Classification and genetics of multiple endocrine neoplasia type 2

INTRODUCTION — Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder with an estimated prevalence of 1 per 30,000 in the general population. MEN2 is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and primary parathyroid hyperplasia. The gene associated with MEN2 is the RET proto-oncogene on chromosome 10. As expected from its autosomal dominant inheritance pattern, males and females with MEN type 2A (MEN2A) are affected in equal proportions.

Although MEN2 is rare, recognition is important both for treatment and for evaluation of family members. MEN2 is often first suspected when a patient is found to have one or more of the tumors, but molecular DNA testing is now available for detecting asymptomatic patients with MEN2.

This topic will review the classification and genetics of the MEN2 syndromes (table 1). The clinical manifestations, diagnosis, and therapy of MEN2 are discussed separately.

●(See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

●(See "Approach to therapy in multiple endocrine neoplasia type 2".)

CLASSIFICATION — Multiple endocrine neoplasia type 2 (MEN2) is subclassified into two distinct syndromes: types 2A (MEN2A) and 2B (MEN2B). Within MEN2A, there are four variants (table 1) [1]:

●Classical MEN2A

●MEN2A with cutaneous lichen amyloidosis (CLA)

●MEN2A with Hirschsprung disease (HD)

●Familial medullary thyroid cancer (FMTC)

In both MEN2A and MEN2B, there is an occurrence of multicentric tumor formation in all organs where the RET proto-oncogene is expressed. The thyroid, parathyroid and adrenal glands, and accessory adrenals are at risk for developing tumors that may reduce life expectancy and quality of life.

Multiple endocrine neoplasia type 2A — Within MEN2A, there are four variants: classical MEN2A, MEN2A with CLA, MEN2A with HD, and FMTC [1].

Classical MEN2A — Classical multiple endocrine neoplasia 2A (MEN2A) is the most common MEN2A variant [1]. It is a heritable predisposition to medullary thyroid cancer (MTC), pheochromocytoma, and primary parathyroid hyperplasia. The respective frequency of these tumors in classical MEN2A is over 90 percent for MTC, approximately 10 to 50 percent for pheochromocytoma, and 10 to 20 percent for multigland parathyroid hyperplasia. The frequency of the development of MTC, pheochromocytoma, and parathyroid hyperplasia depends upon the specific RET mutation [1]. (See 'Germline mutations' below.)

MEN2A with cutaneous lichen amyloidosis — CLA (also known as lichen planus amyloidosis [LPA]) has been described in some families with multiple endocrine neoplasia 2A (MEN2A), predominantly those with the RET codon 634 mutation, although it has also been reported in a patient with a codon 804 mutation [1-4]. The diagnosis of CLA may precede the onset of clinically evident MTC (picture 1A-B). Patients with this variant develop pheochromocytomas and parathyroid hyperplasia with a similar frequency as those with classical MEN2A.

MEN2A with Hirschsprung disease — HD is a motor disorder of the gut that is caused by the failure of neural crest cells (precursors of enteric ganglion cells) to migrate completely during intestinal development. The resulting aganglionic segment of the colon fails to relax, causing a functional obstruction. At least eight genetic mutations have been identified in patients with HD. The predominant gene affected is the RET proto-oncogene. RET malfunction accounts for at least 50 percent of familial and 20 percent of sporadic cases of HD. (See "Congenital aganglionic megacolon (Hirschsprung disease)", section on 'Genetics'.)

In one study, the prevalence of HD in MEN2 was 7.5 percent [5]. The frequency of HD in MEN2A depends upon the specific RET mutation. The co-occurrence of HD and MEN2A is predominantly associated with RET mutations involving codons 609, 611, 618, and 620 [6,7]. In such patients, HD may be the first presentation of MEN2A [8]. Patients with this variant of MEN2A develop MTC, pheochromocytomas, and parathyroid hyperplasia with a similar frequency as those with classical MEN2A.

Familial medullary thyroid cancer — The familial MTC (FMTC) variant of MEN2A is characterized by the presence of a RET germline mutation in families or an individual with MTC who do not develop pheochromocytoma or primary hyperparathyroidism [1]. The clinical distinction of FMTC from MEN2A may be difficult on statistical grounds in small families; even in some large kindreds, the clinical designation of FMTC has been changed to MEN2A after the diagnosis of pheochromocytoma or hyperparathyroidism in a family member. Because FMTC is the most limited variant of MEN2, making the wrong diagnosis of FMTC could result in missing a pheochromocytoma in a patient with MEN2.

Why pheochromocytomas and hyperparathyroidism infrequently develop in these families is still unknown since many FMTC and MEN2A families carry identical RET mutations [9,10]. In rare families, both HD and FMTC appear to segregate [11].

In a report summarizing data from 250 Italian kindreds with hereditary MTC, the prevalence of the FMTC phenotype among RET mutation carriers was higher than MEN2A and MEN2B (57 versus 34 and 6.8 percent, respectively) [12]. This may be related to the introduction of RET screening in the work-up of apparently sporadic MTC and the more extensive search for RET mutations in non-hot spot regions of the gene.

Multiple endocrine neoplasia type 2B — The frequency of MEN2B has been estimated at roughly 6 percent of all MEN2 patients [13]. MEN2B shares the inherited predisposition to MTC and pheochromocytoma that occurs in MEN2A. On the other hand, parathyroid hyperplasia is not a feature of this disorder. There are additional important clinical differences. Patients with MEN2B tend to have mucosal neuromas, typically involving the lips and tongue, and intestinal ganglioneuromas. Disturbances of colonic function are common, including chronic constipation and megacolon. Many of these patients have development abnormalities, a Marfanoid habitus, and myelinated corneal nerves.

MTC is the most common component of the MEN2B syndrome. Furthermore, the tumor is associated with an earlier age of onset than in MEN2A; as a result, early diagnosis and prevention are particularly critical.

MOLECULAR GENETICS — Multiple endocrine neoplasia types 2A (MEN2A) and 2B (MEN2B) are inherited in an autosomal dominant pattern with very high penetrance. The genetic defect in these disorders involves the RET proto-oncogene on chromosome 10 [9,10,14,15].

Structure and function of the normal RET proto-oncogene and its product — The RET protein is a receptor tyrosine kinase that appears to transduce growth and differentiation signals in several developing tissues, including those derived from the neural crest [10]. The protein consists of an extracellular part with a ligand-binding domain, a cadherin (calcium-dependent cell adhesion)-like domain, and a cysteine-rich domain close to the cell membrane. It has a single transmembrane domain and an intracellular part with two tyrosine kinase subdomains, TK1 and TK2.

Activation of RET occurs by the binding of one of its four ligands, glial cell line-derived neurotrophic factor (GDNF), neurturin (TNT), artemin, or persephin, which require their specific co-receptors GDNF-receptor-family-a-1 (GFR-a-1), GFR-a-2, GFR-a-3, and GFR-a-4, respectively [16-20]. Interaction of these molecules results in dimerization of RET, cross-autophosphorylation, and subsequent phosphorylation of intracellular substrates (figure 1). RET is expressed in the C-cells of the thyroid gland, adrenal medulla, neurons, and in other tissues. In mice, GDNF or RET play crucial roles in the differentiation and survival of central nervous system neurons, the development of the peripheral nervous system, and the development of the kidneys and ureters [21-24].

Structure and function of the mutated RET proto-oncogene and its product — There are differences but much overlap in the specific RET gene mutations underlying the MEN2A variants [9,10,25,26]; however, MEN2B is caused by specific RET mutations (figure 2) [14,25,27]. Several studies, including one from the International RET Mutation Consortium [25], have described the relationships between the site of mutation and the type of disease. (See 'Genotype-phenotype correlation' below.)

Germline mutations — The germline RET mutations in MEN2 result in a gain of function [28]. This is different from many other inherited predispositions to neoplasia which are due to heritable "loss-of-function" mutations that inactivate tumor suppressor proteins. The functional constraints for such activating lesions are probably responsible for the small number of sites at which RET mutations are found, a limitation that is of great benefit for molecular diagnosis in this disorder.

Germline mutations in the extracellular domain — The majority of mutations in MEN2A kindreds involve one of five cysteine residues in the cysteine-rich region of the RET protein's extracellular domain encoded in RET exons 10 (codons 609, 611, 618, and 620) or 11 (codon 634) (figure 2) [1]. These extracellular MEN2A cysteine mutations lead to a ligand-independent dimerization of receptor molecules and constitutive activation of intracellular signaling pathways (figure 3). A mutation in codon 634 in exon 11 is associated with hyperparathyroidism and pheochromocytoma in MEN2A and is the most common genetic defect in this disorder (figure 2) [29]. The penetrance of hyperparathyroidism in those with mutations at this site is approximately 20 percent. Even with the same mutation, the penetrance of hyperparathyroidism within families varies from 9 to 34 percent [30]. Somatic RET mutations have been detected in sporadic medullary thyroid cancers (MTCs) and pheochromocytomas, whereas such mutations have not been detected in sporadically occurring parathyroid adenomas.

Germline mutations in the intracellular tyrosine kinase domains — Germline mutations in codons 768 (exon 13), 804 (exon 14), and 891 (exon 15) are predominantly associated with FMTC, but they account for only a minority of cases of this disorder. These sites are part of the intracellular tyrosine kinase domain (figure 2). Less common mutations in MEN2A/FMTC occur in exon 13 (codons 790 and 791) [31]. Codon 804 mutations have been identified as gatekeeper mutations. Alterations at this site influence access to the RET ATP-binding domain and can result in reduced sensitivity to some RET-targeting multikinase inhibitors [32]. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy".)

MEN2B-associated tumors are caused by mutations in the intracellular TK2 domain. A single 918 Met to Thr mutation in exon 16 is responsible for over 95 percent of cases of MEN2B and is found only in this disorder (figure 3). Met 918 is a critical component of the substrate recognition pocket in the tyrosine kinase catalytic core of the RET protein. In more than 50 percent of cases of MEN2B with codon 918 affected, mutations occur as new (de novo) germline mutations [33]. Another mutation, alanine to phenylalanine at codon 883 in exon 15, has been found in some unrelated MEN2B kindreds [27,34,35]. Atypical MEN2B may occur by dual (tandem) mutations in codons 804 and 806 [36] or 804 and 904 [37,38].

Germline mutations causing Hirschsprung disease — Other mutations in the RET gene can produce disorders seemingly unrelated to MEN2, further illustrating the importance of the site of the mutation, its functional consequence (eg, gain versus loss of function) and, perhaps, the influence of other genes upon the ultimate phenotype. In humans, the same mutation (eg, codon 620) can cause both a gain-of-function mutation in the thyroid C cells and an inactivating mutation in the colon, resulting in Hirschsprung disease (HD, congenital megacolon) [6,39-41]. Germline mutations in the RET gene have been reported in approximately 50 percent of inherited forms of HD and in 15 to 20 percent of sporadic HD [42]. In one cohort of 341 patients with 620, 618, 611, and 609 codon mutations, 25 percent of patients were affected by both diseases [6]. Specific inactivating haplotypes may play a role in fetal development of megacolon/HD [7]. In patients with early expression of HD, it is useful to test for MEN2, and this is especially important if a family history of HD or MEN2 is present [6]. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Genetic screening'.)

Somatic mutations — Approximately 75 percent of all MTCs are sporadic. In these sporadic MTC patients, somatic RET mutations were detected in 43 to 65 percent. Most of these mutations are in exon 16 (codon 918), but other exons have also been affected (figure 2). In mutually exclusive fashion with RET, mutations in RAS genes are found in approximately 20 to 25 percent of sporadic cases [43-50]. These mutations are present only in the patient's tumor cells and are not genetically transmitted. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Genetic screening in sporadic MTC'.)

Genotype-phenotype correlation — Extensive studies on large families reveal that there is a clear genotype-phenotype correlation [51]. In four large, classical MEN2A families with a RET codon 634 mutation, before clinical screening started, the average life span of obligate disease gene carriers (who died of extensive MTC metastases) was 48 years compared with 60 years in FMTC variant families with a cysteine codon 618 mutation of the RET gene [52]. There is greater morbidity and mortality in MEN2B than in MEN2A. The survival of patients with MEN2B is similar to that of patients with sporadic MTC who have somatic RET mutations identical with the most common germline mutations causing MEN2B [25].

The age at initial diagnosis of MTC and outcomes after thyroidectomy also correlate with the genotype (table 2) [53]. Periodic examination of family members has shown that the age of conversion from normal to elevated plasma calcitonin levels during a C-cell stimulation test was 18 to 31 years (mean 23 years) in FMTC variant families, compared with 6 to 33 years (mean 16 years) in classical MEN2 families [54]. Among carriers of the RET oncogene who had thyroidectomy, all 11 patients with mutations in codons 790, 791, 804, or 891 were cured, while 5 of 35 patients with mutations in codons 618, 620, 630, or 634 (which are associated with more aggressive disease) failed to be cured [55].

The clinical manifestations of MEN2, the role of genetic screening, and monitoring for MEN2-associated tumors are discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Genetic screening' and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Monitoring for MEN2-associated tumors'.)

Genetic screening — Advances in the molecular genetics underlying the MEN2 syndromes have resulted in DNA testing becoming the optimal test for their detection. In contrast to MEN1, in which the long-term benefit of early diagnosis by genetic screening is not well established, early diagnosis by screening of "at-risk" family members in MEN2 kindreds is essential because MTC is a life-threatening disease that can be cured or prevented by early thyroidectomy. (See "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Preventive surgery'.)

Genetic testing in individuals with suspected MEN2, in their families, and in patients with apparently sporadic MTC is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Diagnosis' and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Genetic screening' and "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Genetic screening in sporadic MTC'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Medullary thyroid cancer".)

SUMMARY

●Classification – Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder with an estimated prevalence of 1 per 30,000 in the general population. MEN2 is subclassified into two distinct syndromes: types 2A (MEN2A) and 2B (MEN2B) (table 1). Within MEN2A, there are four variants. (See 'Classification' above.)

•MEN2A – Classical MEN2A is a heritable predisposition to medullary thyroid cancer (MTC), pheochromocytoma, and primary parathyroid hyperplasia. The respective frequency of these tumors in classical MEN2A is over 90 percent for MTC, approximately 40 to 50 percent for pheochromocytoma, and 10 to 20 percent for multigland parathyroid hyperplasia. The frequency of the development of MTC, pheochromocytoma, and parathyroid hyperplasia depends upon the specific RET mutation. (See 'Multiple endocrine neoplasia type 2A' above.)

•MEN2B – MEN2B shares the inherited predisposition to MTC and pheochromocytoma that occurs in MEN2A. Patients with MEN2B also tend to have mucosal neuromas, intestinal ganglioneuromas, and, in some instances, a Marfanoid habitus; on the other hand, parathyroid hyperplasia is not a feature of this disorder. (See 'Multiple endocrine neoplasia type 2B' above.)

●RET gene – The gene associated with MEN2 is the RET proto-oncogene on chromosome 10. The germline RET mutations in MEN2 result in a gain of function (figure 3). This is different from many other inherited predispositions to neoplasia, which are due to heritable "loss-of-function" mutations that inactivate tumor suppressor proteins. (See 'Germline mutations' above.)

•MEN2A – The majority of pathogenic variants in MEN2A kindreds involve one of five cysteine residues in the cysteine-rich region of the RET protein's extracellular domain encoded in RET exons 10 (codons 609, 611, 618, and 620) or 11 (codon 634) (figure 2). (See 'Germline mutations in the extracellular domain' above.)

•MEN2B – A single Met to Thr variant in exon 16 (codon 918) is responsible for over 95 percent of cases of MEN2B and is found only in this disorder. (See 'Germline mutations in the intracellular tyrosine kinase domains' above.)

●Genotype-phenotype correlation – The distinct clinical course of the disease in a family (frequency of pheochromocytoma and parathyroid gland adenoma, and life expectancy) primarily depends upon the specific RET gene germline mutation that is present. (See 'Genotype-phenotype correlation' above and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

●Genetic screening – Advances in the molecular genetics underlying the MEN2 syndromes have resulted in DNA testing becoming the optimal test for their detection. (See 'Genetic screening' above and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Diagnosis' and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Screening of family members in MEN2 kindreds'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Cornelis J Lips, MD, PhD, who contributed to earlier versions of this topic review.