Multiple Endocrine Neoplasia Type

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant trait with marked intrafamilial variability, characterized by multiple tumors or hyperplasia of endocrine glands (see OMIM 131100). MEN1 is defined by the presence of two of the following three endocrine tumors: parathyroid adenoma or hyperplasia, entero-pancreatic endocrine tumors, and pituitary adenomas. Other possible manifestations include carcinoid tumors, adrenal adenomas, and lipomas. The MEN1 gene was identified through analysis of large kindreds with MEN1. It is located on chromosome 11q13 (80). The gene product, menin, appears to function as a tumor suppressor gene. Loss of one copy of the gene (loss of heterozy-gosity) because of germline mutations leaves cells vulnerable to loss of the second allele through somatic mutations. Loss of the second allele, in turn, leads to tumor formation in affected tissues.

Multiple Endocrine Neoplasia

Fig. 2. Pedigree of a family with Albright hereditary osteodystrophy, demonstrating the effect of paternal imprinting. Hatched squares represent patients mildly affected because of silencing of the imprinted, mutated paternal allele; the black square represents a patient severely affected because of full expression of the nonimprinted, mutated maternal GNAS1 allele and silencing of the imprinted, normal paternal GNAS1 allele.

Fig. 2. Pedigree of a family with Albright hereditary osteodystrophy, demonstrating the effect of paternal imprinting. Hatched squares represent patients mildly affected because of silencing of the imprinted, mutated paternal allele; the black square represents a patient severely affected because of full expression of the nonimprinted, mutated maternal GNAS1 allele and silencing of the imprinted, normal paternal GNAS1 allele.

Commercial testing for MEN1 mutations will identify approx 80-90% of mutations. At-risk relatives of index patients should be tested. Identification of carrier status can identify those patients who require regular screening for the manifestations of MEN1 and exclude noncarriers from screening. In families whose mutation cannot be identified, 11q13 haplotype testing could identify carriers (81).

6.2. MULTIPLE ENDOCRINE NEOPLASIA TYPES 2A AND 2B AND FAMILIAL MEDULLARY THYROID CARCINOMA (MEN2A, MEN2B, AND FMTC) Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant syndrome defined by medullary thyroid carcinoma, pheochromocy-toma, and parathyroid adenomas (OMIM 171400). Ninety percent of MEN2A patients will have medullary thyroid carcinoma, 50% will have pheochromocytomas and 20-30% will have parathyroid tumors of MEN2B consists of medullary thyroid carcinoma and pheochromocytomas in association with marfanoid body habitus and intestinal and mucosal ganglioneu-romatosis. Familial medullary thyroid carcinoma (FMTC) can exist in isolation. Hirschsprung's disease can be seen in association with either MEN2A or FMTC.

All three disorders (MEN2A, MEN2B, and FMTC) are caused by mutations in the RET gene (OMIM 164761). RET is located on chromosome 10 and encodes a membrane-bound tyrosine kinase. A limited number of mutations are associated with the MEN2 syndromes, mainly in exons 10, 11, 13, 14, 15, and 16. Testing of these exons is commercially available and will detect the majority of mutations. Prior to the availability of RET testing, patients who were possible carriers were monitored for medullary thyroid carcinoma (MTC) by following basal and stimulated calcitonin levels; however, these have higher false-positive and false-negative rates than mutation testing (81). Determining RET carrier status in children at risk is particularly important because prophylactic thyroidectomy might be life-saving. In one study, 67% of juvenile RET mutation carriers subsequently shown to have MTC or C-cell hyper-plasia (a premalignant lesion) at thyroidectomy had normal basal calcitonin levels (82). MTC has been reported in infancy, highlighting the need for early testing and decisions about prophylactic thyroidectomy.

6.3. PATHOLOGIC ALLELIC VARIANTS OF THE RET GENE The major disease-causing mutations are nonconserv-ative 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 (83). All of these variants have been identified in families with MEN2A, and some have been identified in families with FMTC. Mutations in these sites have been detected in 95% of MEN2A families (84). Approximately 95% of all individuals with the MEN2B phenotype have a singlepoint mutation in the tyrosine kinase domain of the RET gene at codon 918 in exon 16, which substitutes a threonine for methionine (85,86). A second point mutation at codon 883 has been found in four MEN2B patients (87,88). 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 (89-92). A mutation at codon 603 was reported in one family and appeared to be associated with both MTC and papillary thyroid cancer (93). Duplication mutations have been reported in two families (94,95). Rare families have two mutations in cis configuration; for example, alteration of both codons 634 and 635 in one family with MEN2A (96), alteration of both codons 804 and 844 in one family with FMTC (97), and alteration of codons 804 and 806 in an individual with MEN2B (98).

6.4. MOLECULAR GENETIC TESTING IN MEN SYNDROMES The MEN syndromes are a group of conditions in which molecular genetic testing guides therapy and can be life-saving. Testing for MEN1 or RET mutations can confirm the diagnosis in affected patients and, in the case of RET mutations, guide optimal timing of thyroidectomy. For unaffected patients at risk, testing can identify carriers who will need life-long surveillance for the manifestations of these syndromes and can exclude noncarriers from costly and invasive testing.

6.4.1. Resources for Genetic Testing Molecular diagnostic tests are increasingly available through commercial laboratories. Testing for conditions such as MEN2A and MEN2B is often performed in a two-tiered manner, with initial testing for the most common variants followed by screening of the whole gene only if the most common variants are not present. For some conditions, testing is available through research laboratories only. Websites such as GeneTests-GeneClinics (http://www.geneclinics.org/) provide listings of clinical and research laboratories that offer molecular genetic testing. For example, at the time of this writing, there are 3 clinical laboratories offering genetic testing and 2 research laboratories soliciting samples for MEN1, and 12 clinical labs offering RET testing and 1 research lab soliciting samples for MEN2. Referral to a geneticist or genetic counselor might be useful in obtaining assistance in diagnosis and management and in counseling the patient and family members regarding issues such as risk of recurrence of a disorder, reproductive decisions, or testing of additional family members.

6.4.2. Genetic Testing in Children Genetic testing in children presents special considerations. In general, genetic testing in children should only be considered when the results would make an immediate and important change in the patient's management. For example, a young child with a positive test for an MEN2B-associated RET mutation would be referred for thyroidectomy. Predictive testing for adult-onset diseases such as Huntington's chorea or carrier testing for diseases such as Tay-Sachs disease is generally not recommended until the child is old enough to decide for himself or herself. Prior to performing any genetic testing in children, informed consent from the parent or legal guardian and assent from the child should be obtained. For further discussion of issues related to genetic testing in children, the reader is referred to the published statements of the American Academy of Pediatrics and the American Society of Human Genetics (99,100).

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