present. The diarrhea is thought to be due to the release of humoral factors such as calcitonin by the hyperplastic C-cells [37]. Intestinal ganglioneuromatosis is present anywhere from the oral mucosa to the rectum (Fig. 4). Pathological specimens demonstrate hypertrophy and disorganization of the myenteric plexus and proliferation of ganglions. The ganglioneuromatosis causes defective peristalsis and poor contractility [38]. Patients with intestinal

114

N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118

Fig. 4. Intestinal ganglioneuromatosis is present in nearly all MEN 2B patients, with nodular neuromas present on the mucosal surfaces of the bowel.

Fig. 5. Medullary thyroid carcinoma is usually multicentric and bilateral, and is located at the junction of the upper and middle 1/3 of the thyroid lobes, where the greatest concentration of C-cells is present.

ganglioneuromatosis exhibit similar symptoms to patients with Hirschsprung's disease. Interestingly, Hirschsprung's disease has also been linked to defects in the RET gene. While RET mutations in MEN lead to activating gain-of-function mutations which lead to uncontrolled cellular proliferation, the mutations causing Hirschprung's disease instead cause loss of function and absence of intestinal ganglia [39,40]. Essentially, all MEN 2B patients develop medullary thyroid cancer, which is a tumor of calcitonin-secreting parafollicular C cells [41]. Patients with MEN 2B who are not diagnosed based on the typical phenotype usually present "rst with a neck mass due to the medullary thyroid carcinoma. Medullary thyroid cancer presents at an earlier age in MEN 2B and follows a more virulent

course, with earlier metastasis and a poorer prognosis compared to MEN 2A and FMTC [13]. Metastases appear "rst in the regional cervical or mediastinal lymph nodes, followed by distant metastases in the liver, lungs, and bone [17]. The mean age at diagnosis of MTC was 20 years in MEN 2B, as compared to 25 years in MEN 2A, 29 years in FMTC, and 47 years in sporadic cases [42]. The medullary thyroid carcinoma in MEN is almost always multicentric and bilateral, whereas sporadic cases of MTC are usually unilateral [15]. C-cells are located primarily in the superior poles of the thyroid, at the junction of the upper and middle thirds, and the medullary thyroid tumors develop here as whitish brown, well-circumscribed nodules [17] (Fig. 5). C-cell hyperplasia is thought to be a precursor of MTC, and has been

N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118

documented in MEN 2B patients as young as 3 months [43]. Fine-needle aspiration biopsies typically show characteristic changes for MTC including multinucleation, amyloid, and calci"cations as well as trabecular, alveolar, and spindle cell patterns of tumor growth, and can be con"rmed by staining for calcitonin [44]. Patients with C-cell hyperplasia or MTC have elevations in plasma calcitonin levels due to secretion of calcitonin by the C-cells. A serum calcitonin level greater than 1000 pg/ml associated with an elevated carcinoembryonic antigen con"rms the diagnosis [15]. Provocative tests with calcium and pentagastrin are used to detect tumors when the plasma calcitonin is normal. The calcitonin level is measured before and 1}3 and 5 min after intravenous infusion of 2 mg/kg/min calcium gluconate and 0.5
g/kg/5 s pentagastrin [45]. However, this test is associated with unpleasant side e!ects such as diarrhea, abdominal cramping, #ushing, and vomiting. The test may also be associated with both false-positive and false-negative results, which decreases its utility for screening. With the development of direct genetic testing for RET mutations, the provocative test is now reserved for detecting persistent or recurrent MTC after total thyroidectomy [14]. Direct testing of peripheral leukocytes for RET mutations requires only a single blood sample and is highly accurate and speci"c. Mutations of the RET gene are detected using PCR ampli"cation and analysis of restriction endonuclease digestion of RET fragments or by direct DNA sequencing [46]. Since MTC is almost always bilateral in MEN, pre-operative radiologic studies are not usually needed, but CT, MRI and somatostatin receptor scintigraphy can be used to localize recurrences or metastases [47]. MTC is resistant to radiation and chemotherapy; thus surgical resection o!ers the only chance for cure. The standard for MTC is to perform total thyroidectomy with central neck lymph node dissection [42]. Patients with MEN 2A have a 30% risk of developing hyperparathyroidism and so the parathyroids are usually removed, with autotransplantation to the forearm. Unlike MEN 2A, patients with MEN 2B are not at risk for hyperparathyroidism and the parathyroid glands can be grafted onto the sternocleidomastoid [15]. Early diagnosis of MTC is essential given the highly aggressive nature and metastatic potential of the disease. Genetic testing should be performed by age 5 for patients at risk for MEN 2A, and even as early as 1 year for patients at risk for MEN 2B. Prophylactic thyroidectomy should be performed once a RET mutation is detected, and can be done even in infancy [48]. Thyroidectomy for MTC in the setting of MEN 2B has been performed on patients as young as 7 months [49]. In a study of MEN 2 patients undergoing thyroidectomy based on the clinical or biochemical indications, MTC was found in 45 of 46 patients (98%) and C-cell hyperplasia in one patient. Those patients who had thyroidectomy based on a positive

115

genetic result for RET mutations had MTC in 3 of 7 patients (43%) and C-cell hyperplasia in 4 of 7 (57%) [50]. Wells et al. performed genetic testing on 58 kindred members at risk for MEN 2A and found that 21 had inherited a RET mutation. Of these, 18 underwent thyroidectomy and all were found to have C-cell hyperplasia. Nine had microscopic MTC and 5 had macroscopic MTC [51]. These and other studies demonstrate that genetic screening for RET mutations allows thyroidectomy to be performed at an earlier stage of disease than relying on clinical symptoms or standard biochemical tests. Pheochromocytoma is present in 50% of patients with MEN 2B, and presents at a median age of 28 [45]. Unlike sporadic pheochromocytoma, greater than half have bilateral tumors. Only about 10% are malignant, and are rarely extra-adrenal. Hyperplasia of the adrenal medulla is found as a precursor to pheochromocytoma. Symptoms and signs include diaphoresis, headache, anxiety, palpitations, and hypertension, although some patients are asymptomatic [52]. Diagnosis is made through a combination of biochemical tests and radiologic studies. Traditionally, biochemical tests rely on a 24-h urinary collection to measure urinary noreprinephrine and epinephrine, metanephrines, and vanillylmandelic acid, as well as plasma norepinephrine and epinephrine. However, these tests have had problems with low sensitivity and speci"city [53]. Recently, measurements of plasma normetanephrine and metanephrine have been shown to be more sensitive and speci"c for detecting pheochromocytoma in MEN 2 and von Hippel Lindau disease [54]. All patients with MEN 2 had high plasma concentrations of metanephrine, whereas the patients with von Hippel Lindau disease had elevations of normetanephrine alone. The sensitivity of the plasma normetanephrine and metanephrine was 97% compared to 47}74% for the other biochemical tests, and had a speci"city of 96%. CT, MRI, and meta-iodobenzylguanidine (MIBG) scintigraphy are used to localize the tumor [55]. Sensitivity of combined CT and MRI was 87% with a speci"city of 100% and diagnostic accuracy of 89%. MIBG scintigraphy had a sensitivity of 92%, speci"city of 17% and diagnostic accuracy of 77%. MIBG scintigraphy is sensitive, but has a lower speci"city in distinguishing between medullary hyperplasia and small pheochromocytomas. CT or MRI should be performed "rst, and MIBG scintigraphy reserved for patients with clinically or biochemically suspected tumor not localized by CT or MRI. Patients diagnosed with pheochromocytoma should undergo adrenalectomy. Because of the lower risk of malignancy of pheochromocytoma, some have favored unilateral adrenalectomy when only one adrenal gland is a!ected, to avoid the risk of Addisonian crisis and dependence on exogenous steroid replacement with bilateral adrenalectomy [52]. Others advocate initial bilateral

116

N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118

total adrenalectomy given the high incidence of bilateral disease at the cellular level, which would eliminate the possibility of future catecholamine crisis or metastases [56]. Laparoscopic adrenalectomy has been performed for pheochromocytoma, including bilateral and partial adrenalectomy, with no di!erence in intraoperative hemodynamics or morbidity compared to open adrenalectomy [57,58]. Intraoperative laparoscopic ultrasound is useful for detecting pheochromocytomas, especially on the left-hand side [59]. Pheochromocytoma should be tested for and ruled out in all patients with MEN 2B before any surgical procedures such as thyroidectomy, because an undetected pheochromocytoma could cause fatal catecholamine crisis intraoperatively. If pheochromocytoma is discovered, adrenalectomy should be performed before thyroidectomy [17]. Screening for RET mutations should be performed as early as possible in patients at risk, such as immediate family members of known MEN patients. Screening can be performed as early as 1 year of age [49]. In the future prenatal screening for MEN may become possible. Other patients who should be o!ered genetic testing are patients with newly diagnosed MTC or pheochromocytoma. Although most cases of MTC and pheochromocytoma are sporadic, it is important to rule out de novo germline RET mutations which can be passed on to o!spring [10]. Although the prognosis for MEN 2B patients is generally worse than with the other endocrine neoplastic disorders, medullary thyroid cancer accounts for most of the fatalities. Therefore, with the advent of earlier testing and prophylactic thyroidectomy for MEN, the prognosis is expected to improve. In summary, MEN 2B is a heritable endocrine disorder characterized by medullary thyroid carcinoma, pheochromocytoma, and a characteristic phenotype which includes mucosal neuromas, musculoskeletal abnormalities and a Marfanoid habitus. The disease is caused by a mutation in the RET proto-oncogene on chromosome 10q11.2 involving a methionine to threonine substitution at codon 918. The disease is heritable in an autosomal dominant fashion. MEN 2B comprises only 10% of cases of MEN 2, but is more aggressive, presents at an earlier age, and has a poorer prognosis than MEN 2A. Pheochromocytoma is present 50% of the time, and half are bilateral, but the tumors are usually benign. Laparoscopic adrenalectomy can be performed, with intraoperative ultrasound to aid in localization of tumor. Medullary thyroid carcinoma, which is nearly universal in MEN 2B patients, accounts for most of the mortality and is usually multicentric and bilateral with early metastasis. C-cell hyperplasia, a precursor of MTC, is present as young as 3 months in MEN 2B patients. Patients at risk for MEN 2B should undergo genetic screening starting as early as 1 year of age, and patients found to have the RET mutation should undergo total thyroidectomy. The development of direct genetic

screening for RET mutations enables thyroidectomy to be performed at an earlier stage of disease, which should improve the prognosis for this aggressive form of endocrine disease.

References [1] Erdheim J. Zur normalen und pathologischen histologie der glandula thyroidea, parathyroidea, und hypophysis. Beitraege zur Pathologischen Anatomie und Allgemeinen Pathologie 1903;33:158. [2] Wermer P. Genetic aspects of adenomatosis of endocrine glands. American Journal of Medicine 1954;16:363}71. [3] Hazard JB, Hawk WA, Crile G. Medullary (solid) carcinoma of the thyroid * a clinicopathologic entity. Journal of Clinical Endocrinology and Metabolism 1959;19:152}61. [4] Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. American Journal of Medicine 1961;31:163}6. [5] Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism, and Cushing's disease: multiple endocrine neoplasia, type 2. Medicine 1968;17:371}409. [6] Williams ED, Pollock DJ. Multiple mucosal neuromata with endocrine tumours: a syndrome allied to Von Recklinghausen's disease. Journal of Pathology and Bacteriology 1966;91:71}80. [7] Gorlin RJ, Sedano HO, Vickers RA, Cervenka J. Multiple mucosal neuromas, pheochromocytoma and medullary carcinoma of the thyroid * a syndrome. Cancer 1968;22:293}9. [8] Schimke RN, Hartmann WH, Prout TE, Rimoin DL. Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma and multiple neuromas. New England Journal of Medicine 1968;279(1):1}7. [9] Chong GC, Beahrs OH, Sizemore GW, Woolner LH. Medullary carcinoma of the thyroid gland. Cancer 1975;35:695}704. [10] Ponder BA, Smith D. The MEN II syndromes and the role of the ret proto-oncogene. Advances in Cancer Research 1996;70: 180}222. [11] Farndon JR, Leight GS, Dilley WB, Baylin SB, Smallridge RC, Harrison TS, Wells SA. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. British Journal of Surgery 1986;73:278}81. [12] Eng C. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschprung's disease. New England Journal of Medicine 1996;335(13):943}51. [13] Norton JA, Froome LC, Farrell RE, Wells SA. Multiple endocrine neoplasia type IIb * the most aggressive form of medullary thyroid carcinoma. Surgical Clinics of North America 1979;59(1): 109}18. [14] Le HN, Norton JA. Perspective on RET proto-oncogene and thyroid cancer. The Cancer Journal 2000;6(2):50}7. [15] Raue F, Frank-Raue K, Grauer A. Multiple endocrine neoplasia type 2 * clinical features and screening. Endocrinology and Metabolism Clinics of North America 1994;23(1):137}56. [16] Carlson KM, Bracamontes J, Jackson CE, Clark R, Lacroix A, Wells SA, Goodfellow PJ. Parent-of-origin e!ects in multiple endocrine neoplasia type 2B. American Journal of Human Genetics 1994;55:1076}82. [17] Miller CA, Ellison EC. Multiple endocrine neoplasia type 2B. In: Clark OH, Duh QY, editors. Textbook of Endocrine Surgery. Philadelphia: W.B. Saunders Company, 1997. p. 619}25. [18] Takashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA arrangement. Cell 1985;42: 581}8.

N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118 [19] Mathew CG, Chin KS, Easton DF, Thorpe K, Carter C, Liou GI, Fong SL, Bridges CD, Haak H, Nieuwenhuijzen-Kruseman AC, Schifter S, Hansen HH, Telenius H, Telenius-Berg M, Ponder BA. A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10. Nature 1987;328:527}30. [20] Gardner E, Papi L, Easton D, Cummings T, Jackson CE, Kaplan M, Love DR, Mole SE, Moore JK, Mulligan LM, Norum RA, Ponder MA, Reichlin S, Stall G, Telenius H, Telenius-Berg M, Tunnacli!e A, Ponder BA. Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2. Human Molecular Genetics 1993;2(3): 241}6. [21] Pasini B, Hofstra RM, Yin L, Bocciardi R, Santamaria G, Grootscholten P, Ceccherini I, Patrone G, Priolo M, Buys CH, Romeo G. The physical map of the human RET proto-oncogene. Oncogene 1995;11:1737}43. [22] Santoro M, Melillo RM, Carlomagno F, Visconti R, DeVita G, Salvatore G, Lupoli G, Fusco A, Vecchio G. Molecular biology of the MEN2 gene. Journal of International Medicine 1998;243: 505}8. [23] Ponder BA. The phenotypes associated with ret mutations in the multiple endocrine neoplasia type 2 syndrome. Cancer Research 1999;59(Suppl):1736}42. [24] Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 1994;367: 380}3. [25] Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH, Di Fiore PP. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 1995;267:381}3. [26] Lairmore TC, Howe JR, Korte JA, Dilley WG, Aine L, Aine E, Wells SA, Donis-Keller H. Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A. Genomics 1991;9:181}92. [27] Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, Wells SA, Goodfellow PJ, Donis-Keller H. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proceedings of the National Academy of Science USA 1994;91:1579}83. [28] Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, Romeo G, Lips CJ, Buys CH. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994;367:375}6. [29] Acton DS, Velthuyzen D, Lips CJ, Hoppener JW. Multiple endocrine neoplasia type 2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice. Oncogene 2000;19:3121}5. [30] Eng C, Mulligan LM, Smith DP, Healey CS, Frilling A, Raue F, Neumann HP, Pfragner R, Behmel A, Lorenzo MJ, Stonehouse TJ, Ponder MA, Ponder BA. Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma. Genes, Chromosomes and Cancer 1995;12:209}12. [31] Zedenius J, Larsson C, Bergholm U, Bovee J, Svensson A, Hallengren B, Grimelius L, Backdahl M, Weber G, Wallin G. Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism 1995;80(10):3088}90. [32] Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mulligan LM, Zajac JD, Robinson BG, Eng C. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. Journal of Clinical Endocrinology and Metabolism 1997;82(11):3902}4.

117

[33] Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 1997;15:1213}7. [34] Eng C, Clayton D, Schu!enecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips C, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendey G, Gharib H, Thibodeau SN, Lacroix A, Frilling A, Ponder BA, Mulligan LM. The relationship between speci"c RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2 * International RET Mutation Consortium Analysis. Journal of the American Medical Association 1996;276(19):1575}9. [35] Schimke RN. Phenotype of malignancy: the mucosal neuroma syndrome. Pediatrics 1973;52(2):283}4. [36] Fink A, Lapidot M, Spierer A. Ocular manifestations in multiple endocrine neoplasia type 2b. American Journal of Ophth 1998;126(2):305}7. [37] Saad MF, Ordonez NG, Rashid RK, Guido RK, Hill CS, Hickey RC, Samaan NA. Medullary carcinoma of the thyroid * a study of the clinical features and prognostic factors in 161 patients. Medicine 1984;63(6):319}42. [38] Carney JA, Go VL, Sizemore GW, Hayles AB. Alimentary-tract ganglioneuromatosis. New England Journal of Medicine 1976; 295(23):1287}91. [39] Romeo G, Ceccherini I, Celli J, Priolo M, Betsos N, Bonardi G, Seri M, Yin L, Lerone M, Jasonni V, Martucciello G. Association of multiple endocrine neoplasia type 2 and Hirschprung disease. Journal of International Medicine 1998;243:515}20. [40] Pasini B, Borrello MG, Greco A, Bongarzone I, Luo Y, Mondellini P, Alberti L, Miranda C, Arighi E, Bocciardi R, Seri M, Barone V, Radice MT, Romeo G, Pierotti MA. Loss of function e!ect of RET mutations causing Hirschsprung disease. Nature Genetics 1995;10:35}40. [41] Morrison PJ, Nevin NC. Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome). Journal of Medical Genetics 1996;33:779}82. [42] Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma * clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000;88(5):1139}48. [43] Samaan NA, Draznin MB, Halpin RE, Bloss RS, Hawkins E, Lewis RA. Multiple endocrine syndrome type IIb in early childhood. Cancer 1991;68:1832}4. [44] Heshmati HM, Hofbauer LC. Multiple endocrine neoplasia type 2: recent progress in diagnosis and management. European Journal of Endocrinology 1997;137:572}8. [45] Moley JF. The molecular genetics of multiple endocrine neoplasia type 2A and related syndromes. Annual Review of Medicine 1997;48:409}20. [46] Kambouris M, Jackson CE, Feldman GL. Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B, and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Human Mutation 1996;8:64}70. [47] Krausz Y, Rosler A, Guttmann H, Ish-shalom S, Shibley N, Chisin R, Glaser B. Somatostatin receptor scintigaphy for early detection of regional and distant metastases of medullary carcinoma of the thyroid. Clinical Nuclear Medicine 1999;24(4):256}60. [48] Telander RL, Zimmerman D, van Heerden JA, Sizemore GW. Results of early thyroidectomy for medullary thyroid carcinoma in children with multiple endocrine neoplasia type 2. Journal of Pediatric Surgery 1986;21(12):1190}4. [49] O'Riordain DS, O'Brien T, Crotty TB, Gharib H, Gran CS, van Heerden JA. Multiple endocrine neoplasia type 2B: more than an endocrine disorder. Surgery 1995;118(6):936}42. [50] Learoyd DL, Marsh DJ, Richardson AL, Twigg SM, Delbridge L, Robinson BG. Genetic testing for familial cancer * consequences

118

[51]

[52]

[53] [54]

[55]

N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118 of RET proto-oncogene mutation analysis in multiple endocrine neoplasia, type 2. Archives of Surgery 1997;132:1022}5. Wells SA, Skinner MA. Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. Experimental and Clinical Endocrinology and Diabetes 1998;106:29}34. Evans DB, Lee JE, Merrell RC, Hickey RC. Adrenal medullary disease in multiple endocrine neoplasia type 2. Endocrinology and Metabolism Clinics of North America 1994;23(1):167}85. Peplinski GR, Norton JA. The predictive value of diagnostic tests for pheochromocytoma. Surgery 1994;116:1101}10. Eisenhofer G, Lenders JW, Linehan WM, Walter MM, Goldstein DS, Keiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. New England Journal of Medicine 1999;340(24):1872}9. De Graaf JS, Dullaart RP, Piers DA, Zwierstra RP. Limited role of meta-iodobenzylguanidine scintigraphy in imaging

[56]

[57]

[58]

[59]

phaeochromocytoma in patients with multiple endocrine neoplasia type II. European Journal of Surgery 2000;166: 289}92. Van Heerden JA, Sizemore GW, Carney JA, Grant CS, ReMine WH, Sheps SG. Surgical management of the adrenal glands in the multiple endocrine neoplasia type II syndrome. World Journal of Surgery 1984;8:612}21. Walther MM, Herring J, Choyke PL, Linehan WM. Laparoscopic partial adrenalectomy in patients with hereditary forms of pheochromocytoma. Journal of Urology 2000;164:14}7. Inabnet WB, Pitre J, Bernard D, Chapuis Y. Comparison of the hemodynamic parameters of open and laparoscopic adrenalectomy for pheochromocytoma. World Journal of Surgery 2000; 24:574}8. Heniford T, Iannitti DA, Hale J, Gagner M. The role of intraoperative ultrasonography during laparoscopic adrenalectomy. Surgery 1997;122:1068}74.