Multiple endocrine neoplasia type IIA is an autosomal dominant syndrome of multiple endocrine neoplasms, including medullary thyroid carcinoma, pheochromocytoma, and parathyroid adenomas.
For a discussion of genetic heterogeneity of multiple endocrine neoplasia, see MEN1 (131100).
In the Netherlands, Vasen et al. (1987) demonstrated the usefulness of screening and a central registry for the long-term follow-up of cases. In an 18-year study of a large kindred, Gagel et al. (1988) found that prospective screening ... In the Netherlands, Vasen et al. (1987) demonstrated the usefulness of screening and a central registry for the long-term follow-up of cases. In an 18-year study of a large kindred, Gagel et al. (1988) found that prospective screening and early treatment of manifestations of multiple endocrine neoplasia can prevent metastasis of medullary thyroid carcinoma and the morbidity and mortality of pheochromocytoma. Medullary carcinoma of the thyroid is the most consistent single manifestation of this disorder and occurs in almost all cases by age 40. Before age 40 in particular, it is necessary to use a provocative test of the combined calcitonin secretagogues enterogastrone and calcium in order to detect the disorder since the basal levels are not elevated (Baylin, 1989). As part of a French national program, Sobol et al. (1989) used DNA probes in a genetic linkage study of 130 members of 11 families of European and North African origin who were ascertained through members with MEN2A. No recombination was found between the mutation causing MEN2A and 2 of 3 markers used. All 11 families were informative for at least 1 of the markers and linkage information was adequate to permit genetic counseling in 8 families. Sobol et al. (1989) concluded that RFLP analysis is more useful in predicting the carrier state than conventional endocrine challenge, especially in younger persons, but accuracy is maximal when both methods are used. Mathew et al. (1991), including 23 members of the MEN2A International Collaborative Group, described 4 markers from the pericentric region of chromosome 10 that are tightly linked to MEN2A and are useful for testing for carrier status in individuals genetically at risk but showing a negative biochemical screening test for thyroid C-cell hyperplasia. The tests were also accurate for prenatal diagnosis. Calmettes et al. (1992) reported the consensus on biochemical and genetic screening formulated by the European Community Concerted Action on the subject of medullary thyroid carcinoma. For biochemical screening, measurement of the basal and pentagastrin- and/or calcium-stimulated serum levels of calcitonin by radioimmunoassay was considered essential starting at the age of 3 and continuing annually until the age of 35. Furthermore, annual screening for pheochromocytoma by measurement of urinary excretion of catecholamines and for hyperparathyroidism by serum calcium determination was considered indicated. Biochemical screening can be reserved for gene carriers in some families; genetic screening using genetic markers can be done with 95% accuracy in informative families whenever DNA is available from at least 2 family members proven to be affected. Total thyroidectomy at an early stage usually cures the patient with medullary thyroid carcinoma. On the basis of studies in a very large kindred, Landsvater et al. (1993) found 7 individuals with abnormal calcitonin test results. Five of these people were thyroidectomized, and C-cell hyperplasia was diagnosed. Four were the offspring of a mother at risk for the development of MEN2A who showed, however, normal calcitonin test results throughout the years, whereas the father, who was not at risk, had abnormal test results over a period of 10 years, without evidence of progressive elevation. None of the 7 individuals developed other manifestations of MEN2A. DNA analysis using markers linked to the MEN2A gene demonstrated, with more than 99% likelihood, that none of the persons who could be genotyped was a gene carrier. Thus, C-cell hyperplasia due to some mechanism other than the presence of the MEN2A gene may occur in MEN2A kindreds. Schuffenecker et al. (1997) reported that 5.6% to 9% of cases of MEN2A/MTC are de novo cases with no family history. They reported further that new mutations in the RET oncogene in these cases were demonstrated exclusively on the paternal allele. Retrospective analysis on 274 MEN2A cases revealed that in 40.2% of patients pheochromocytoma occurred 2 to 11 years subsequent to MTC. Schuffenecker et al. (1997) concluded that all apparently sporadic MTC patients should be examined for de novo RET mutations. Sporadic medullary thyroid carcinoma has usually been found to result from a mutational event occurring at the single-cell level, indicating that they are monoclonal. By clonality assay of medullary carcinoma of the thyroid in MEN type 2, Ferraris et al. (1997) showed the carcinomas they studied to be polyclonal in most instances. They used a polymorphic trinucleotide repeat of the X-linked human androgen receptor gene (313700) to demonstrate that 10 out of 11 MTCs expressed a polyclonal pattern of X inactivation; furthermore, a significant percentage of cases clinically defined as sporadic showed a polyclonal pattern. Brandi et al. (2001) authored a consensus statement covering the diagnosis and management of MEN1 (131100) and MEN2, including important contrasts between them. The most common tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial MTC. They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy. Gourgiotis et al. (2003) reported the case of a 42-year-old woman with MEN2A in whom biopsy-proven recurrent MTC was detected by 6-[18F]fluorodopamine PET scanning. The study showed a focus of radionuclide accumulation corresponding to the parapharyngeal mass. After resection of the latter, pathology confirmed metastatic MTC.
Schimke and Hartmann (1965) described a syndrome of pheochromocytoma and medullary thyroid carcinoma with abundant amyloid stroma. A similar but distinct condition is described under neuromata, mucosal, with endocrine tumors (MEN2B; 162300). Steiner et al. (1968) described a ... Schimke and Hartmann (1965) described a syndrome of pheochromocytoma and medullary thyroid carcinoma with abundant amyloid stroma. A similar but distinct condition is described under neuromata, mucosal, with endocrine tumors (MEN2B; 162300). Steiner et al. (1968) described a family with 11 cases in successive generations. The pheochromocytomas were bilateral, parathyroid adenoma was present in several, and one patient had Cushing syndrome. Steiner et al. (1968) referred to this disorder as 'multiple endocrine neoplasia, type II' to distinguish it from the multiple endocrine adenomatosis described by Wermer (MEN1; 131100) and called type I by Steiner et al. (1968). Urbanski (1967) found parathyroid adenoma to be part of the syndrome also. Meyer and Abdel-Bari (1968) presented observations consistent with the view that medullary carcinoma is a thyrocalcitonin-producing neoplasm of parafollicular cells of the thyroid. Parathyroid hyperplasia or adenomas in some of these patients may be secondary to hypocalcemic effects of thyrocalcitonin. Johnston et al. (1970), as well as others, have shown calcitonin-secretion by medullary thyroid carcinoma. Kaplan et al. (1970) showed that the adrenal medulla produces a calcitonin-like material indistinguishable from that of the thyroid by bio- and radioimmunoassay. They suggested that the parafollicular cells of the thyroid are of neural crest origin. The finding that medullary carcinoma of the thyroid arises from parafollicular cells and that, like the cell of origin, it sometimes produces thyrocalcitonin may account for the association of parathyroid hyperplasia and perhaps parathyroid adenoma. Poloyan et al. (1970) was impressed with the histologic similarity between the medullary thyroid cancer and pheochromocytoma metastases. Keiser et al. (1973) pointed out that histaminase is useful in the identification of metastases of medullary carcinoma. In their opinion parathyroid adenomas are a primary feature of the disorder. Pearson et al. (1973) studied 21 members of a kindred with surgically confirmed multiple endocrine neoplasms. All 21 had medullary carcinoma of the thyroid. Adrenal pheochromocytomas were present in 10 and were bilateral in 6. Three had one or more parathyroid glands showing adenomatous hyperplasia and 10 showed chief cell hyperplasia. The thyroid cancer metastasized to other areas including the liver, lungs, and bone in several of the patients. All patients had elevated peripheral thyrocalcitonin. Peripheral parathyroid hormone was elevated in only 2; however, parathyroid hormone was elevated in the inferior thyroid vein of all patients examined. Hamilton et al. (1978) suggested that an increased urinary epinephrine fraction is a sensitive and reliable screening test for pheochromocytoma in MEN II, comparable to the calcitonin radioimmunoassay for medullary carcinoma of the thyroid. Carney et al. (1975) found bilateral adrenal medullary hyperplasia in an asymptomatic 12-year-old girl. She had bilateral thyroid carcinoma and hyperparathyroidism. The adrenals were explored because of elevated urinary levels of vanillylmandelic acid. Migrating neural crest cells are able to decarboxylate and store precursors of aromatic amines that fluoresce after exposure to formaldehyde vapor. The last is a method for identifying neural crest origin of enterochromaffin, argyrophil cells of the bronchi, islets of Langerhans, and parafollicular cells of the thyroid, among others. These are collectively termed the amine precursor uptake and decarboxylase (APUD) system (Pearse, 1969). Tischler et al. (1976) extended the evidence of neural origin by demonstrating that cultured cells from medullary carcinoma of the thyroid, bronchial carcinoid, and pheochromocytoma display all-or-nothing action potentials of short duration. Le Marec et al. (1980) reported congenital megacolon with plexus hyperplasia in a family with Sipple syndrome. Megacolon of this type seems to be more usual in MEN III than in MEN II. Cameron et al. (1978) described the Zollinger-Ellison syndrome with type II MEA, a first. These families represent an overlap of phenotypic features in the 3 forms of MEN. Gagel et al. (1989), Nunziata et al. (1989), and Kousseff et al. (1991) observed primary localized cutaneous amyloidosis (PLCA) in association with MEN2A. Gagel et al. (1989) and Kousseff et al. (1991) referred to it as cutaneous lichen amyloidosis. In a family with 6 affected members in 5 generations, a mother and her daughter had interscapular cutaneous pruritic lesions (Kousseff et al., 1991). Kousseff (1992) provided a pedigree and photographs of the skin lesions. Cutaneous lichen amyloidosis as an apparently independent autosomal dominant trait has also been described (105250). The skin deposits of amyloid associated with pruritus in the interscapular region represents a form of 'friction amyloidosis' (Wong and Lin, 1988). It is related to notalgia paresthetica, an inherited neuropathy of the posterior dorsal nerve rami. ('Notalgia' means 'back pain.') The neuropathy hypothesis was supported by the finding of mutations in the RET protooncogene which is expressed in the peripheral and central nervous system. Ceccherini et al. (1994) demonstrated a specific cys634-to-tyr missense mutation (164761.0004) in affected members of a pedigree in which MEN2A was combined with localized cutaneous lichen amyloidosis. Easton et al. (1989) estimated on the basis of clinical history that 41% of gene carriers are asymptomatic at age 70. Screening by the standard tests for detecting the earliest manifestations of the syndrome increased the penetrance to an estimated 93% by age 31. There was some suggestion of an earlier onset of medullary thyroid cancer in female gene carriers, and of a tendency for pheochromocytoma to cluster in families. Multiple endocrine neoplasia type 2A can be subclassified as: (1) medullary thyroid carcinoma with pheochromocytomas and parathyroid tumors; (2) medullary thyroid carcinoma with pheochromocytomas alone; or (3) medullary thyroid carcinoma with parathyroid tumors alone. Hereditary medullary thyroid carcinoma alone (see 155240) may be a fourth phenotype resulting, in some instances, from mutation at the MEN2 locus. Eisenhofer et al. (2001) examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in MEN2 and von Hippel-Lindau syndrome to underlying differences in the expression of tyrosine hydroxylase (TH; 191290), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT; 171190), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN2 patients and 30 von Hippel-Lindau patients with adrenal pheochromocytomas. MEN2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than von Hippel-Lindau patients. MEN2 patients all had elevated plasma concentrations of the epinephrine metabolite metanephrine, whereas von Hippel-Lindau patients showed specific increases in the norepinephrine metabolite normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from von Hippel-Lindau than from MEN2 patients.
Mathew et al. (1987) found deletion of a hypervariable region of DNA on 1p in 7 of 14 tumors (pheochromocytomas and medullary carcinomas) developing in patients with MEN2. In 1 of 2 families examined, the deleted chromosome was ... Mathew et al. (1987) found deletion of a hypervariable region of DNA on 1p in 7 of 14 tumors (pheochromocytomas and medullary carcinomas) developing in patients with MEN2. In 1 of 2 families examined, the deleted chromosome was that inherited from the affected parent. Thus, the site of deletion presumably does not represent the location of the inherited gene. The deleted region was distal to the breakpoint commonly detected in neuroblastomas (256700), which share with the tumors of MEN2 embryologic origin from neuroectoderm. The most frequent breakpoint involved in neuroblastomas is 1p32, whereas the genes deleted in the tumors studied by Mathew et al. (1987) were located at 1p35-p33. In an analysis of tumor DNA from 42 patients with MEN2A, Landsvater et al. (1989) showed that markers on chromosome 10 were lost in only 1 tumor, a result that contrasts with studies in other tumors for which both familial and sporadic cases are known. That MEN2A is genetically heterogeneous is suggested by the linkage in some families to markers at the 10q11.2 region and the lack of linkage in other families. The basis of the above subclassification, whether different mutations in one gene or mutations in adjacent genes in the 10q11.2 region, is not clear (Simpson, 1992). The subclasses do seem to 'breed true' in different families. In a panel of 34 families with MEN2A, Narod et al. (1992) found no evidence of genetic heterogeneity. No recombination was observed between MEN2A and any of 4 DNA marker loci. Narod et al. (1992) constructed haplotypes for 11 polymorphisms in the MEN2A region for mutation-bearing chromosomes in 24 French families and for 100 spouse controls. One haplotype was present in 4 MEN2A families but was not observed in any control (P = less than 0.01). Two additional families shared a core segment of this haplotype near the MEN2A gene. Narod et al. (1992) suggested that these 6 families had a common affected ancestor. Because the incidence of pheochromocytoma among carriers varied from 0.0 to 74% in these 6 families, they suggested that additional factors modify the expression of the gene. Curiously, the most consistent molecular genetic abnormality that has been found in pheochromocytomas and medullary thyroid cancers, either sporadic or part of MEN2, is loss of heterozygosity (LOH) on 1p. Using RFLP analysis, Moley et al. (1992) identified loss of all or a portion of 1p in 12 of 18 pheochromocytomas. LOH of 1p was found in all 9 pheochromocytomas in MEN2A and MEN2B patients, compared with only 2 of 7 sporadic pheochromocytomas. They also found 1p LOH in the pheochromocytoma of 1 of 2 von Hippel-Lindau patients (193300). LOH on 1p was noted in only 3 of 24 informative medullary thyroid carcinomas, and these were from patients with MEN2A. Mulligan et al. (1993) identified missense mutations in the RET protooncogene in 20 of 23 apparently distinct MEN2A families, but not in 23 normal controls. Of these 20 mutations, 19 affected the same conserved cysteine residue at the boundary of the RET extracellular and intracellular domains. Quadro et al. (2001) reported a patient affected by MEN2A bearing a heterozygous cys634-to-arg (164761.0011) germline mutation in exon 11 and an additional somatic mutation (164761.0012) of the RET protooncogene. A large intragenic deletion spanning exon 4 to exon 16 affected the normal allele and was detected by quantitative PCR, Southern blot analysis, and screening of several polymorphic markers. This deletion causes RET loss of heterozygosity exclusively in the metastasis and not in the primary tumor, thus suggesting a role for this second mutational event in tumor progression. No additional mutations were found in the other exons analyzed. The authors concluded that this unusual genetic profile may be related to the clinical course and very poor outcome. Huang et al. (2000) and Koch et al. (2001) identified 2 second-hit mechanisms involved in the development of MEN2-associated tumors: trisomy 10 with duplication of the mutant RET allele and loss of the wildtype RET allele. However, some of the MEN2-associated tumors investigated did not demonstrate either mechanism. Huang et al. (2003) studied the TT cell line, derived from MEN2-associated medullary thyroid carcinoma with a RET germline mutation in codon 634, for alternative mechanisms of tumorigenesis. Although they observed a 2-to-1 ratio between mutant and wildtype RET at the genomic DNA level in this cell line, FISH analysis revealed neither trisomy 10 nor loss of the normal chromosome 10. Instead, a tandem duplication event was responsible for amplification of mutant RET. In further studies Huang et al. (2003) demonstrated for the first time that the genomic chromosome 10 abnormalities in this cell line cause an increased production of mutant RET mRNA. The authors concluded that these findings provided evidence for a third second-hit mechanism resulting in overrepresentation and overexpression of mutant RET in MEN2-associated tumors. Abu-Amero et al. (2006) identified nonsynonymous germline mitochondrial DNA (mtDNA) mutations in both normal and tumor tissue from 20 (76.9%) of 26 cases of medullary thyroid carcinoma, including 9 (69.2%) of 13 sporadic cases and 11 (84.6%) of 13 familial cases; 10 of 13 familial cases were patients with MEN2. The familial cases tended to have transversion mtDNA mutations rather than transition mutations. All 13 familial cases also had germline RET mutations. Abu-Amero et al. (2006) suggested that mtDNA mutations may be involved in medullary thyroid carcinoma tumorigenesis and/or progression.