Medullary Thyroid Cancer
Multiple Endocrine Neoplasia Type 2

Clinical Description Prevalence Medullary Thyroid Cancer and C-Cell Hyperplasia Pheochromocytoma Diagnosis of MEN 2 Subtypes         MEN 2A         Familial Medullary Thyroid Carcinoma         MEN 2B         Other Subtypes Genetically Related Disorders         Hirschsprung Disease         Multiple Endocrine Neoplasia Type 1 Molecular Genetics of MEN 2         Mutation Analysis Functional Effects of RET Mutations and Genotype-Phenotype Correlations Genetic Variants in RET with Unknown Functional Effect Genetic Testing         Linkage Analysis Interventions         Prophylactic Thyroidectomy         Screening of At-Risk Individuals for Pheochromocytoma         Screening of At-Risk Individuals for Parathyroid Hyperplasia or Adenoma         Screening of At-Risk Individuals in Kindreds Without an Identifiable RET Mutation         Treatment for Those with MTC         Treatment for Those with Pheochromocytoma         Treatment for Those with Parathyroid Hyperplasia or Adenoma Genetic Counseling         Mode of Inheritance         Psychosocial Issues

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Medullary Thyroid Cancer

Thyroid cancer represents approximately 1% of malignancies occurring in the United States, accounting for an estimated 23,600 cancer diagnoses and 1,460 [1] cancer deaths per year. Of these cancers, 3% to 4% are medullary thyroid cancer (MTC).[2] Average survival for MTC is lower than that for more common thyroid cancers, e.g., 83% 5-year survival for MTC compared with 90% to 94% 5-year survival for papillary and follicular thyroid cancer.[2,3] Survival is correlated with stage at diagnosis, and decreased survival in MTC can be accounted for in part by a high proportion of late-stage diagnoses.[2-4] A Surveillance, Epidemiology, and End Results (SEER) population-based study of papillary, follicular, and medullary thyroid cancers found that survival varied by extent of local disease. For example, among men, 5-year survival rates ranged from 84% for disease confined to the thyroid gland to 35% for extensive, locally advanced disease.[3]

MTC arises from the parafollicular calcitonin-secreting cells of the thyroid gland. MTC occurs in sporadic and familial forms, and may be preceded by C-cell hyperplasia (CCH), although CCH is a relatively common abnormality in middle-aged adults. In a population-based study in Sweden, 26% of patients with MTC were familial.[5] A French national registry and a US clinical series both reported a higher proportion of familial cases (43% and 44%, respectively).[4,6] Familial cases often indicate the presence of multiple endocrine neoplasia type 2 (MEN 2), a group of autosomal dominant genetic disorders caused by inherited mutations in the RET oncogene.

In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, familial versus sporadic, and diagnosis by biochemical screening (that is, screening for calcitonin elevation) versus symptoms.[4-6]

References

1. American Cancer Society.: Cancer Facts and Figures 2004. Atlanta, Ga: American Cancer Society, 2004. Also available online. ¹ Last accessed September 27, 2004. 
   
   
2. Hundahl SA, Fleming ID, Fremgen AM, et al.: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments] Cancer 83 (12): 2638-48, 1998.  [PUBMED Abstract]
   
   
3. Bhattacharyya N: A population-based analysis of survival factors in differentiated and medullary thyroid carcinoma. Otolaryngol Head Neck Surg 128 (1): 115-23, 2003.  [PUBMED Abstract]
   
   
4. Modigliani E, Vasen HM, Raue K, et al.: Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med 238 (4): 363-7, 1995.  [PUBMED Abstract]
   
   
5. Bergholm U, Bergström R, Ekbom A: Long-term follow-up of patients with medullary carcinoma of the thyroid. Cancer 79 (1): 132-8, 1997.  [PUBMED Abstract]
   
   
6. Kebebew E, Ituarte PH, Siperstein AE, et al.: Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88 (5): 1139-48, 2000.  [PUBMED Abstract]
   
   

Multiple Endocrine Neoplasia Type 2

Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disorder associated with a high lifetime risk of medullary thyroid cancer (MTC). It is caused by germline mutations in the RET proto-oncogene.

The disorder is classified into 3 subtypes based on the presence of other clinical complications: MEN 2A, familial medullary thyroid carcinoma (FMTC), and MEN 2B. All 3 subtypes have a high risk of developing MTC; MEN 2A has an increased risk of pheochromocytoma and parathyroid adenoma and/or hyperplasia. MEN 2B has an increased risk of pheochromocytoma and includes additional clinical features such as mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and an asthenic “Marfanoid” body habitus.

The age of onset of MTC varies in different subtypes of MEN 2. MTC typically occurs in early childhood for MEN 2B, early adulthood for MEN 2A, and middle age for FMTC.

All MEN 2 subtypes are inherited in an autosomal dominant manner. Offspring of affected individuals have a 50% chance of inheriting the gene mutation.

DNA-based testing of the RET gene (chromosomal region 10q11) identifies disease-causing mutations in about 95% of individuals with MEN 2A and MEN 2B and in about 85% of individuals with FMTC.

The endocrine disorders observed in MEN 2 are MTC, its precursor C-cell hyperplasia (CCH), pheochromocytoma, and parathyroid adenomas and/or hyperplasia. Bilateral or multifocal areas of MTC and CCH are usually observed at the time of thyroidectomy in patients undergoing prophylactic thyroidectomy.[1] Metastatic spread of MTC to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites such as the liver is common and often has occurred in patients who present with a palpable thyroid mass or diarrhea.[2,3] Although pheochromocytomas rarely metastasize, they can be lethal because of intractable hypertension or anesthesia-induced hypertensive crises. Parathyroid abnormalities can range from benign parathyroid adenomas to clinically evident hyperparathyroidism with hypercalcemia and renal stones.

Clinical findings in the 3 MEN 2 subtypes are summarized in Table 1. All 3 subtypes have a high risk of MTC, MEN 2A and MEN 2B have an increased risk of pheochromocytoma, and MEN 2A has an increased risk of parathyroid hyperplasia and adenoma. Classifying a patient or family by MEN 2 subtype is useful for determining prognosis and management.

The prevalence of MEN 2 has been estimated to be 1 in 30,000. A study in the United Kingdom estimated the incidence of MTC at 20 to 25 new cases per year among a population of 55 million.[6]

Medullary thyroid cancer (MTC) originates in calcitonin-producing cells (C-cells) of the thyroid gland. MTC is diagnosed when nests of C-cells appear to extend beyond the basement membrane and to infiltrate and destroy thyroid follicles. C-cell hyperplasia (CCH) is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C-cells. Not all CCH proceeds to MTC in individuals with disease-associated RET mutations.[7,8] MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration. In provocative testing, plasma calcitonin concentration is measured before (basal level) and at 2 and 5 minutes after intravenous administration of calcium (stimulated level). A positive test is one in which the peak stimulated level is more than 3 times the basal level, or exceeds 300 picograms per milliliter.[8] CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population; therefore, the plasma calcitonin responses to stimulation do not always distinguish CCH from small MTC.[7,8]

MTC accounts for 3% to 4% of new cases of thyroid cancer diagnosed annually in the United States,[9] although this figure may be an underrepresentation of true incidence due to changes in diagnostic techniques. A study of 10,864 patients with nodular thyroid disease found 44 (1/250) cases of MTC after stimulation with calcitonin, none of which were clinically suspected. Consequently, half of these patients had no evidence of MTC on fine-needle biopsy and thus might not have undergone surgery without the positive calcitonin stimulation test.[10] The total number of new cases of MTC diagnosed annually is between 1,000 and 1,200, about 75% of which are sporadic; that is, they occur in the absence of a family history of either MTC or other endocrine abnormalities seen in MEN 2. The peak incidence of the sporadic form is in the fifth and sixth decades of life.[2,11] In the absence of a positive family history, MEN 2 may be suspected when MTC occurs at an early age or is multifocal. While small series of apparently sporadic MTC cases have suggested a higher prevalence of germline RET mutations,[12,13] the two largest series indicate a prevalence range of 1.5% to 12.5%.[14,15] It is widely recommended that RET gene mutation testing be performed for all cases of MTC.[1,16,17]

Pheochromocytoma is suspected among patients with refractory hypertension or when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites (i.e., norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid) in 24-hour urine collections. Abdominal MRI is usually performed when a pheochromocytoma is suspected clinically or when urinary catecholamine values are increased. It is unusual for an individual with pheochromocytoma and no family history of endocrine tumors to have MEN 2A or a disease-causing mutation in the RET gene.[18-20] When pheochromocytoma is diagnosed in a person suspected of having MEN 2, I¹³¹-metaiodobenzylguanidine (MIBG) scintigraphy or positron emission tomography (PET) imaging may be used for further evaluation because of the high frequency of multiple tumors.[8,21,22]

MEN 2 is not the only genetic disorder that includes a predisposition to pheochromocytoma. Other disorders include neurofibromatosis 1 (NF1), von Hippel-Lindau disease (VHL),[23] and the hereditary paraganglioma syndromes.[24] A recent report detailed molecular genetic analyses of a consecutive series of 271 patients with apparently sporadic pheochromocytoma and documented 13 patients (5%) who had a germline mutation in the RET gene.[25] An additional 20% of patients had a germline mutation in one of the other pheochromocytoma susceptibility genes (i.e., VHL, SDHD, and SDHB). During subsequent follow-up, 6 of 13 patients with RET mutations and 12 of 30 patients with VHL mutations developed a personal or family history of other tumors related to their genetic disorders. Possible explanations for the detection of germline mutations in persons with apparently sporadic pheochromocytoma include the following:

• The presence of new germline mutations.
• Reduced penetrance of the relevant gene, resulting in less-dramatically affected families.
• Parental imprinting (e.g., SDHD - hereditary paraganglioma).
• Incomplete family history information.

These data indicate that almost one fourth of apparently sporadic pheochromocytoma patients may be carriers of germline genetic mutations, a substantial proportion of which are attributable to RET. These findings raise the possibility that routine analysis for mutations in a panel of these genes, including RET, might be considered in “sporadic” pheochromocytoma patients, in order to identify important cancer susceptibility syndromes that might otherwise be missed.

The diagnosis of the 3 MEN 2 clinical subtypes relies on a combination of clinical findings, family history, and molecular genetic testing of the RET gene (chromosomal region 10q11).

MEN 2A is diagnosed clinically by the occurrence of 2 or more specific endocrine tumors (MTC, pheochromocytoma, or parathyroid adenoma/hyperplasia) in a single individual or in close relatives.

The MEN 2A subtype makes up about 60% to 90% of MEN 2 cases. The MEN 2A subtype was initially called Sipple syndrome.[26] Since genetic testing for RET mutations has become available, it has become apparent that about 95% of individuals with MEN 2A will develop MTC, about 50% will develop pheochromocytoma, and about 20% to 30% will develop hyperparathyroidism.[27]

MTC is generally the first manifestation of MEN 2A. In asymptomatic young at-risk individuals, provocative testing may reveal elevated plasma calcitonin levels and the presence of CCH or MTC. In families with MEN 2A, the biochemical manifestations of MTC generally appear between the ages of 5 and 25 years (mean, 15 years).[8] If presymptomatic screening is not done, MTC typically presents as a neck mass or neck pain at about age 5 to 20 years. More than 50% of such patients have cervical lymph node metastases.[2] Diarrhea, the most frequent systemic symptom, occurs in patients with a plasma calcitonin level of more than 10 nanograms per milliliter and implies a poor prognosis.[2] Up to 30% of patients with MTC present with diarrhea and advanced disease.[28]

Pheochromocytomas usually present after MTC, typically with intractable hypertension, and are often bilateral.[5] Sudden death from anesthesia-induced hypertensive crisis has been described in patients with MEN 2A and unsuspected pheochromocytoma.[2] Malignant transformation is uncommon and is estimated to occur in about 4% of familial cases.[29]

A series of 56 patients with MEN 2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group.[30] The median age at diagnosis was 38 years, documenting that this disorder is rarely the first manifestation of MEN 2. Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid carcinoma in 43 patients (77%). Two thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, 4 double adenomas, and 25 hyperplastic glands. Notably, other genetic causes of familial hyperparathyroidism have been identified, including the hyperparathyroidism–jaw tumor syndrome, MEN 1, and NF1.[31,32] Germline mutations in the HRPT2 tumor suppressor gene have been described in several families with familial isolated hyperparathyroidism.[31]

A small number of families with MEN 2A have pruritic skin lesions known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC.[33,34]

Familial medullary thyroid carcinoma (FMTC) subtype makes up about 5% to 35% of MEN 2 cases and is diagnosed in families with 4 or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia.[27] Families in which there are 2 or 3 cases of MTC and incompletely documented screening for pheochromocytoma and parathyroid disease may represent MEN 2A; it has been suggested that these families should be considered “unclassified.”[6] Misclassification of families with MEN 2A as having FMTC (due to small family size or later onset of other manifestations of MEN 2A) may result in overlooking the risk of pheochromocytoma, a disease with significant morbidity and mortality.

MEN 2B is diagnosed clinically by the presence of mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies with enlarged lips, an asthenic Marfanoid body habitus, and MTC.[35-37]

The MEN 2B subtype makes up about 5% of MEN 2 cases. The MEN 2B subtype was initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome.[38] MEN 2B is characterized by the early development of an aggressive form of MTC in all patients.[38,39] Patients with MEN 2B who do not undergo thyroidectomy at an early age (approximately 1 year) are likely to develop metastatic MTC at an early age. Before intervention with early prophylactic thyroidectomy, the average age of death in patients with MEN 2B was 21 years. Pheochromocytomas occur in about 50% of MEN 2B cases; about half are multiple and often bilateral. Patients with undiagnosed pheochromocytoma may die from a cardiovascular crisis perioperatively. Clinically apparent parathyroid disease is very uncommon.[4,27,40]

Patients with MEN 2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.

About 40% of patients have diffuse ganglioneuromatosis of the gastrointestinal tract. Associated symptoms include abdominal distension, megacolon, constipation, and diarrhea. About 75% of patients have a Marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.[36,37]

The International RET Mutation Consortium classified MEN 2 into 6 separate phenotypes for the purpose of correlating specific mutations with clinical expression.[12,27] They specified 3 forms of MEN 2A: MEN 2A(1), MEN 2A(2), MEN 2A(3), and single forms of MEN 2B, FMTC, and “Other,” which included families that did not conform to the other phenotypes or were not objectively documented. The clinical usefulness of these additional subtypes for MEN 2A has not been demonstrated, although these classifications were created as a tool for evaluation of genotype-phenotype correlations.

Hirschsprung disease (HSCR), a disorder of the enteric plexus of the colon that typically results in enlargement of the bowel and constipation or obstipation in neonates, is observed in a small number of individuals with MEN 2A, FMTC, or very rarely, MEN 2B.[41] Up to 40% of familial cases of HSCR, and 3% to 7% of sporadic cases are associated with germline mutations in the RET proto-oncogene and are designated HSCR1.[42,43] Some of these RET mutations are located in codons that lead to the development of MEN 2A or FMTC (i.e., codons Cys609, Cys618, and Cys620).[41,44]

In a study of 44 families, 7 families (16%) had cosegregation of MEN 2A and HSCR1. The probability that individuals in a family with MEN 2A and an exon 10 Cys mutation would manifest HSCR1 was estimated to be 6% in 1 series.[42] Furthermore, in a multicenter international RET mutation consortium study, 6 of a total of 62 kindreds carrying either the C618R or C620R mutation also had HSCR.[27]

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN 2; however, the similar nomenclature for MEN 1 and MEN 2 may cause confusion. MEN 1 is caused by mutations in the MEN1 gene (chromosomal region 11q13). MEN 1 is characterized by a triad of pituitary adenomas, pancreatic islet cell tumors, and parathyroid disease consisting of hyperplasia or adenoma. Patients can also have adrenal cortical tumors, carcinoid tumors, and lipomas.[45] Rarely, patients with MEN 1 have pituitary adenomas and pheochromocytomas, which has led to the hypothesis of an “overlap” syndrome with MEN 2.[46]

MEN 2 syndromes are due to inherited mutations in the RET gene, located on chromosome region 10q11.[47-49] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[50,51] A partial sequence was cloned in 1988.[52] Renumbering of the full-length sequence added 254 codons to the original assignments.[53] Early publications that described allelic variants utilized the codon numbering for the partial sequence. Neutral sequence variants that do not alter the risk of the disease have been described.[54,55]

RET encodes a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. Details of RET receptor and ligand interaction in this signalling pathway have been reviewed.[56] Briefly, the extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region that interacts with 1 of 4 ligands identified to date. These ligands, e.g., glial-derived neurotropic factor (GDNF), neurturin (NTN), persephin (PSF), and artemin (ATF), also interact with one of 4 coreceptors in the GDNFRa family.[56] The tyrosine kinase catalytic core is located in the intracellular domain, which causes downstream signaling events through a variety of second messenger molecules. Normal tissues contain transcripts of several lengths.[57-59]

A significantly higher frequency of CCH has been found in peritumoral thyroid tissue of radiation-induced epithelial thyroid tumors, than in the surrounding tissue of sporadic thyroid tumors or control thyroid tissue.[60] Further, the RET Gly691Ser polymorphism was present with a much higher frequency in radiation-induced epithelial tumors (55%) as compared with either sporadic thyroid tumors (20%) or control thyroid (15%). In those radiation-induced thyroid tumors that had CCH in the surrounding tissue, there was an 88% frequency of the polymorphism.

At least 95% of families with MEN 2A have a RET mutation in exon 10 or 11.[14,53,61] Mutations of codon Cys634 in exon 11 occur in about 85% of families; mutation of cysteine codons at amino acid positions 609, 611, 618, and 620 in exon 10 together account for the remainder of identifiable mutations.[14] Other rare mutations have been reported in single families.[62-64]

Approximately 85% of families with FMTC have an identifiable RET mutation.[53,61] These mutations typically affect 1 of the 5 cysteine residues (codons 618, 620, 634, 609, and 611), with mutations of the first three each accounting for 25% to 35% of all mutations. The 634 mutations in FMTC are rarely, if ever, C634R.[14] Mutations in the extracellular domain of RET, at Cys630, and in the intracellular domain, at codons Glu768, Leu790, Tyr791, Val804, and Ser891, have also been identified.[65-69]

Approximately 95% of individuals with the MEN 2B phenotype have a single point mutation in the tyrosine kinase domain of the RET gene at codon Met918 in exon 16, which substitutes a threonine for methionine (Met918Thr).[70,71] A second mutation at codon Ala883 in exon 15 has now been identified in at least 4 MEN 2B patients without a Met918Thr mutation.[72,73]

Mutations in codons in the cysteine-rich extracellular domain (609, 611, 618, 620, and 634) cause ligand-independent RET dimerization, leading to constitutive activation (i.e., gain of function) of tyrosine kinase.[74,75] The disease-causing point mutation in codon Met918 that causes 95% of the MEN 2B phenotype lies within the catalytic core of the tyrosine kinase and causes an alteration in substrate specificity of the normal RET.[74-76] Mutations in cysteine codons 609, 618, and 620 are associated with lower transforming activity of RET when compared with codons Cys634 and MET918.[74,75] In contrast to the activating mutations in MEN 2, mutations that cause HSCR result in loss of function.[77]

The following genotype-phenotype correlations have been suggested for RET mutations:

• RET germline Met918Thr and A883F mutations are associated only with MEN 2B. Somatic mutations in these codons are frequently observed in sporadic MTC.[71,78,79]
• Mutations at codons 768 or 804 may be FMTC-specific [27] and might represent important contributors to apparently sporadic MTC.[80]
• Mutations involving the cysteine codons 609, 618, and 620 are associated with either MEN 2A, FMTC, or HSCR1. Mutations in these codons are detected in about 10% of families with MEN 2A and 65% of families with FMTC.[27]
• Mutations in codons Glu768 in exon 13 and Val804 in exon 14 may only be associated with the development of MTC, since these mutations have been identified primarily in the FMTC subtype.[14,27,66,81]
• Any RET mutation at codon Cys634 in exon 11 results in higher incidence of pheochromocytomas and hyperparathyroidism.[27,53]
• Among the mutations at codon Cys634, it has been reported that Cys634Arg significantly correlates with the presence of hyperparathyroidism,[27,53] but other studies do not confirm this correlation.[82,83] This discrepancy may be explained by differences in study methodology.
• Some mutations, such as those involving cysteine codons 609, 618, and 620 in exon 10 and Val804 in exon 14, may be associated with milder forms of the disease.[27,61,84,85]
• Possible correlation between the presence of mutations in codon Cys634 in the RET gene and the skin lesion cutaneous lichen amyloidosis has been noted.[27,86,87]

Many polymorphisms in both coding and noncoding sequences have been identified in the RET gene, and have been evaluated with respect to disorders associated with RET gene mutations. Of these, a C→T change resulting in a silent polymorphism, Ser836Ser, has been found to be more frequent in sporadic, nonfamilial German patients with MTC.[88,89] Substantially more information will be required to determine if this variant is truly an MTC risk factor.

MEN 2 is a well-defined hereditary cancer syndrome for which genetic testing is considered an important part of the management for at-risk family members; it meets the criteria related to indications for genetic testing for cancer susceptibility outlined by the American Society of Clinical Oncology (ASCO) in its most recent genetic testing policy statement.[90] At-risk individuals are defined as first-degree relatives (parents, siblings, and children) of a person known to have MEN 2. Testing allows the identification of people with asymptomatic MEN 2 who can be offered prophylactic thyroidectomy and biochemical screening as preventive measures. A negative mutation analysis in at-risk relatives, however, is informative only after a disease-causing mutation has been identified in an affected relative. (Refer to the PDQ summary Elements of Cancer Genetics Risk Assessment and Counseling ³ for more information.) Because early detection of at-risk individuals affects medical management, testing of children who have no symptoms is considered beneficial.[91,92]

Testing for the common mutations in exons 10, 11, 13, 14, and 16 is available at a number of clinical laboratories; some laboratories also include analysis of some of the rarer mutations. Methods used to detect mutations in RET include polymerase chain reaction (PCR) followed by restriction enzyme digestion of PCR products, heteroduplex analysis, single-strand conformation polymorphism analysis, and DNA sequencing.[54,93-95]

A small number of families with MEN 2 have been described without detectable abnormalities in the RET coding sequence. There is considerable diversity in the approach to RET mutation testing among the various laboratories that perform this procedure. These range from selective testing of those exons most likely to harbor MEN 2 mutations, to full sequencing of the entire gene. These differences represent important considerations for selecting a laboratory to perform a test and in interpreting the test result. (Refer to the PDQ summary on Elements of Cancer Genetics Risk Assessment and Counseling ³ for more information on clinical validity.) There is no evidence, however, for involvement of other genetic loci, and all mutation-negative families analyzed to date have demonstrated linkage to the RET gene.

When a disease-causing mutation in the RET gene cannot be identified, linkage analysis can be considered in families with more than 1 affected family member in 2 or more generations. Linkage studies are based on accurate clinical diagnosis of MTC and/or pheochromocytoma in the affected family members and accurate understanding of the genetic relationships in the family. Linkage analysis is dependent on the availability and willingness of all family members to be tested. The markers used for linkage are highly informative and very tightly linked to the RET gene; thus, they can be used in more than 95% of informative families with MEN 2 with greater than 95% accuracy.[96]

Linkage testing is not possible in families in which there is a single affected individual.

Prophylactic thyroidectomy with reimplantation of 1 or more parathyroid glands into the neck or nondominant forearm is a preventive option for all subtypes of MEN 2. In order to implement this management strategy, biochemical screening to identify CCH or genetic testing to identify persons who carry causative RET mutations is needed to identify candidates for prophylactic surgery (see below). The optimal timing of surgery, however, is controversial.[3] Current recommendations are based on clinical experience and vary for different MEN 2 subtypes, as noted below.

In a study of biochemical screening in a large family with MEN 2A done before mutation analysis became available, 22 family members without evidence of clinical disease had elevated calcitonin and underwent thyroidectomy. During a mean follow-up period of 11 years, all remained free of clinical disease, and 3 out of 22 had transient elevation of postoperative calcitonin levels.[97]

Two case series provide data supporting early prophylactic thyroidectomy following testing for RET mutations.[98,99] Cases reported in both series could reflect selection biases: 1 study reported 71 patients from a national registry who had been treated with thyroidectomy, but did not specify how these patients were selected, while the other study reported 21 patients seen at a referral center.[98,99] In both, a series of children from families with MEN 2 or FMTC who were found to have RET mutations were screened for CCH and treated with prophylactic thyroidectomy. These studies documented MTC in 93% of patients with MEN 2 and 77% of patients with FMTC. The larger study found a correlation between age and larger tumor size, nodal metastases, postoperative recurrence of disease, and mean basal calcitonin levels. Surgical complications were rare.[98] No studies have compared the outcome of thyroidectomy based on mutations testing with thyroidectomy based on biochemical screening.

In the most comprehensive literature review published to date, 260 MEN 2A subjects aged 0 to 20 years were identified as having undergone either "early total thyroidectomy" (ages 1-5) [n=42], or late thyroidectomy (ages 6-20) [n=218].[100] There was a significantly lower rate of invasive or metastatic MTC among those operated on at an early age (57%) compared with those operated on late (76%). Follow-up information was available on only 28% of the cohort, due to the limitations of study design, with a median follow-up of only 2 years for this nonsystematically selected subgroup. Persistent or recurrent disease was reported among 0 of 9 early-surgery subjects, versus 21 of 65 late-surgery subjects. Both findings are consistent with the hypothesis that patients undergoing surgery prior to age 6 have a more favorable outcome, but the nature of the data prevent this being a definitive conclusion. Finally, there was evidence to suggest that subjects carrying the Cys634 mutation were much more likely to present with invasive or metastatic MTC, and more likely to develop persistent or recurrent disease, than were those with the Cys804, Cys618, or Cys620 mutations.

In these and other studies, thyroid glands removed from individuals with a disease-causing mutation who had normal plasma calcitonin levels have been found to contain MTC.[8,38] Therefore, although thyroidectomy prior to biochemical evidence of disease may reduce the risk of recurrent disease, continued monitoring for residual or recurrent MTC is still recommended.[3] All individuals who have undergone thyroidectomy and autotransplantation of the parathyroids need thyroid hormone replacement therapy and monitoring for possible hypoparathyroidism.

Questions remain concerning the natural history of MEN 2. As more information is acquired, recommendations regarding the optimal age for thyroidectomy and the potential role for genetics and biochemical screening may change. For example, a case report documents MTC before age 5 in 2 siblings with MEN 2A.[101] Conversely, another case report documents onset of cancer in midlife or later in some families with FMTC, as well as in elderly relatives who carry the FMTC genotype but have not developed cancer.[102] The possibility that certain specific mutations (e.g., Cys634) might convey a significantly worse prognosis, if confirmed, may permit tailoring intervention based on knowing the specific RET mutation.[100] These clinical observations suggest that the natural history of the MEN 2 syndromes is variable and could be subject to modifying effects related to specific RET mutations, other genes, behavioral factors, or environmental exposures.

As noted above, there is controversy about the age at which to perform prophylactic thyroidectomy, in part because outcome data are limited to uncontrolled studies or relatively small populations. Observational studies of the genotype-phenotype correlations suggest significant differences in biological aggressiveness of the medullary thyroid cancers that occur in MEN 2A, MEN 2B, and FMTC.[16,87] A European multicenter study of 207 RET mutation carriers supported previous suggestions that some mutations are associated with early-onset disease. For example, this study found that individuals with the C634Y mutation developed MTC at a significantly younger age (mean 3.2 years, 95% confidence interval (CI), 1.2-5.4) compared with the C634R mutation (mean 6.9 years, 95% CI, 4.9-8.8). In the former group of patients, prophylactic thyroidectomy warrants consideration before the age of 5 years. Although limited by small numbers, this same study did not support a need for prophylactic thyroidectomy in asymptomatic carriers of mutations in codons 609, 630, 768, 790, 791, 804, or 891 before the age of 10 years, or for central lymph node dissection before the age of 20 years.[103] Some authors suggest using these differences as the basis for decisions on the timing of prophylactic thyroidectomy and the extent of surgery.[16] A summary of current practice in referral centers suggests the following:[104]

MEN 2A: In most centers, thyroidectomy is performed in patients by the age of 5 years or when a mutation is identified.[16,17]

FMTC: Some centers recommend management similar to that for MEN 2A.

MEN 2B: In most centers, surgery is performed within the first 6 months of life, preferably within the first month, because of the very early age of MTC onset and the particularly aggressive biologic behavior of MTC in the patients.[16]

Level of evidence: 5

The presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening before thyroidectomy in any patient with MEN 2A or MEN 2B. In addition, annual biochemical screening is recommended, followed by MRI only if the biochemical results are abnormal.[29,104] Other screening studies, such as abdominal ultrasound examination or CT scan, may be warranted in some patients. In addition to surgery, there are other clinical situations in which patients with catecholamine excess face special risk. An example is the healthy at-risk female patient who becomes pregnant. Pregnancy, labor, or delivery may precipitate a hypertensive crisis in persons who carry an unrecognized pheochromocytoma. Pregnant patients who are found to have catecholamine excess require appropriate pharmacotherapy before delivery. Typical surveillance recommendations are as follows:

MEN 2A: Annual biochemical screening.

FMTC: Screening as for MEN 2A because not all families classified as FMTC are MTC-only.[84]

MEN 2B: Same as MEN 2A.[104]

Unclassified: Same as MEN 2A.

Level of evidence: 5

MEN 2-related hyperparathyroidism is generally associated with mild, often asymptomatic hypercalcemia early in the natural history of the disease—which, if left untreated, may become symptomatic.[30] Annual biochemical screening is recommended for those patients who have not had parathyroidectomy and autotransplantation, as follows:

MEN 2A: Starting at the time of diagnosis.[104]

FMTC: Screening as for MEN 2A because not all families classified as FMTC are MTC-only.[84]

MEN 2B: Same as MEN 2A although clinically apparent hyperparathyroidism is seldom observed in MEN 2B.[104]

Unclassified: Same as MEN 2A.

Level of evidence: 5

MEN 2A: Prophylactic thyroidectomy is not offered routinely to at-risk individuals in whom the disorder has not been confirmed. The screening protocol for MTC is an annual calcitonin stimulation test; however, caution needs to be used in interpreting test results because CCH that is not a precursor to MTC occurs in about 5% of the population.[7,8,105] In addition, there is significant risk of false-negative test results in patients younger than 15 years.[8] Screening for pheochromocytoma and parathyroid disease is the same as described above.

FMTC: Annual screening for MTC, as for MEN 2A.

Level of evidence: 5

Standard treatment for MTC is surgical removal of the entire thyroid gland, including the posterior capsule, and central lymph node dissection. Chemotherapy and radiation are not effective against this type of cancer.[3,106,107]

Level of evidence: 5

Pheochromocytoma may be either unilateral or bilateral in patients with MEN 2. Laparoscopic adrenalectomy is recommended by some authorities for the treatment of unilateral pheochromocytoma.[16] It is unclear whether bilateral adrenalectomy should be performed routinely in patients with MEN 2-related pheochromocytoma, in the absence of bilateral pheochromocytomas.

In 1 series, 23 patients with a unilateral pheochromocytoma and a macroscopically normal contralateral adrenal gland were treated initially with unilateral adrenalectomy.[108] A pheochromocytoma developed within the retained gland in 12 (52%) of these subjects, occurring a mean of 11.9 years after initial surgery. During follow-up subsequent to unilateral adrenalectomy, no patient experienced a hypertensive crisis or other problems attributable to an undiagnosed pheochromocytoma. In contrast, 10 (23%) of 43 patients treated with bilateral adrenalectomy experienced at least 1 episode of acute adrenal insufficiency; 1 of these patients died. Unilateral adrenalectomy appears to represent a reasonable management strategy for unilateral pheochromocytoma in patients with MEN 2,[109,110] when coupled with periodic surveillance (serum or urinary catecholamine measurements) for the development of disease in the contralateral adrenal gland.

Cortical-sparing adrenalectomy represents an additional approach to disease management in patients with bilateral pheochromocytomas.[111] Fourteen (93%) of 15 patients undergoing laparotomy for bilateral pheochromocytomas were treated with a procedure that spared as much normal-appearing adrenal cortex as possible. Thirteen patients did not require postoperative steroid hormone supplementation, and none experienced acute adrenal insufficiency. Three patients developed recurrent pheochromocytomas at 10 to 27 years after surgery. Similar results were obtained in a series of 26 patients undergoing cortex-sparing surgery for hereditary pheochromocytoma (including MEN 2).[112] Adrenal cortex-sparing surgery may also be accomplished laparoscopically, with intraoperative ultrasound guidance.[113] These approaches require long-term patient follow-up, as recurrence may develop many years after the initial operation.

Level of evidence: 5

Most patients with MEN2-related parathyroid disease are either asymptomatic or diagnosed incidentally at the time of thyroidectomy. Typically, the hypercalcemia (when present) is mild, although it may be associated with increased urinary excretion of calcium and nephrolithiasis. As a consequence, the indications for surgical intervention are generally similar to those recommended for patients with sporadic, primary hyperparathyroidism.[16] In general, fewer than 4 of the parathyroid glands are involved at the time of detected abnormalities in calcium metabolism. Uncertainty exists regarding the criteria that would indicate parathyroidectomy and the role of parathyroid autotransplantation in the management of these patients.

Cure of hyperparathyroidism was achieved surgically in 89% of 1 large series of patients;[30] however, 22% of resected patients in this study developed postoperative hypoparathyroidism. Five patients (9%) had recurrent hyperparathyroidism. This series employed various surgical techniques, including total parathyroidectomy with autotransplantation to the nondominant forearm, subtotal thyroidectomy, and resection only of glands that were macroscopically enlarged. Postoperative hypoparathyroidism developed in 4 (36%) of 11 patients, 6 (50%) of 12 patients, and 3 (10%) of 29 patients, respectively. These data indicate that excision of only those parathyroid glands that are enlarged appears to be sufficient in most cases.

Some investigators have suggested using the MEN 2 subtype to decide where to place the parathyroid glands that are identified at the time of thyroid surgery. For patients with MEN 2B, in whom the risk of parathyroid disease is quite low, the parathyroid glands may be left in the neck. For patients with MEN 2A and FMTC, it is suggested that the glands be implanted in the nondominant forearm to minimize the need for further surgery on the neck after prophylactic thyroidectomy and a central lymph node dissection.[114]

All of the MEN 2 subtypes are inherited in an autosomal dominant manner. For the child of someone with MEN 2, the risk of inheriting the MEN 2 mutation is 50%. Some individuals with MEN 2, however, carry a de novo mutation; that is, they carry a new mutation that was not present in previous generations of their family and thus do not have an affected parent. The proportion of individuals with MEN 2 who have an affected parent varies by subtype.

MEN 2A: About 95% of affected individuals have an affected parent. It is appropriate to evaluate the parents of an individual with MEN 2A for manifestations of the disorder. In the 5% of cases that are not familial, either de novo gene mutations or incomplete penetrance of the mutant allele is possible.[115]

FMTC: Multiple family members are affected, and thus all affected individuals have inherited the mutant gene from a parent.

MEN 2B: About 50% of affected individuals have de novo RET gene mutations, and 50% have inherited the mutation from a parent.[116,117] The majority of de novo mutations are paternal in origin, but cases of maternal origin have been reported.[118]

Siblings of a proband: The risk to siblings depends on the genetic status of the parent, which can be clarified by pedigree analysis and/or DNA-based testing. In situations of apparent de novo gene mutations, germline mosaicism in an apparently unaffected parent needs to be considered, even though such an occurrence has not yet been reported.

The psychosocial impact of genetic testing for MEN 2 is not extensively studied. Several review articles outline both the medical and psychological issues, especially those related to the testing of children.[119-121] The medical value of early screening and prophylactic treatment are contrasted with the loss of decision-making autonomy for the individual. Lack of agreement between parents about the value and timing of genetic testing and surgery may spur the development of emotional problems within the family. Identification as the carrier of a deleterious mutation may affect self-esteem and family relationships. Misconceptions about genetic disease may stir blame and guilt within families. Medicalization of a developing child and social stigmatization may occur. Difficulty maintaining confidentiality and privacy, as well as potential conflict between cultural and family values and adoption of genetic counseling and testing, are additional problem areas. One case report details the development of a serious psychosomatic condition, trichotillomania, following genetic testing and prophylactic thyroidectomy in a 13-year-old girl from a family with MEN 2A.[122]

A descriptive study drawn as convenience samples from the MTC clinics of 2 French hospitals compared 3 groups—RET-mutation carriers with MTC, sporadic MTC patients, and unaffected members of MTC families who had been found on genetic testing to be noncarriers of RET mutations—using the Hospital Anxiety and Depression Scale (HADS) [123] and the Subjective Quality of Life Profile (SQLP).[124,125] Mutation carriers were found to have less satisfaction and higher expectations/hopes for future improvement, especially in the areas of sexuality, interpersonal relationships, self-esteem, and relationships with medical providers.[126]

A Dutch study reports on a cohort of adults (N=87) applying to be tested for MEN 2 and their partners and another cohort of parents applying for the genetic testing of their children (N=36).[127] Utilizing quantitative and qualitative measures, the researchers found that knowledge gaps remained after genetic counseling. Unanticipated shock was seen in carriers following disclosure, typically followed by rapid progression toward surgery. At 2 weeks after disclosure, half of the carriers reported continuing psychosomatic complaints, with complaints dropping to 20% of the carriers by 1 year after diagnosis. Family communication and contact improved among carriers within most extended families, sometimes at the expense of the noncarriers, who felt excluded.

Among the noncarriers who were spared further physiological testing on the basis of their genetic test result, anxiety and psychosomatic complaints nonetheless remained high at 2 weeks after disclosure. Some emptiness and isolation were reported by family members testing negative soon after disclosure, with distress at normal levels by 12 months. Family members who felt coerced to undergo genetic testing were more likely to have adverse emotional reactions following disclosure. Parents who had surgery for MEN during adolescence were sometimes reluctant to allow their children to have surgery before adolescence. Communication within and beyond the family contributed to strain; friends were often not told about the condition. Little adverse effect was seen on job application, work situation, or insurance coverage.

In a related report, mean psychological distress of those applying for genetic testing was not higher than population norms, although about 9% had psychological morbidity, including high anxiety and somatic complaints. Prominent in this troubled group were applicants who were younger (aged 15-20 years), single, and at high risk of being mutation carriers.[128] A general predisposition to anxiety or distress enhanced the likelihood of high test-related anxiety. Nearly half of the parents believed that they would want continued clinical surveillance for their children, regardless of the DNA result. The need for attention to the potential psychological vulnerability of young individuals undergoing genetic testing for conditions with potentially favorable medical outcomes is highlighted.

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88. Borrego S, Wright FA, Fernández RM, et al.: A founding locus within the RET proto-oncogene may account for a large proportion of apparently sporadic Hirschsprung disease and a subset of cases of sporadic medullary thyroid carcinoma. Am J Hum Genet 72 (1): 88-100, 2003.  [PUBMED Abstract]
    
    
89. Griseri P, Pesce B, Patrone G, et al.: A rare haplotype of the RET proto-oncogene is a risk-modifying allele in hirschsprung disease. Am J Hum Genet 71 (4): 969-74, 2002.  [PUBMED Abstract]
    
    
90. American Society of Clinical Oncology.: American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 21 (12): 2397-406, 2003.  [PUBMED Abstract]
    
    
91. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol 14 (5): 1730-6; discussion 1737-40, 1996.  [PUBMED Abstract]
    
    
92. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 57 (5): 1233-41, 1995.  [PUBMED Abstract]
    
    
93. Xue F, Yu H, Maurer LH, et al.: Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. Hum Mol Genet 3 (4): 635-8, 1994.  [PUBMED Abstract]
    
    
94. McMahon R, Mulligan LM, Healey CS, et al.: Direct, non-radioactive detection of mutations in multiple endocrine neoplasia type 2A families. Hum Mol Genet 3 (4): 643-6, 1994.  [PUBMED Abstract]
    
    
95. 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. Hum Mutat 8 (1): 64-70, 1996.  [PUBMED Abstract]
    
    
96. Howe JR, Lairmore TC, Mishra SK, et al.: Improved predictive test for MEN2, using flanking dinucleotide repeats and RFLPs. Am J Hum Genet 51 (6): 1430-42, 1992.  [PUBMED Abstract]
    
    
97. Gagel RF, Tashjian AH Jr, Cummings T, et al.: The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 318 (8): 478-84, 1988.  [PUBMED Abstract]
    
    
98. Niccoli-Sire P, Murat A, Baudin E, et al.: Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC). Eur J Endocrinol 141 (5): 468-74, 1999.  [PUBMED Abstract]
    
    
99. Wells SA Jr, Skinner MA: Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. Exp Clin Endocrinol Diabetes 106 (1): 29-34, 1998.  [PUBMED Abstract]
    
    
100. Szinnai G, Meier C, Komminoth P, et al.: Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis. Pediatrics 111 (2): E132-9, 2003.  [PUBMED Abstract]
     
     
101. van Heurn LW, Schaap C, Sie G, et al.: Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children. J Pediatr Surg 34 (4): 568-71, 1999.  [PUBMED Abstract]
     
     
102. Hansen HS, Torring H, Godballe C, et al.: Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome? Cancer 89 (4): 863-7, 2000.  [PUBMED Abstract]
     
     
103. Machens A, Niccoli-Sire P, Hoegel J, et al.: Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 349 (16): 1517-25, 2003.  [PUBMED Abstract]
     
     
104. Wells SA Jr, Donis-Keller H: Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes. Endocrinol Metab Clin North Am 23 (1): 215-28, 1994.  [PUBMED Abstract]
     
     
105. Marsh DJ, McDowall D, Hyland VJ, et al.: The identification of false positive responses to the pentagastrin stimulation test in RET mutation negative members of MEN 2A families. Clin Endocrinol (Oxf) 44 (2): 213-20, 1996.  [PUBMED Abstract]
     
     
106. Samaan NA, Schultz PN, Hickey RC: Medullary thyroid carcinoma: prognosis of familial versus nonfamilial disease and the role of radiotherapy. Horm Metab Res Suppl 21: 21-5, 1989.  [PUBMED Abstract]
     
     
107. Scherübl H, Raue F, Ziegler R: Combination chemotherapy of advanced medullary and differentiated thyroid cancer. Phase II study. J Cancer Res Clin Oncol 116 (1): 21-3, 1990.  [PUBMED Abstract]
     
     
108. Lairmore TC, Ball DW, Baylin SB, et al.: Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 217 (6): 595-601; discussion 601-3, 1993.  [PUBMED Abstract]
     
     
109. Okamoto T, Obara T, Ito Y, et al.: Bilateral adrenalectomy with autotransplantation of adrenocortical tissue or unilateral adrenalectomy: treatment options for pheochromocytomas in multiple endocrine neoplasia type 2A. Endocr J 43 (2): 169-75, 1996.  [PUBMED Abstract]
     
     
110. Inabnet WB, Caragliano P, Pertsemlidis D: Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery 128 (6): 1007-11;discussion 1011-2, 2000.  [PUBMED Abstract]
     
     
111. Lee JE, Curley SA, Gagel RF, et al.: Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery 120 (6): 1064-70; discussion 1070-1, 1996.  [PUBMED Abstract]
     
     
112. Yip L, Lee JE, Shapiro SE, et al.: Surgical management of hereditary pheochromocytoma. J Am Coll Surg 198 (4): 525-34; discussion 534-5, 2004.  [PUBMED Abstract]
     
     
113. Pautler SE, Choyke PL, Pavlovich CP, et al.: Intraoperative ultrasound aids in dissection during laparoscopic partial adrenalectomy. J Urol 168 (4 Pt 1): 1352-5, 2002.  [PUBMED Abstract]
     
     
114. Norton JA, Brennan MF, Wells SA Jr: Surgical Management of Hyperparathyroidism. In: Bilezikian JP, Marcus R, Levine MA: The Parathyroids: Basic and Clinical Concepts. New York: Raven Press, 1994, pp 531-551. 
     
     
115. Schuffenecker I, Ginet N, Goldgar D, et al.: Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine. Am J Hum Genet 60 (1): 233-7, 1997.  [PUBMED Abstract]
     
     
116. Norum RA, Lafreniere RG, O'Neal LW, et al.: Linkage of the multiple endocrine neoplasia type 2B gene (MEN2B) to chromosome 10 markers linked to MEN2A. Genomics 8 (2): 313-7, 1990.  [PUBMED Abstract]
     
     
117. Carlson KM, Bracamontes J, Jackson CE, et al.: Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 55 (6): 1076-82, 1994.  [PUBMED Abstract]
     
     
118. Kitamura Y, Scavarda N, Wells SA Jr, et al.: Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B. Hum Mol Genet 4 (10): 1987-8, 1995.  [PUBMED Abstract]
     
     
119. Johnston LB, Chew SL, Trainer PJ, et al.: Screening children at risk of developing inherited endocrine neoplasia syndromes. Clin Endocrinol (Oxf) 52 (2): 127-36, 2000.  [PUBMED Abstract]
     
     
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121. Grosfeld FJ, Lips CJ, Beemer FA, et al.: Psychological risks of genetically testing children for a hereditary cancer syndrome. Patient Educ Couns 32 (1-2): 63-7, 1997 Sep-Oct.  [PUBMED Abstract]
     
     
122. Giarelli E: Spiraling out of control: one case of pathologic anxiety as a response to a genetic risk of cancer. Cancer Nurs 22 (5): 327-39, 1999.  [PUBMED Abstract]
     
     
123. Zigmond AS, Snaith RP: The hospital anxiety and depression scale. Acta Psychiatr Scand 67 (6): 361-70, 1983.  [PUBMED Abstract]
     
     
124. Dazord A, Mercier C, Manificat S: Evaluation de la qualité de la vie : mise au point d'un instrument d'évaluation dans un contexte francophone. Revue Européenne de Psychologie Appliquée 45 (4): 271-8, 1995. 
     
     
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126. Freyer G, Dazord A, Schlumberger M, et al.: Psychosocial impact of genetic testing in familial medullary-thyroid carcinoma: a multicentric pilot-evaluation. Ann Oncol 10 (1): 87-95, 1999.  [PUBMED Abstract]
     
     
127. Grosfeld FJ, Lips CJ, Ten Kroode HF, et al.: Psychosocial consequences of DNA analysis for MEN type 2. Oncology (Huntingt) 10 (2): 141-6; discussion 146, 152, 157, 1996.  [PUBMED Abstract]
     
     
128. Grosfeld FJ, Lips CJ, Beemer FA, et al.: Distress in MEN 2 family members and partners prior to DNA test disclosure. Multiple endocrine neoplasia type 2. Am J Med Genet 91 (1): 1-7, 2000.  [PUBMED Abstract]
     
     

Disclaimer

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Changes to This Summary (09/30/2004)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was extensively revised.

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database ⁶.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment ⁷

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment ⁸

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive Care ⁹

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer) ¹⁰

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention ¹¹

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics ¹²

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine ¹³

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Glossary Terms

One of two or more DNA sequences occurring at a particular gene locus. Typically one allele (“normal” DNA sequence) is common, and other alleles (mutations) are rare.

Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).

A change in the usual DNA sequence at a particular gene locus. Mutations (including polymorphisms) can be harmful, beneficial, or neutral.

A graphic illustration of family history.

A characteristic of a genotype; it refers to the likelihood that a clinical condition will occur when a particular genotype is present.

This term has two meanings. It is sometimes used to differentiate cancers occurring in people who do not have a germline mutation that confers increased susceptibility to cancer from cancers occurring in people who are known to carry a mutation. Cancer developing in people who do not carry a high-risk mutation is referred to as sporadic cancer. The distinction is not absolute, because genetic background may influence the likelihood of cancer even in the absence of a specific predisposing mutation. Alternatively, sporadic is also sometimes used to describe cancer occurring in individuals without a family history of cancer.