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Multiple Endocrine Neoplasia Type 2

[MEN2, MEN2 Syndrome. Includes: Multiple Endocrine Neoplasia Type 2A (MEN 2A); Multiple Endocrine Neoplasia Type 2B (MEN 2B, Mucosal Neuroma Syndrome); Familial Medullary Thyroid Carcinoma (FMTC)]

Summary

Disease characteristics.  Multiple endocrine neoplasia type 2 (MEN 2) is classified into three subtypes: MEN 2A, FMTC (familial medullary thyroid carcinoma) and MEN 2B. All three subtypes carry a high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B carry an increased risk for pheochromocytoma; MEN 2A carries an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and an asthenic "Marfanoid" body habitus. The onset of MTC is typically in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC.

Diagnosis/testing.   RET is the only gene known to be associated with MEN type 2. Molecular genetic testing of the RET gene identifies disease-causing mutations in 95% of individuals with MEN 2A and MEN 2B and in about 88% of families with FMTC. Such testing is available clinically and is used primarily for presymptomatic identification of at-risk individuals in order to reduce morbidity and mortality through early intervention.

Genetic counseling.  All MEN 2 subtypes are inherited in an autosomal       dominant manner. The probability of a de novo gene mutation is 5% or less in index cases with MEN 2A and 50% in index cases with MEN 2B. Offspring of affected individuals have a 50% chance of inheriting the mutant gene. Prenatal testing is possible.

Diagnosis

Clinical Diagnosis

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

Familial medullary thyroid carcinoma (FMTC) is diagnosed in families with four cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia [Eng et al 1996].

Unclassified.   Families in which there are two or three cases of MTC and incompletely documented screening for pheochromocytoma and parathyroid disease may represent MEN 2A and should more appropriately be considered "unclassified" [Ponder 1997], although this terminology is not universally accepted.

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 [Morrison & Nevin 1996].

Testing

Diagnosis of medullary thyroid carcinoma (MTC) and C-cell hyperplasia (CCH).   MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration, a specific and sensitive marker. In provocative testing, plasma calcitonin concentration is measured before (basal level) and two and five minutes after intravenous administration of calcium (stimulated level). A positive test is one in which the peak stimulated level is more than three times the basal level, or exceeds 300 ng/L [Lips et al 1994]. 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 is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C-cells. Of note, not all CCH proceeds to MTC [Landsvater et al 1993 , Lips et al 1994].

Diagnosis of pheochromocytoma.  Pheochromocytoma is suspected when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites [i.e., norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid (VMA)] in 24-hour urine collections [Pacak et al 2005]. Abdominal MRI is performed whenever a pheochromocytoma is suspected clinically and whenever urinary catecholamine values are increased. Because of the high frequency of multiple tumors, MIBG (¹³¹I-metaiodobenzylguanidine) scintigraphy is used for further evaluation of individuals with biochemical or radiographic evidence of pheochromocytoma [Lips et al 1994].

Diagnosis of parathyroid abnormalities.   The diagnosis of parathyroid abnormalities is made when biochemical screening reveals simultaneously elevated serum concentrations of calcium and parathyroid hormone (PTH) with an elevated urinary calcium-to-creatinine ratio [Learoyd et al 1995]. Postoperative parathyroid localizing studies may be helpful if hyperparathyroidism recurs [Learoyd et al 1995].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   RET is the only gene known to be associated with MEN 2.

• MEN 2A.  Approximately 95% of families with MEN 2A have a RET mutation in exon 10 or 11 [Mulligan et al 1994 , Mulligan et al 1995]. Mutations of codon 634 Cys occur in about 85% of families; mutation of cysteine residues at codons 609, 611, 618, and 620 together account for the remainder of identifiable mutations in exons 10 and 11. Other rare mutations, including codon 804 alterations, have been reported in a few cases [Lips et al 1994 , Hoppner & Ritter 1997 , Hoppner et al 1998 , Gibelin et al 2004].

• FMTC.   Approximately 88% of families with FMTC have an identifiable RET mutation [Mulligan et al 1994 , Mulligan et al 1995]. These mutations occur at one of the five cysteine residues (codons 609, 611, 618, 620, and 634) with mutations of codons 618, 620, and 634 each accounting for 25% to 35% of mutations. Mutations in exons 13 and 14 (at codons 768 and 804) appear to account for a small percent of mutations in families with FMTC [Bolino et al 1995 ; Eng, Smith et al 1995 ; Boccia et al 1997 ; Feldman et al 2000 ; Frohnauer & Decker 2000]. Mutations in codons 533, 630, 631, 790, 791, 844, and 891 (exons 8, 11, 13, 14, and 15) have also been identified in a small number of families [Hofstra et al 1997 , Berndt et al 1998 , Dang et al 1999 , Fugazzola et al 2002 , Da Silva et al 2003].

• MEN 2B.   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 918 in exon 16, which substitutes a threonine for methionine [Carlson, Dou et al 1994 ; Eng et al 1994]. A second mutation at codon 883 in exon 15, A883F has been identified in several affected individuals without a p.Met918Thr mutation [Gimm et al 1997 , Smith et al 1997]. The presence of two mutations, p.Val804Met and p.Tyr806Cys in cis configuration, has recently been identified in an individual with MEN 2B [Miyauchi et al 1999].

Clinical uses

• Confirmatory diagnostic testing
• Predictive testing
• Prenatal diagnosis

Clinical testing

• Targeted mutation analysis.  Testing for known common and rarer mutations is performed by some laboratories.

• Sequence analysis of select exons.  Mutation scanning and/or sequence analysis of exons 10, 11, 13, 14, 15, and 16 (exons included in testing vary across laboratories) can be used to detect both common and rare mutations.

• Sequence analysis.  Sequence analysis of all RET exons may be helpful if a mutation is not identified through testing of select gene regions or targeted mutation analysis.

Research testing

• A RET oligonucleotide microarray has demonstrated utility in a research setting [Kim et al 2002].
• Other causative and/or modifying loci are being investigated. For example, DNA variants in GFRA4 identified in individuals with MEN 2 may alter the formation of RET signalling complexes [Vanhorne et al 2005]. Mouse models are also being used to investigate modifier genes [Cranston & Ponder 2003].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in MEN 2

Disease Name	Test Method	Mutations Detected	Mutation Detection Rate	Test Availability
MEN 2A	Mutation scanning and/or sequence analysis	RET sequence alterations exons 10 and 11	95%	Clinical
FMTC		RET sequence alteration in exons 10, 11, 13, and 14	88%
MEN 2B	Targeted mutation analysis	p.Met918Thr, p.Ala883Phe	95%

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

• Linkage analysis.  Linkage analysis may be an option to clarify the genetic status of at-risk relatives for families in which a RET mutation has not been identified. Samples from at least two affected family members are necessary to perform linkage analysis. The markers used in MEN 2 linkage analysis are very tightly linked to the RET gene and accuracy may be greater than 95% [Howe et al 1992].

  Note: The accuracy of linkage  analysis is also dependent on 1) the informativeness of genetic markers in the affected individual's family and 2) the accuracy of the clinical diagnosis of MEN 2 in affected family members.

Genetically Related (Allelic) Disorders

RET mutations are associated with the following disorders:

HSCR1.  Hirschsprungdisease (HSCR) is a disorder of the enteric plexus of the colon that typically results in enlargement of the bowel and constipation or obstipation in neonates. Overall, about 20-40% of all cases of HSCR are caused by germline mutations in the RET proto-oncogene and are designated HSCR1 [Attie et al 1995]. However, most of the mutations that cause HSCR1 occur outside of the codons that are mutated in MEN 2A [Eng, Mulligan et al 1995].

Papillary thyroid carcinoma (PTC).  Approximately 40% of PTC is associated with somatic gene rearrangements that cause juxtaposition of the tyrosine kinase domain of RET to various gene partners [Tallini et al 1998].

Clinical Description

Natural History

The endocrine disorders observed in MEN 2 are medullary thyroid carcinoma and/or its precursor, C-cell hyperplasia; pheochromocytoma; and parathyroid adenoma or hyperplasia. Bilateral or multifocal areas of MTC and C-cell hyperplasia are usually observed at the time of thyroidectomy in affected individuals undergoing prophylactic thyroidectomy [Lips et al 1994]. Metastatic spread to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites such as the liver is common and has often occurred in individuals with a palpable thyroid mass or diarrhea [Robbins et al 1991 , Moley et al 1998 , Cohen & Moley 2003]. 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.

MEN 2 is classified into three subtypes: MEN 2A, FMTC, and MEN 2B. All three subtypes have a high risk for MTC; MEN 2A and MEN 2B have an increased risk for pheochromocytoma; MEN 2A has an increased risk for parathyroid hyperplasia or adenoma (Table 2). Classifying an individual or family by MEN 2 subtype is useful for determining prognosis and management.

MEN 2A.   The MEN 2A subtype makes up about 60-90% of cases of MEN 2. Since genetic testing for RET mutations has become available, it has become apparent that 95% of individuals with MEN 2A develop MTC, about 50% develop pheochromocytoma, and about 20-30% develop hyperparathyroidism [Eng 1996].

MTC is generally the first manifestation of MEN 2A. In asymptomatic young individuals, provocative testing may reveal elevated plasma concentration of calcitonin and the presence of CCH or MTC. In families with MEN 2A, the biochemical manifestations of MTC generally appear between the ages of five and 25 years (mean 15 years) [Lips et al 1994]. If individuals with the mutation are untreated, MTC typically presents as a neck mass or neck pain at about age 15 to 20 years. However, more than 50% of such individuals already have cervical lymph node metastases [Robbins et al 1991]. Diarrhea, the most frequent systemic symptom, occurs in affected individuals with a plasma calcitonin concentration of more than 10 ng/mL and implies a poor prognosis [Robbins et al 1991]. Up to 30% of individuals with MTC present with diarrhea and advanced disease [Raue et al 1994].

Pheochromocytomas usually present after MTC, typically with intractable hypertension. They are often bilateral [Conte-Devolx et al 1997]. Sudden death from anesthesia-induced hypertensive crisis has been described in individuals with MEN 2A and unsuspected pheochromocytoma [Robbins et al 1991]. Malignant transformation occurs in about 4% of cases [Modigliani et al 1995]. Since pheochromocytoma can be the first manifestation of MEN 2A in some individuals, the diagnosis of pheochromocytoma in an individual warrants further investigation for MEN 2A [Inabnet et al 2000 , Neumann et al 2002].

A small number of families with MEN 2A have pruritic cutaneous lichen amyloidosis (PCLA), also known as cutaneous lichen amyloidosis (CLA). This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC [Bugalho et al 1992 , Robinson et al 1992].

In one study, seven of 44 families (16%) had cosegregation of MEN 2A and Hirschsprung disease (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 one series [Decker et al 1998]. The cosegregation of MEN 2A and HSCR1 seems to be associated with mutations at specific codons (i.e., 609, 618, and 620) in exon 10 of RET [Decker et al 1998 , Romeo et al 1998 , Inoue et al 1999 , Takahashi et al 1999].

FMTC.   The FMTC subtype comprises about 5-35% of cases of MEN 2. MTC is the only clinical manifestation of FMTC; however, 9% of individuals with a mutation at codon 790, 791, or 804 have papillary thyroid carcinoma [Brauckhoff et al 2002].

MEN 2B.   The MEN 2B subtype comprises about 5% of cases of MEN 2. MEN 2B is characterized by the early development of an aggressive form of MTC in all affected individuals [O'Riordain et al 1994 , Skinner et al 1996]. Individuals with MEN 2B who do not undergo thyroidectomy at an early age (~1 year) are likely to develop metastatic MTC at an early age. Prior to intervention with early prophylactic thyroidectomy, the average age of death in individuals with MEN 2B was age 21 years. Pheochromocytomas occur in 50% of individuals with MEN 2B; about half are multiple and often bilateral. Individuals with undiagnosed pheochromocytoma may die from a cardiovascular crisis peri-operatively. Parathyroid disease is very uncommon [Vasen et al 1992 , Eng 1996 , Eng et al 1996].

Individuals with MEN 2B may be identified in infancy or early childhood by the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx and a distinctive facial appearance. The lips become prominent (or "blubbery") 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 affected individuals have diffuse ganglioneuromatosis of the gastrointestinal tract. Associated symptoms include abdominal distension, megacolon, constipation, or diarrhea.

About 75% of affected individuals have a Marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.

On rare occasion, individuals with MEN 2B and the p.Met918Thr mutation have been found to have HSCR1 [Romeo et al 1998].

Genotype-Phenotype Correlations

Mutations involving the cysteine codons 609, 618, and 620 are associated with MEN 2A, FMTC, and HSCR1.

• Mutations in these codons are detected in about 10% of families with MEN 2A and two-thirds of families with FMTC and are associated with low transforming activity of RET [Takahashi et al 1998].
• Some mutations, such as those involving codons 618 and 620 in exon 10, may be associated with milder forms of the disease [Mulligan et al 1995 , Moers et al 1996].

RET germline p.Met918Thr mutations are only associated with MEN 2B; however, somatic mutations at this codon are frequently observed in individuals with MTC and no known family history of MTC [Zedenius et al 1994 , Zedenius et al 1995].

Any RET mutation at codon 634 in exon 11 results in a higher incidence of pheochromocytomas and hyperparathyroidism [Eng et al 1996 , Yip et al 2003].

• Among the mutations at codon 634, it has been reported that C634R significantly correlates with the presence of hyperparathyroidism [Mulligan et al 1994], but other studies do not confirm this correlation [Schuffenecker et al 1994 , Frank-Raue et al 1996].
• Another report indicates that C634R is associated with a higher probability of having metastases at diagnosis than other codon 634 mutations [Punales et al 2003].
• Codon 634 mutations are also associated with development of cutaneous lichen amyloidosis [Seri et al 1997]. Among 25 individuals from three families with a codon 634 mutation, 36% had cutaneous lichen amyloidosis [Verga et al 2003].

Mutations in codon 768 in exon 13 and in codon 891 in exon 15 may only be associated with the development of MTC, since these mutations have been identified only in the FMTC subtype [Eng, Mulligan et al 1995 ; Bolino et al 1995 ; Boccia et al 1997 ; Dang et al 1999].

Mutations at codons 804 and 891 that were initially only associated with MTC have subsequently been found in families with MEN 2A.

• Although initially it was thought that mutations in codon 804 in exon 14 may only be associated with MTC, subsequent data have identified pheochromocytoma with mutations at this codon (i.e., V804L and V804M) [Nilsson et al 1999 , Hoie et al 2000 , Gibelin et al 2004 , Jimenez et al 2004].
• Disease expression of mutations at codon 804 has been shown to be highly variable, even within the same family [Feldman et al 2000 , Frohnauer & Decker 2000]. Some individuals with such mutations have MTC at age five years and fatal metastatic MTC at age 12 years, whereas other individuals with the same mutation have been shown to have normal thyroid histology at age 27 years, normal biochemical screening at age 40 years, and no clinical evidence of MTC at age 86 years.
• In the presence of Y806C in cis configuration, V804M has been associated with MEN 2B in one individual [Miyauchi et al 1999].
• In another large family with a high level of consanguinity, biochemical testing indicated expression of thyroid disease in individuals homozygous but not heterozygous for V804M [Lecube et al 2002].

A consensus statement resulting from the Seventh International MEN Workshop held in 1999 classified mutations based on their risk for aggressive MTC [Brandi et al 2001]. The classification was used: in recommendations regarding ages at which to perform prophylactic thyroidectomy (see Management) [Brandi et al 2001 , Massoll & Mazzaferri 2004 , Machens et al 2005]; in predicting phenotype [Szinnai et al 2003]; and for determining the need to screen for pheochromocytoma [Yip et al 2003].

• Level 3 mutations, associated with the highest risk for aggressive MTC, included codon 883 and 918 mutations.
• Level 2 mutations were at codons 611, 618, 620, 630.
• Level 1 mutations, associated with the "least high" risk for aggressive MTC, included codons 609, 768, 790, 791, 804, and 891.

In addition to their association with MTC, one study suggests that mutations in codons 790, 791, or 804 may also be associated with papillary thyroid carcinoma [Brauckhoff et al 2002].

Penetrance

The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN 2 subtype (see Table 2). The mutation Y791F, associated with MTC, has been shown to have reduced penetrance [Fitze et al 2002 , Gimm et al 2002 , Vierhapper et al 2004].

Nomenclature

The MEN 2A subtype was initially called Sipple syndrome [Sipple 1961]. The MEN 2B subtype was initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome [Morrison & Nevin 1996].

Prevalence

The prevalence of MEN 2 has been estimated to be one in 30,000. However, the incidence of MEN 2 has not been accurately calculated. Ponder (1997) estimates the incidence for MTC at 20 to 25 new cases per year among the 55 million residents of the United Kingdom.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

MTC in individuals with no family history of MTC.  Medullary thyroid carcinoma accounts for 5-10% of new cases of thyroid cancer diagnosed annually in the U.S. The total number of new cases of MTC diagnosed annually, therefore, is between 1000 and 1200. About 75-80% of individuals with MTC have no known family history of MTC. The peak incidence of the nonfamilial form is in the fifth and sixth decades of life [Robbins et al 1991 , Gharib et al 1992].

The major issue is to distinguish individuals who have MEN 2 from those with isolated (nonsyndromic, nonfamilial) MTC. This is particularly relevant for individuals who present with multifocal MTC with a negative family history.

• DNA analysis of MTC tissue has revealed a 30-67% incidence of somatic mutations of codon 918 in the absence of a germline mutation [Zedenius et al 1994 , Kitamura et al 1997 , Schilling et al 2001]. Tumors with a somatic codon 918 mutation appear to be more aggressive [Zedenius et al 1995 , Schilling et al 2001].
• In contrast, between 1% and 24% of individuals with simplex medullary thyroid carcinoma (i.e., no known family history of MTC) have disease-causing germline mutations in the RET gene [Eng, Mulligan et al 1995 ; Decker et al 1995 ; Kitamura et al 1997]. Thus, some experts recommend germline RET gene testing for all individuals with MTC [Lips 1998].

C-cell hyperplasia.   C-cell hyperplasia associated with a positive calcitonin stimulation test occurs in about 5% of the general population. Thus, the plasma calcitonin responses to stimulation do not always distinguish CCH from small MTC [Landsvater et al 1993 , Lips et al 1994]. A germline mutation in SDHD has been associated with C-cell hyperplasia in one family [Lima et al 2003].

Pheochromocytoma.   The probability that pheochromocytoma is hereditary is estimated to be 84% for multifocal (including bilateral) tumors, and 59% for tumors with age of onset 18 years or younger [Neumann et al 2002]. Approximately 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma may have an inherited disease caused by a mutation in one of four genes, RET, VHL, SDHD, or SDHB [Neumann et al 2002 , Bryant et al 2003]. Pacak et al (2005) compared biochemical profiles for inherited and sporadic pheochromocytoma.

• RET
  • Approximately 5% of individuals with nonsyndromic pheochromocytoma and no family history of pheochromocytoma demonstrated a RET mutation [Neumann et al 2002].
  • MEN 2A accounted for more than 12% of individuals with hereditary pheochromocytoma being treated at a single institution, with 27% of those presenting with pheochromocytoma as the first manifestation of disease [Inabnet et al 2000].
  • It is also possible that a low penetrance pheochromocytoma susceptibility locus exists in the 5' region of RET [McWhinney et al 2003].
• VHL. Any individual presenting with a pheochromocytoma should be evaluated for von Hippel Lindau (VHL) syndrome [Neumann et al 1995]. It is characterized by pheochromocytoma, renal cell carcinoma, cerebellar and spinal hemangioblastoma, and retinal angioma.
  • Some families with apparent autosomal dominant pheochromocytoma have VHL gene mutations in the absence of other clinical manifestations of VHL [Inabnet et al 2000]. Neumann et al (2002) identified VHL mutations in 11% of individuals with nonsyndromic pheochromocytoma and no family history of pheochromocytoma.
  • In contrast, unilateral pheochromocytoma in one family member is very unlikely to be attributable to VHL [Bar et al 1997].
• Approximately 8.5% of individuals with apparently nonfamilial nonsyndromic pheochromocytoma have been shown to have a mutation in one of the succinate dehydrogenase subunit genes, SDHD or SDHB [Neumann et al 2002]. These genes are associated with familial paragangliomas, which are also known as extra-adrenal pheochromocytomas or glomus tumors [Baysal et al 2000 , Astuti et al 2001].

Pheochromocytomas are observed on occasion in neurofibromatosis type 1 (NF1).

Multiple endocrine neoplasia type 1 (MEN 1).   This autosomal dominant endocrinopathy 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 MEN 1 gene. MEN 1 is characterized by a triad of pituitary adenomas, pancreatic islet cell tumors, and parathyroid disease consisting of hyperplasia or adenoma. Affected individuals can also have adrenal cortical tumors, carcinoid tumors, and lipomas [Giraud et al 1998]. Rarely, individuals with MEN 1 have pituitary adenomas and pheochromocytomas, which has led to the hypothesis of an "overlap" syndrome with MEN 2 [Schimke 1990].

Management

Evaluations at Initial Diagnosis to Establish the Extent of Disease

Biochemical, imaging, and genetic evaluations are indicated, as described in Diagnosis .

Treatment of Manifestations

• Standard treatment for MTC is surgical removal of the thyroid and lymph node dissection.
• All individuals who have undergone thyroidectomy need thyroid hormone replacement therapy.
• Autotransplantation of parathyroid tissue is often performed at the same time as thyroidectomy.
• Pheochromocytomas detected by biochemical testing and radionuclide imaging are removed by adrenalectomy; adrenalectomy may be possible using video-assisted laparoscopy. Some specialists recommend bilateral adrenalectomy at the time of demonstration of tumor on just a single adrenal gland because of the strong probability that the other adrenal gland will develop a tumor within ten years [Learoyd et al 1995].
• Chemotherapy and radiation are less effective against MTC [Samaan et al 1989 , Scherubl et al 1990 , Moley et al 1998 , Cohen & Moley 2003].
• Hypertensive treatment involves the use of α- and β-blockers [Pacak et al 2005].

Prevention of Primary Manifestations

• Prophylactic thyroidectomy with autotransplantation of the parathyroids is the primary preventive measure for individuals with an identified germline RET mutation [Cohen & Moley 2003].

  Prophylactic thyroidectomy is safe for all age groups; however, the timing of the surgery is controversial [Moley et al 1998]. According to the consensus statement from the Seventh International Workshop on MEN and EUROMEN data, the age at which prophylactic thyroidectomy is performed can be guided by the codon position of the RET mutation (see Genotype-Phenotype Correlations) [Brandi et al 2001 , Massoll & Mazzaferri 2004 , Machens et al 2005]. However, these guidelines continue to be modified as more data are available. For example, codon 609 mutations have been moved from level 1 to level 2 based on presence of invasive MTC in a five year old with a codon 609 mutation [Brandi et al 2001 , Simon et al 2002 , Machens et al 2005].

  • Thyroidectomy within the first six months of life and preferably before age one month is advocated for individuals with mutations at codons 883, 918, and 922, which have the highest risk for aggressive MTC.
  • Thyroidectomy before age five years is recommended for individuals with mutations at codons 609, 611, 618, 620, 630, or 634.
  • Thyroidectomy by age five or ten years is recommended for individuals with mutations at codons 609, 768, 790, 804, or 891, which are associated with the lowest risk for aggressive MTC among individuals with germline RET mutations [Brandi et al 2001].
  • Incomplete penetrance of codon 791 mutations suggests that thyroidectomy should be guided by the clinical course in individuals with these mutations [Fitze et al 2002].

• Thyroidectomy for C-cell hyperplasia, before progression to invasive MTC, may allow surgery to be limited to thyroidectomy with sparing of lymph nodes [Brandi et al 2001 , Kahraman et al 2003].

  • For all individuals with a RET mutation, annual biochemical screening is recommended with immediate thyroidectomy if results are abnormal [Szinnai et al 2003].
  • In the Netherlands, the recommendation for individuals with mutations at codons 768, 790 and 791 is thyroidectomy after an abnormal C-cell stimulation test result [Lips et al 2005].

• Prophylactic thyroidectomy is not offered routinely to at-risk individuals in whom the disorder has not been confirmed.

Prevention of Secondary Complications

• Screening for pheochromocytoma.  Prior to any surgery, the presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening in any individual with MEN 2A or MEN 2B. In a prospective study of at-risk family members with the disease-causing mutation, 8% had pheochromocytoma detected at the same time as MTC [Nguyen et al 2001].

  • If pheochromocytoma is detected, adrenalectomy should be performed before thyroidectomy to avoid intraoperative catecholamine crisis [Lee & Norton 2000].

Surveillance

• MTC.  Approximately 50% of individuals diagnosed with MTC who have undergone total thyroidectomy and neck nodal dissections have recurrent disease [Cohen & Moley 2003]. Furthermore, thyroid glands removed from individuals with a disease-causing mutation who had normal plasma calcitonin concentrations have been found to contain MTC [Lips et al 1994 , Skinner et al 1996]. Therefore, continued monitoring for residual or recurrent MTC is indicated after thyroidectomy, even if thyroidectomy is performed prior to biochemical evidence of disease. The screening protocol for MTC is an annual calcitonin stimulation test; however, caution needs to be used in interpreting test results since CCH that is not a precursor to MTC occurs in about 5% of the population [Landsvater et al 1993 , Lips et al 1994].

• Hypoparathyroidism.  All individuals who have undergone thyroidectomy and autotransplantation of the parathyroids need monitoring for possible hypoparathyroidism.

• Pheochromocytoma.  For individuals whose initial screening results are negative for pheochromocytoma, annual biochemical screening is recommended, followed by MRI if the biochemical results are abnormal [Raue et al 1994 , Wells & Donis-Keller 1994 , Pacak et al 2005]. Other screening studies, such as abdominal ultrasound examination or CT scan, may be warranted in some individuals.

  • MEN 2A.  Annual biochemical screening until age 35 years. It has been suggested that individuals with the V804M mutation or mutations at codons 609 or 768, which have not been associated with pheochromocytoma, may be screened for pheochromocytoma later and less frequently [Brandi et al 2001].

  • FMTC.  Screening as for MEN 2A since not all families classified as FMTC are MTC-only [Moers et al 1996]

  • MEN 2B.  Same as MEN 2A [Wells & Donis-Keller 1994]

  • Unclassified.  Same as MEN 2A

• Parathyroid adenoma or hyperplasia.  Annual biochemical screening is recommended for affected individuals who have not had parathyroidectomy and auto-transplantation [Wells & Donis-Keller 1994]. More recently, it has been suggested that only individuals with codon 634 mutations need annual screening and that individuals with other mutations may be screened every two to three years [Brandi et al 2001].

  • MEN 2A.  Starting at the time of diagnosis [Wells & Donis-Keller 1994]

  • FMTC.  Screening as for MEN 2A since not all families classified as FMTC are MTC only [Moers et al 1996]

  • MEN 2B.  Same as MEN 2A [Wells & Donis-Keller 1994]

  • Unclassified.  Same as MEN 2A

Agents/Circumstances to Avoid

Tricyclic antidepressants may provoke a hypertensive crisis in individuals with pheochromocytoma.

Testing of Relatives at Risk

• Identification of individuals with germline RET gene disease-causing mutations.   RET gene molecular genetic testing should be offered to probands with any of the MEN 2 subtypes and to all at-risk members of kindreds in which a germline RET mutation has been identified in an affected family member. American Society of Clinical Oncologists (ASCO) identifies MEN 2 as a Group 1 disorder, i.e., a well-defined hereditary cancer syndrome for which genetic testing is considered part of the standard management for at-risk family members [ASCO policy statement 2003].

• MEN 2A.   RET molecular genetic testing should be offered to at-risk children by age five years, since MTC has been documented in childhood [Lips 1998 , Brandi et al 2001]. The finding of MTC in the thyroid of a two-year old with a MEN 2A mutation suggests that molecular genetic testing should be performed even earlier when possible [van Heurn et al 1999].

• FMTC.   Recommendations for families with known FMTC are the same as for MEN 2A.

• MEN 2B.   RET molecular genetic testing should be performed as soon as possible after birth in all children known to be at risk [Brandi et al 2001]. In a child who does not have a family history of MEN 2B, RET molecular genetic testing should be performed as soon as the clinical diagnosis is suspected [Morrison & Nevin 1996].

Therapies Under Investigation

• Viral mediated gene therapy for MTC is being investigated using animal models. Use of a calcitonin promoter allows restriction of thymidine kinase or IL-12 gene expression to thyroid cells resulting in destruction of tumor [de Groot & Zhang 2004].
• Adenoviral vectors expressing a dominant-negative truncated form of RET, termed RET(DeltaTK), were able to induce apoptosis in MTC cells in vitro and also led to tumor regression in transgenic mice [Drosten et al 2004].
• Santoro et al (2004) reviewed the potential of tyrosine kinase inhibitors as therapeutic agents for MTC. In vitro studies using cells with mutant RET suggest therapeutic potential for RPI-1, a novel 2-indolinone Ret tyrosine kinase inhibitor [Cuccuru et al 2004]. Other inhibitors of tyrosine kinase, PP2 and genistein, have been shown to decrease proliferation of a human MTC cell line [Liu et al 2004].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Improved imaging methods for detection of metastases of MTC are being investigated. For example, the high sensitivity of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) suggests utility in follow-up for residual or recurrent disease after thyroidectomy [de Groot et al 2004]. Scintigraphy with the radiolabeled receptor ligand 99mTc-EDDA/HYNIC-TOC also showed higher sensitivity than conventional imaging methods [Parisella et al 2004].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

All of the MEN 2 subtypes are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband.   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.
  • In the 5% of cases that are not familial, either de novo germline mutations [Schuffenecker et al 1997] or incomplete penetrance of the mutant allele is possible.
  • It is always appropriate to evaluate the parents of an individual with MEN 2A for manifestations of the disorder.

• FMTC.   By definition, individuals with FMTC have multiple family members who are affected.

• MEN 2B

  • About 50% of affected individuals have a de novo germline mutation, and 50% have inherited the mutation from a parent [Norum et al 1990 ; Carlson, Bracamontes et al 1994].
  • The majority of de novo mutations are paternal in origin, but cases of maternal origin have been reported [Kitamura et al 1995].

Sibs of a proband

• The risk to sibs depends upon the genetic status of the parent, which can be clarified by pedigree analysis and/or molecular genetic testing.
• If a parent has the gene mutation, the risk is 50%.
• In situations of apparent de novo germline mutations, germline  mosaicism in an apparently unaffected parent needs to be considered, even though such an occurrence has not yet been reported.

Offspring of a proband

• Each child of an individual with MEN 2 has a 50% chance inheriting the RET mutation.
• The probability that the offspring of an individual with simplex MTC (i.e., no known family history of MTC) and no identifiable RET germline mutation would inherit a RET mutation is 0.18% [Brandi et al 2001 , Massoll & Mazzaferri 2004]. This is based on a 95% mutation detection rate and on empiric data that 7% of individuals with sporadic MTC have a germline mutation.

Other family members of a proband.   The risk to other family members depends upon the status of the proband's parents. If a parent is found to have a gene mutation, his or her family members are at risk.

Testing of at-risk individuals.   Consideration of DNA-based testing of at-risk family members is appropriate for surveillance [Lips et al 1994] (see Management). Molecular genetic testing (see Molecular Genetic Testing) can be used for testing of at-risk relatives only if a disease-causing germline mutation has been identified in an affected family member. When a known disease-causing mutation is not identified, linkage analysis (see Molecular Genetic Testing) can be considered in families with more than one affected family member from different generations. Because early detection of at-risk individuals affects medical management, testing of asymptomatic children is beneficial [ASCO policy statement 2003]. Education and genetic counseling of at-risk children and their parents prior to genetic testing are appropriate.

Related Genetic Counseling Issues

Genetic cancer risk assessment and counseling. For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see:

• Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of Genetic Counselors

• Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ^®, National Cancer Institute)

Considerations in families with an apparent de novo mutation.   When the parents of a proband with an autosomal dominant condition do not have the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible nonmedical explanations including alternate paternity or undisclosed adoption could also be explored.

Family planning.   The optimal time for determination of genetic risk and availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of the at-risk asymptomatic family are best made before pregnancy.

DNA banking.   DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as MEN 2 that do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Normal allelic variants: The RET proto-oncogene is composed of 21 exons over 55 kb of genomic material [Kwok et al 1993 , Myers et al 1995].

• Normal polymorphisms have been described [Ceccherini et al 1994 , Saez et al 1997]. R694Q is classified as a normal variant based on lack of transforming activity [Orgiana et al 2004].
• Some variants, such as R600Q and I852M, have undetermined significance [Saez et al 2000 , Demeester et al 2001].
• It is speculated that some rare variants, e.g., V648I, may modify the phenotype when inherited with a pathogenic mutation [Nunes et al 2002].
• Evidence suggests that other variants may be predisposition factors. For example, G691S and S904S may predispose individuals with a pathologic mutation to an earlier age at onset of MEN 2A [Gil et al 2002 , Robledo et al 2003] and may be low penetrance risk factors for development of MTC [Elisei, Cosci, Romei, Bottci et al 2004 ; Robledo et al 2003] and S836S has been associated with an increased risk of nonfamilial MTC in one study [Ruiz et al 2001] but not in another [Berard et al 2004].

Pathologic allelic variants: The major disease-causing mutations are non-conservative substitutions located in one of six cysteine codons in the extracellular domain of the encoded protein. They include codons 609, 611, 618, and 620 in exon 10 and codons 630 and 634 in exon 11 [Takahashi et al 1998]. All of these variants have been identified in families with MEN 2A and some have been identified in families with FMTC. Mutations in these sites have been detected in 95% of families with MEN 2A [Mulligan et al 1995]. Approximately 95% of all individuals with the MEN 2B phenotype have a single point mutation in the tyrosine kinase domain of the RET gene at codon 918 in exon 16, which substitutes a threonine for methionine [Carlson, Dou et al 1994 ; Eng et al 1994]. A second point mutation at codon 883 has been found in several individuals with MEN 2B [Gimm et al 1997 , Smith et al 1997]. In addition to the mutations of the cysteine residues in exons 10 and 11 that have been found in families with MEN 2A, mutations in codons 631, 768, 790, 791, 804, 844, and 891 have also been identified in a small number of families [Eng, Smith et al 1995 ; Bolino et al 1995 ; Hofstra et al 1997 ; Berndt et al 1998]. A mutation at codon 603 was reported in one family and appeared to be associated with both MTC and papillary thyroid cancer [Rey et al 2001]. The mutation P912R appeared to be associated with FMTC in one family [Jimenez, Dang et al 2004]. Duplication mutations have been reported in two families [Hoppner & Ritter 1997 , Hoppner et al 1998]. Homozygosity for A883T has been observed in one family with MTC [Elisei, Cosci, Romei, Agate et al 2004]. Rare families have two mutations in cis configuration, for example, alteration of both codons 634 and 635 in one family with MEN 2A [Lips et al 1994]; alteration of both codons 804 and 844 in one family with FMTC [Bartsch et al 2000]; and alteration of codons 804 and 806 in an individual with MEN 2B [Miyauchi et al 1999].

Normal gene product: RET produces a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. The extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region. The encoded protein plays a role in signal transduction by interaction with the glial-derived neurotropic factor (GDNF) family of ligands: GDNF, neurturin, persephin, and artemin. Ligand interaction is via the ligand-binding GDNF family receptors (GFRα) to which RET protein binds the encoded protein complexes. Formation of a complex containing two RET protein molecules leads to RET autophosphorylation and intracellular signaling whereby phosphorylated tyrosines become docking sites for intracellular signaling proteins [Santoro et al 2004]. The RET tyrosine kinase catalytic core, which is located in the intracellular domain, interacts with the docking protein FRS2 and causes downstream activation of the mitogen-activated protein (MAP) kinase signaling cascade [Manie et al 2001]. Normal tissues contain transcripts of several lengths [Takaya et al 1996].

Abnormal gene product: 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 [Santoro et al 1995 , Takahashi et al 1998]. In vitro assays demonstrate that the transforming activity of cysteine 634 mutations is three- to fivefold higher than that of codon 609, 611, 618, or 620 mutations [Takahashi et al 1998]. In vitro studies demonstrated that the transforming activity of the double mutant p.Val804Met and p.Tyr806Cys causing MEN 2B was significantly higher than that of p.Val804Met or p.Tyr804Met alone [Iwashita et al 2000].

The disease-causing point mutation codon 918 that causes 95% of the MEN 2B phenotype lies within the catalytic core of the tyrosine kinase and causes a constitutive activation (i.e., gain of function) of the RET kinase independent of the normal ligand-binding and dimerization steps [Santoro et al 1995 , Takahashi et al 1998].

In contrast to the activating mutations in MEN 2, mutations that cause Hirschsprung disease result in a decrease in the transforming activity of RET [Iwashita et al 1996]. For families in which MEN 2A and HSCR cosegregate, models to explain how the same mutation can cause gain of function and loss of function have been proposed [Takahashi et al 1999].

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

• American Society of Clinical Oncology (2003) Statement on genetic testing for cancer susceptibility

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