Multiple Endocrine Neoplasia—Syndromes of the Twentieth Century

Rajesh V. Thakker

MRC Molecular Endocrinology Group Imperial College School of Medicine Hammersmith Hospital London W12 0NN

Address correspondence and requests for reprints to: Professor R.V. Thakker, MRC Molecular Endocrinology Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. E-mail: rthakker{at}rpms.ac.uk


    Introduction
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 Introduction
 Multiple endocrine neoplasia...
 Multiple endocrine neoplasia...
 Conclusions
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The multiple endocrine neoplasia (MEN) syndrome, which consists of several subtypes (Table 1Go), was first described in the early 1900’s, and during the century, the clinical features, biochemical characteristics, inheritance and genes, together with the encoded proteins for the MENs, have been defined (reviewed in references 1 and 2). Thus, the MENs represent syndromes of the 20th century, and the progress in these studies culminating with the four publications (3, 4, 5, 6) in this issue will be reviewed. MEN is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. This disorder has previously been referred to as multiple endocrine adenopathy (MEA) and the pluriglandular syndrome. However, glandular hyperplasia and malignancy may also occur in some patients, and the term multiple endocrine neoplasia (MEN) is now the preferred term. There are two major forms of MEN, type 1 (MEN1, Wermer’s syndrome) and type 2 (MEN2, Sipple’s syndrome); each form is characterized by the development of tumors within specific endocrine glands (Table 1Go). The MEN syndromes are uncommon, but because they are inherited as autosomal dominant disorders, the finding of MEN in a patient has important implications for other family members; first degree relatives have about a 50% risk of developing the disease. Occasionally, the MEN syndromes may arise sporadically (i.e. without a family history). It may be difficult to make the distinction between sporadic and familial forms; in some cases the family history may be absent because the parent with the disease may have died before developing any manifestations. Thus, biochemical and genetic screening may have important roles in the lives of MEN patients and their families.


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Table 1. The multiple endocrine neoplasia (MEN) syndromes, their characteristic tumors and associated genetic abnormalities

 

    Multiple endocrine neoplasia type 1 (MEN1)
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MEN1 is characterized by the combined occurrence of tumors of the parathyroids, pancreatic islet cells, and anterior pituitary (reviewed in reference 1). Parathyroid tumors occur in 95% of MEN1 patients, resulting in the hypercalcemia of primary hyperparathyroidism. Parathyroid tumors detected by hypercalcemia are the first manifestation of MEN1 in about 90% of patients. Pancreatic islet cell tumors occur in 40% of MEN1 patients. Gastrinomas are the most common type, and insulinomas are the second most common. Glucagonomas and VIPomas are rare, whereas pancreatic polypeptidomas (PPomas) are more common but remain asymptomatic. Gastrinomas, leading to the Zollinger-Ellison syndrome, are the most important cause of morbidity and mortality in MEN1 patients. Anterior pituitary tumors occur in 30% of MEN1 patients. Most (60%) are prolactinomas, somatotrophinomas are the next most common (20%), and corticotrophinomas and nonfunctioning tumors represent less than 15% of MEN1 pituitary tumors. Associated tumors, which occur less commonly in MEN1, include adrenal cortical tumors (5%), carcinoid tumors (4%), lipomas (1%) angiofibromas (<1%), and collagenomas (<1%).

The MEN1 gene. The gene causing MEN1 was localized to chromosome 11q13 by genetic mapping studies that investigated MEN1 associated tumors for loss of heterozygosity (LOH) and by segregation studies in MEN1 families (reviewed in reference 1). The results of these studies, which were consistent with Knudson’s model for tumor development, indicated that the MEN1 gene represented a putative tumor suppressor gene. Further genetic mapping studies defined a less than 300 Kb region as the minimal critical segment that contained the MEN1 gene, and characterization of genes from this region led to the identification of the MEN1 gene (7, 8), which consists of 10 exons with a 1,830 bp coding region that encodes a novel 610 amino acid protein, referred to as "MENIN" (7). Mutations of the MEN1 gene have been identified (7, 8, 9, 10), and the study by Teh et al. (3), in this issue, reports a further 29 germ-line MEN1 mutations that were found amongst 58 MEN1 families and 8 sporadic MEN1 patients. Interestingly, a similar analysis of 8 families with isolated acromegaly and 4 families with isolated hyperparathyroidism did not detect any germ-line MEN1 mutations (3), and it seems likely that these 2 inherited endocrine disorders may have a different genetic etiology. The total number of germ-line mutations of the MEN1 gene that have now been identified (3, 7, 8, 9, 10) in MEN1 patients is approximately 140 and approximately 25% are nonsense mutations, 45% are deletions, 15% are insertions, less than 5% are donor-splice mutations, and 10% are missense mutations. Thus, the majority (>80%) of these mutations are inactivating and are consistent with those expected in a tumor suppressor gene. The mutations are not only diverse in their types but are also scattered throughout the 1,830 bp coding region of the MEN1 gene with no evidence for clustering as observed in MEN2 (see below). However, some of the mutations have been observed to occur several times in unrelated families (Table 1Go), and the 3 deletional and insertional mutations involving codons 83 and 84, 209 to 211, and codons 514 to 516, account for approximately 25% of all the germ-line MEN1 mutations and thus may represent potential "hot" spots. Such deletional and insertional hot spots may be associated with DNA sequence repeats that may consist of long tracts of either single nucleotides or shorter elements, ranging from dinucleotides to octanucleotides. Indeed, the DNA sequence in the vicinity of codons 83 and 84 in exon 2, and codons 209 to 211 in exon 3, contains CT and CA dinucleotide repeats, respectively, flanking the 4 bp deletions (Table 1Go); these would be consistent with a replication-slippage model in which there is misalignment of the dinucleotide repeat during replication, followed by excision of the 4 bp single-stranded loop (10). The deletions and insertions of codon 516 involve a poly(C)7 tract, and a slipped-strand mispairing model is also the most likely mechanism to be associated with this mutational hot spot (10). Thus, the MEN1 gene appears to contain DNA sequences that may render it susceptible to deletional and insertional mutations.

Correlations between the MEN1 mutations and the clinical manifestations of the disorder appear to be absent. For example a detailed study of 5 unrelated families with the same 4 bp deletion (CAGT) in codons 210 and 211 (Table 2Go) revealed a wide range of MEN1-associated tumors (10); all the affected family members had parathyroid tumors, but members of families 1, 3, 4, and 5 had gastrinomas, whereas members of family 2 had insulinomas. In addition, prolactinomas occurred in members of families 2, 3, 4, and 5 but not family 1, which was affected with carcinoid tumors. More than 10% of the MEN1 mutations arise de novo and may be transmitted to subsequent generations (3, 9, 10). It is also important to note that between 5% to 20% of MEN1 patients may not harbor mutations in the coding region of MEN1 gene (3, 7, 8, 9, 10), and that these individuals may have mutations in the promoter or untranslated regions (UTRs), which remain to be investigated. These together with the wide diversity of mutations in the 1,830 bp coding region of the MEN1 gene and an apparent lack of genotype-phenotype correlations, which contrasts with the situation in MEN2 (see below), will make mutational analysis for diagnostic purposes in MEN1 time-consuming and expensive.


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Table 2. MEN1 associated tumors in five unrelated families with a 4bp (CAGT) deletion at codons 210 and 211 (from reference 10)

 
MEN1 mutations in sporadic non-MEN1 endocrine tumors. Parathyroid, pancreatic islet cell, and anterior pituitary tumors may occur either as part of MEN1 or more commonly as sporadic, nonfamilial, tumors. Tumors from MEN1 patients have been observed to harbor the germ-line mutation together with a somatic LOH involving chromosome 11q13, as expected from Knudson’s model and the proposed role of the MEN1 gene as a tumor suppressor. However, LOH involving chromosome 11q13, which is the location of the MEN1, has also been observed in 5–50% of sporadic endocrine tumors, implicating the involvement of the MEN1 gene in the etiology of these tumors. This has been investigated, and the studies by Farnebo et al. (4) and Carling et al. (5), in this issue, have examined the role of the MEN1 gene in the etiology of sporadic parathyroid tumors. These studies (4, 5) revealed that LOH involving chromosome 11q13 and mutations of the MEN1 gene occurred in less than 30% and less than 15%, respectively, of the sporadic parathyroid tumors (Table 3Go). The involvement of the MEN1 gene in the etiology of sporadic pituitary tumors has also been investigated, and the study by Tanaka et al. (6), in this issue, reveals that this is very infrequent at 0.03% (Table 3Go). These findings in sporadic parathyroid (4, 5) and pituitary (6) tumors are in agreement with those of other reports (11, 13, 14), and the results of all such studies of sporadic parathyroid tumors, gastrinomas, insulinomas, anterior pituitary adenomas, carcinoid tumors, and lipomas (Table 3Go) have revealed chromosome 11q13 LOH in 0.03–93%, and somatic MEN1 mutations in 0.03–36% of these tumors. The occurrence of MEN1 mutations in sporadic parathyroid tumors, gastrinomas, and carcinoid tumors was greater than that observed in anterior pituitary adenomas. The tumors harbouring a somatic MEN1 mutation all had chromosome 11q13 LOH as the other genetic abnormality, or "hit," consistent with Knudson’s hypothesis. These studies (4, 5, 6, 11, 12, 13, 14, 15, 16) indicate that although inactivation of the MEN1 gene may have a role in the etiology of some sporadic endocrine tumors, the involvement of other genes with major roles in the etiology of such sporadic endocrine tumors is highly likely.


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Table 3. Frequency of MEN1 mutations and chromosome 11q13 LOH in sporadic endocrine tumors

 
Function of MEN1 protein (MENIN). Analysis of the predicted amino acid sequence encoded by the MEN1 gene did not reveal homologies to any other proteins, sequence motifs, signal peptides, or consensus nuclear localization signals (7), and thus, the putative function of the protein (MENIN) could not be deduced. Recent studies based on immunofluorescence, Western blotting of subcellular fractions, and epitope tagging with enhanced green fluorescent protein, have revealed that MENIN is located primarily in the nucleus (17). Furthermore, enhanced green fluorescent protein-tagged MENIN deletional constructs have identified at least two independent nuclear localization signals that are located in the C-terminal quarter of the protein. Interestingly, none of the MEN1 germ-line missense or in-frame deletions (3, 7, 8, 9, 10) alter either of these putative nuclear localization signals. However, all of the truncated MEN1 proteins that would result from the nonsense and frameshift mutations, if expressed, would lack these nuclear localization signals. The nuclear localization of MENIN suggests that it may act either in the regulation of transcription, or DNA replication, or the cell cycle. However, the precise roles of MENIN in the nucleus and in the regulation of endocrine cell growth control remain to be elucidated.


    Multiple endocrine neoplasia type 2 (MEN2)
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MEN2 describes the association (Table 1Go) of medullary thyroid carcinoma (MTC), pheochromocytomas, and parathyroid tumors (reviewed in reference 2). Three clinical variants of MEN2 are recognized—MEN2a, MEN2b, and MTC-only (Table 1Go). MEN2a is the most common variant, and the development of MTC is associated with pheochromocytomas (50% of patients), which may be bilateral, and parathyroid tumors (20% of patients). MEN2b, which represents 5% of all MEN2 cases, is characterized by the occurrence of MTC and pheochromocytoma in association with a Marfanoid habitus, mucosal neuromas, medullated corneal fibers, and intestinal autonomic ganglion dysfunction leading to multiple diverticulae and megacolon. Parathyroid tumors do not usually occur in MEN2b. MTC only is a variant in which medullary thyroid carcinoma is the sole manifestation of the syndrome.

The MEN2 gene (c-ret). The gene causing all three MEN2 variants was mapped to chromosome 10cen-10q11.2, a region containing the c-ret proto-oncogene, which encodes a tyrosine kinase receptor with cadherin-like and cysteine-rich extracellular domains, and a tyrosine kinase intracellular domain (reviewed in reference 2). Specific mutations of c-ret have been identified for each of the three MEN2 variants (Table 1Go). Thus, in 95% of patients MEN2a is associated with mutations of the cysteine-rich extracellular domain, and mutations in codon 634 account for 85% of MEN2a mutations. MTC-only is also associated with mutations in the cysteine-rich extracellular domain, and most mutations are in codon 618. However, MEN2b is associated with mutations in codon 918 of the intracellular tyrosine kinase domain in 95% of patients. Interestingly, the c-ret proto-oncogene is also involved in the etiology of papillary thyroid carcinomas and in Hirschsprung’s disease. Mutational analysis of c-ret to detect mutations in codons 609, 611, 618, 634, 768, and 804 in MEN2a and MTC-only, and codon 918 in MEN2b, has been used in the diagnosis and management of patients and families with these disorders (reviewed in reference 2).


    Conclusions
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 Introduction
 Multiple endocrine neoplasia...
 Multiple endocrine neoplasia...
 Conclusions
 References
 
The twentieth century has seen enormous advances in the MENs, from their initial, clinical recognition to identifying the genes and molecular defects, and in defining some functions of the encoded proteins. However, many challenges remain. For example, the mutational diversity of the MEN1 mutations and the apparent lack of genotype-phenotype correlations, which contrast to that found in MEN2, require further investigation to bring the benefits of mutational screening and tumor prevention to the patients. In addition, elucidating the functional role of MENIN in the nucleus will help to gain a better understanding of endocrine cell growth and proliferation, and thereby facilitate the design of potential novel therapies. These will be some of the challenges for the MEN syndromes in the forthcoming twenty-first century.


    Acknowledgments
 
I am grateful to: the Medical Research Council (MRC), UK, for support; to my colleagues J.D.H. Bassett, S.A. Forbes, and A.A.J. Pannett for helpful discussions; and to S. Kingsley for typing the manuscript.

Received June 2, 1998.

Accepted June 5, 1998.


    References
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  1. Thakker RV. 1995 Multiple Endocrine Neoplasia Type 1. In: DeGroot LJ, ed. Endocrinology, 3rd ed. Philadelphia: WB Saunders; 2815–2831.
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