Pheochromocytomas and C-cell thyroid neoplasms in transgenic c-mos mice: a model for the human multiple endocrine neoplasia type 2 syndrome.

Transgenic mice carrying and expressing a mos protooncogene, linked to the Moloney murine sarcoma virus long terminal repeat, develop severe neurological defects and lens abnormalities. Here we report that after long latent periods, mice in three of four of these mos transgenic lines develop a high frequency of multicentric pheochromocytomas and/or medullary thyroid neoplasms. The pattern of tumor formation is remarkably similar to the human autosomal dominantly inherited neoplastic syndrome, multiple endocrine neoplasia type 2 (MEN 2), and tumors from these transgenic animals display the same neuroendocrine marker staining pattern as seen in MEN 2. The similarity between the tumor pathologies and presentation patterns of MEN 2 patients and mos transgenic mice suggests that they may arise through related pathways. The type of tumor presentation varies in a line-dependent manner indicating that there is interaction between the transgene and the genetic background. Moreover, when the non-tumor-bearing mos transgenic line is crossed to a different mouse background, the F1 offspring display the MEN 2 phenotype. These studies indicate that penetrance of the autosomal dominant mos transgenic phenotype is dependent on both integration site and background.     

A case report of multiple endocrine neoplasia type 2b

A 10-year-old girl was admitted displaying a medullary thyroid carcinoma, accompanying neurinomas of the tongue, marfanoid habitus, megacolon, and scoliosis. Although her adrenal glands were found to be unremarkable on both CT and ultrasonogram examination an MIBG scintiscan showed a 131-1 uptake, suggesting the presence of medullary hyperplasia. Remarkable nodal involvement with invasive features witnessed in the upper mediastinum during tertiary surgery four years later, following a total thyroidectomy. The TCT and CEA profiling was not sufficient enough to predict a recurrence. At the present state there is difficulty in providing an early diagnosis; through node dissection, however, is considered to be necessary at time of primary thyroid operation in cases with MEN type 2b.     

Update multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN2) is a autosomal dominat inherited tumour-syndrome caused by germline activating mutations of the RET proto-oncogene on chromosome 10. It is clinically characterized by the presence of medullary thyroid carcinoma (MTC), bilateral pheochromocytoma and primary hyperparathyroidism (MEN2A) within a single patient. Three distinct clinical forms have been described depending on the phenotype: the classical MEN 2A, MEN 2B, an association of MTC, pheochromocytoma and mucosal neuroma, (FMTC) familial MTC with a low incidence of other endocrinopathies. Each variant of MEN2 results from different RET gene mutation, with a good genotype phenotype correlation. Genetic testing detects nearly 100% of mutation carriers and is considered the standard of care for all first degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on a classification into four risk levels utilizing the genotype-phenotype correlations. MEN 2 gives a unique model for early prevention and cure of cancer and for stratified roles of mutation-based diagnosis of carriers.     

Adenomatous polyposis coli and multiple endocrine neoplasia type 2b. A pathogenetic relationship

A young man presenting with Cushing's syndrome was found to have multiple endocrine neoplasia type 2b MEN 2b and adenomatous colonic polyposis with duodenal and gastric polyps. The entire syndrome of MEN 2b was present, including metastatic medullary carcinoma of the thyroid, a pheochromocytoma, and peripheral nerve abnormalities. The concurrence of these two inherited multiple neoplasia syndromes may reflect a common pathogenetic step in this patient.     

Multiple endocrine neoplasia type 2b. Clinical, diagnostic and therapeutic aspects

Multiple Endocrine Neoplasia type 2b (MEN 2b) is a rare syndrome. The principal features are: medullary thyroid carcinoma (MTC), dysmorphism, a ganglioneuromatosis and pheochromocytomas. Eight cases of MEN 2b have been observed at the Institute Gustave Roussy, between 1968 and 1983. Seven involved children under 15 years of age. Eight had a bilateral MTC; six had dysmorphism; six had mucosal tongue neuromas. Six were troubled with visceral ganglioneuromatosis of whom two had intestinal obstruction and one urinary chronic retention. One patient had pheochromocytoma with hypertension. From this experience and other data it appears that: the dysmorphism is frequently poorly interpreted; the visceral ganglioneuromatosis is an early and severe feature; it is important to examine the patient for pheochromocytoma; the MTC must be detected by calcitonin dosage after stimulation, and requires total thyroidectomy; familial screening must be done. To improve the poor prognosis of MEN 2b, early diagnosis and aggressive treatment are necessary.     

A case of multiple endocrine neoplasia type 2B

A sporadic case of multiple endocrine neoplasia type 2B in a twenty-six year old man who manifested medullary thyroid carcinoma, multiple mucosal neuromas of the tongue and a marfanoid habitus is reported. At the time of diagnosis, he also had multiple liver and lung metastases. Genetic analysis of his lymphocytes revealed a point mutation in exon 16 of the RET proto-oncogene. Since multiple endocrine neoplasia type 2B has a relatively poor prognosis because of the occasional aggressive behavior of medullary thyroid carcinoma, the necessity of the genetic diagnosis of multiple endocrine neoplasia in the early stage is suggested.      

Bronchopulmonary carcinoid in multiple endocrine neoplasia type 1

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal-dominant syndrome associated with neoplasia of pituitary, pancreas, parathyroid, and foregut lineage neuroendocrine tissue. Although enteropancreatic carcinoid has been well described in patients with MEN 1, it was believed that bronchopulmonary carcinoid was relatively uncommon, occurring in approximately 5% of patients. It is unclear whether the increased screening of asymptomatic patients with MEN 1 will facilitate early diagnosis of this tumor and improve patient prognosis. METHODS: The authors reviewed the patient records and, when available, thoracic computed tomographic (CT) images of 129 MEN 1-affected adult members of a single family to determine the prevalence and prognosis of bronchopulmonary nodules and carcinoid. RESULTS: Among 129 patients, a diagnosis of bronchopulmonary carcinoid was noted in the records for 6 individuals (1 male and 5 females; 5%). Thoracic CT scans also were available for review from 32 of those patients. Twelve patients (38%) had pulmonary nodules evident on CT scans. Only hypergastrinemia was significantly more common in patients with pulmonary nodules; otherwise, the spectrum of neoplasia was similar between individuals with and without pulmonary lesions. Histologic diagnoses were available in four patients (three female) with abnormal CT images, and carcinoid was confirmed in each patient. No deaths or distant metastases occurred among the patients despite long-term follow-up (mean, 127 months). CONCLUSIONS: The findings suggested that bronchopulmonary carcinoid is more prevalent in patients with MEN 1 than was recognized previously. Furthermore, the diagnosis did not appear to portend a poor prognosis in the majority of affected patients.     

Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN 2) is an inherited disease caused by germline mutations in the RET proto-oncogene, and is responsible for the development of endocrine neoplasia. Its prognosis is dependent on the appearance and spread of medullary thyroid carcinoma (MTC). Relatives at risk can be identified before clinical or biochemical signs of the disease become evident. METHODS: Twenty-one families with MEN 2 (16 families with MEN 2A and 5 families with MEN 2B) were studied. Peripheral blood DNA was amplified by polymerase chain reaction. DNA sequence or restriction enzyme analysis was performed to detect mutations of RET proto-oncogene exons 10, 11, and 16. Molecular analysis was carried out in all index patients as well as in 98 relatives of MEN 2A patients (60 juveniles, ages 6 months to 21 years, and 38 adults, ages 22 to 81 years) and in 13 relatives (6 juveniles ages 10 to 21 years, and 7 adults ages 41 to 66 years) from MEN 2B families. RESULTS: Molecular studies showed a mutation at codon 634, exon 11 in all MEN 2A patients. All MEN 2B patients showed an ATG to ACG (Met918Thr) mutation. In MEN 2A families, 42 out of 98 relatives were affected. Total thyroidectomy was performed in 18 juvenile carriers ages 17 months to 21 years. Histopathologic studies of the glands revealed parafollicular cell (C-cell) hyperplasia in all of these carriers, medullary thyroid carcinoma in 15 carriers, and only one carrier with lymph node metastases. CONCLUSIONS: The consistent finding of C-cell disease in all the juvenile carriers who underwent preventive thyroidectomy emphasizes the relevance of early screening in children at risk of developing MTC. The presence of MTC in the specimen of prophylactic thyroidectomy from a 17 month old girl highlights the importance of thyroidectomy as soon as the molecular diagnosis is confirmed.     

Presymptomatic thyroidectomy in multiple endocrine neoplasia 2a.

AIMS: To evaluate the value of prophylactic total thyroidectomy in multiple endocrine neoplasia 2a (MEN 2a), based on results of genetic testing, in a presymptomatic early stage of the disease. METHODS: Fourteen presymptomatic patients genetically diagnosed and surgically treated at our centre. We analysed age, gender, location of the RET mutation, calcitonin tests, surgery, histologic findings, TNM classification, and postoperative follow-up. RESULTS: The 14 patients belonged to two families with MTC (MEN 2a). Median age was 16 years. The RET mutation was located in codon 618 and 634. Basal calcitonin (CT) levels were normal in all patients. Twelve had pathologic peak CT measurements. Total thyroidectomy was performed in all and associated central neck dissection in 12 patients. Pathohistologic assessment showed C-cell hyperplasia in all specimens and 11 MTCs; the median size of the tumours was 0.2 cm; two patient had lymph-node metastases. According to TNM, three had stage 0, nine had stage I, one had stage II, and one had stage III disease. Postsurgery basal and peak CT values were normal in all but one patients, indicating a biochemical curative rate of 95%. Calcitonin determination did not distinguish between MTC and C-cell hyperplasia. CONCLUSION: Prophylactic thyroidectomy based on genetic testing allows identification and treatment of patients at an early stage of the disease. Pathologic peak CT values are markers for the presence of microscopic MTC and should be considered in selecting operative procedures for these patients.     

Metastatic C-cell carcinoma with bone marrow carcinosis in type IIa multiple endocrine neoplasia (MEN). Diagnostic and therapeutic problems

The course of the disease in a patient with multiple endocrine neoplasia type IIa over a period of seven years is described. In spite of multiple diagnostic procedures, only a bone marrow biopsy was able to prove metastatic disease. All therapeutic measures, such as combination chemotherapy, sandostatin, bromocriptine, and 131Iodinemethylendiphosphonate-therapy were not effective in reducing tumor load or symptoms.     

Multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome. Predisposition to MEN 2 is caused by germline mutations of the RET proto-oncogene on chromosome 10q11.2 [1]. There are three clinically distinct forms of MEN 2 syndrome – MEN 2A, familial medullary thyroid carcinoma (FMTC), and MEN 2B. In all of these subtypes, medullary thyroid carcinoma (MTC) is a key. MEN 2A is the most common subtype of MEN 2. Clinical features of the MEN 2A syndrome include medullary thyroid carcinoma (MTC) and/or C-cell hyperplasia (CCH) in almost all affected individuals, pheochromocytoma (approximately 50%) and hyperparathyroidism (HPT) (15–30%). MEN type 2B is the most aggressive of the MEN 2 variants and accounts for approximately 5% of all cases of MEN 2. MEN 2B is similar to MEN 2A but is characterized by the earlier onset of the disease and by developmental abnormalities. In FMTC, the third form of MEN 2, MTC is the only clinical feature. Introduced in recent years and still developing genetic testing of individuals at highest hereditary risk of MEN 2 syndrome holds the possibility of early detection and improved treatment and prognosis.     

Multiple endocrine neoplasia type 2

Opinion statement Multiple endocrine neoplasia type 2 (MEN-2) is a hereditary syndrome that is transmitted in an autosomal dominant pattern. MEN-2A, MEN-2B, and familial medullary thyroid cancer (MTC) comprise the MEN-2 syndrome. A germline mutation in the RET proto-oncogene is responsible for the MEN-2 syndrome. Recent data indicate that in 99% of MEN-2 cases, a germline RET mutation can be identified by genetic testing. The phenotypic variation of MEN-2 is diverse and partly related to the codon and specific point mutation in the RET proto-oncogene. There are increasing data on the genotype-phenotype correlations in patients with MEN-2 and this information should be used for screening at-risk patients and treatment of RET mutation carriers. All patients (especially if young) with MTC or bilateral pheochromocytoma should have a careful family history taken and genetic screening for RET germline mutations. Patients who are RET germline mutation carriers but without clinical or biochemical evidence of MTC should have a prophylactic total thyroidectomy. The optimal age of thyroidectomy should be based on the RET genotype (eg, high-risk mutations [codons 634, 883, 918, and 922] within the first year of life, intermediate-risk mutations [codons 611, 618, and 620] by 5 years of age, and low-risk mutations [codons 609, 630, 768, 790, 791, 804, and 891] by 10 years of age). Patients who are diagnosed with clinical or biochemical evidence of MTC should have a total or a near total thyroid-ectomy and at least a central neck lymph node dissection. Patients who have pheochro-mocytoma and a unilateral adrenal tumor on a localizing study should have a unilateral laparoscopic adrenalectomy after preoperative α-blockade. However, patients with bilat-eral adrenal tumors on localizing studies should have bilateral laparoscopic adrenalectomy. A cortical-sparing (subtotal) adrenalectomy may be considered, if technically feasible, to avoid long-term steroid dependence and to reduce the risk of Addisonian crisis. Patients with biochemical evidence of primary hyperparathyroidism should have a bilateral neck exploration and total parathyroidectomy and autotransplantation (30-60 mg of the most normal parathyroid tissue) to the nondominant forearm if asymmetric parathyroid hyper-plasia is present. Rarely, patients may have only single-gland disease and excision may be performed if the other parathyroid glands are not found with biopsy to be hyperplastic. All unresected parathyroid glands should be marked with a clip because patients with MEN-2A have a high risk of persistent and recurrent primary hyperparathyroidism. Patients with familial MTC may have not manifested the other features of MEN-2A, thus these patients should have continued follow-up for pheochromocytoma and primary hyperparathyroidism.     

Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and hyperparathyroidism. MEN 2 is caused predominantly by germ-line mutations of the RET proto-oncogene. This study aimed to clarify the genotype-phenotype correlation in MEN 2 patients in Japan in order to modify the clinical management according to the genotype. METHODS: Constitutive DNA of 64 MEN 2 patients (48 kindreds) were searched for mutations at exons 10, 11, 13, 14 and 16 of the RET proto-oncogene using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing and restriction enzyme digestion. The clinical characteristics of the patients were obtained from a previous nationwide questionnaire survey. RESULTS: Overall, 62 (96.9%) out of 64 patients had a germ-line point mutation at the hot spots. MTC and pheochromocytoma occurred equally in every genotype except C630S. Specific genotype had a correlation between tumor size and age at the operation for MTC or extent of MTC, i.e. C618S developed late onset type of MTC as compared with that of C634R, C634Y and M918T. Small MTC in C634R may be less aggressive than those in C634Y and M918T. CONCLUSIONS: DNA testing has good clinical implications for the management of patients with MEN 2 and the timing and operative procedures of thyroidectomy can be modified according to the genotype.      

Prophylactic neck surgery for second-generation multiple endocrine neoplasia type 2B

There is no evidence-based guidance on the extent of prophylactic neck surgery for second-generation multiple endocrine neoplasia type 2B (MEN 2B), a newly emerging entity in the molecular era.In this investigation of MEN 2B children who inherited the M918T RET germline mutation from a phenotypically affected MEN 2B parent, 6 MEN 2B children (4 girls and 2 boys) from 5 MEN 2B parents (4 mothers and 1 father) were identified. None of the 6 second-generation MEN 2B children who had preoperative calcitonin serum levels between 2 and 105 pg/mL and underwent prophylactic total thyroidectomy before the age of 4 years after receiving a positive RET gene test harbored node metastases. There was no recurrent laryngeal nerve palsy or postoperative hypoparathyroidism.Within the limitations of this study, total thyroidectomy alone is adequate therapy for second-generation MEN 2B children aged 1–4 years old with preoperative calcitonin serum levels ≤100 pg/mL.     

Association of mitochondrial DNA transversion mutations with familial medullary thyroid carcinoma/multiple endocrine neoplasia type 2 syndrome

Medullary thyroid carcinoma (MTC) is a malignant tumour of the calcitonin-secreting parafollicular C cells of the thyroid, and occurs sporadically or as a component of the multiple endocrine neoplasia (MEN) type 2/familial medullary thyroid carcinoma (FMTC) syndromes. In the present study, we investigated the frequency of mtDNA mutations in 26 MTC tumour specimens (13 sporadic and 13 familial MTC) and their matched normal tissues by sequencing the entire coding regions of mitochondrial genome. Nonsynonymous mutations were detected in 20 MTC samples (76.9%): nine out of 13 sporadic MTC (69.2%) and 11 out of 13 (84.6%) familial MTC/MEN2. Both transition and transversion types of mutations were found in the samples. Interestingly, 76.2% (16/21) of transversion mutations were found in FMTC/MEN2 patients, whereas 66.7% (12/18) of transition mutations were in sporadic MTC. Synonymous mutations were found in 12 MTC samples. In total, we identified 27 transversion mutations (21 nonsynonymous and six synonymous) in MTC. Of them, 22 (81.5%) were from FMTC/MEN2, and five (18.5%) were from sporadic MTC. The association of transversion mutation with familial MTC/MEN2 was statistically significant (P = 0.0015, binomial test). Majority of the mutations were involved in the genes located in the complex I of the mitochondrial genome, and were often resulting in a change of a moderately or highly conserved amino acid of their corresponding protein. Mitochondrial respiratory function was also compromised in a TT cell line, which carries mtDNA mutation at nt 4917 and 11,720, and in peripheral lymphocytes of MTC patients with mtDNA mutations. These data suggest that mtDNA mutation may be involved in MTC tumourigenesis and progression. Given that mtDNA mutation spectra are different between sporadic and familial MTC, different mechanisms of oxidative DNA damage may occur in the disease process.     

A nationwide clinical survey of patients with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma in Japan

MEN (multiple endocrine neoplasia) type 2 syndrome is an inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism and/or developmental anomalies. Germ-line mutations of the RET proto-oncogene have recently been identified as the underlying cause of the syndrome. Accordingly, several investigators have advocated prophylactic total thyroidectomy for medullary thyroid carcinoma at an early age in MEN 2 gene carriers identified by DNA analysis. Before applying this strategy in Japan, the biological behavior of each category of tumor in MEN 2 syndrome, and medullary thyroid carcinoma in particular, should be well understood. We conducted a nationwide questionnaire survey to clarify the clinicopathological features of MEN 2 in Japan, obtaining data for 230 patients diagnosed as having MEN 2. They included 84 males and 146 females, with a median age of 37.5 years (range 5-83). Patients were categorized as 179 with MEN 2A, 17 with MEN 2B, 12 with familial medullary thyroid carcinoma and 22 'other'. Medullary thyroid carcinoma, pheochromocytoma and parathyroid lesions occurred in 224 (97%), 132 (57%) and 25 (11%) patients respectively. Twelve patients (5.2%) died of medullary thyroid carcinoma and 11 patients died of other or unknown causes. Of 163 patients for whom follow-up data were obtained, 82 (50%) experienced recurrences of medullary thyroid carcinoma, including symptomatic recurrent tumors in 24 patients and elevated calcitonin levels alone in 54. In the era of RET mutational analysis for screening relatives of patients with MEN 2, these data provide useful information about surgical management for patients with MEN 2 in Japan.      

Tight linkage of the ret proto-oncogene with the multiple endocrine neoplasia type 2A locus.

The ret proto-oncogene has been mapped to 10q11.2 near the MEN2A locus by in situ hybridization. We carried out a linkage study of Japanese multiple endocrine neoplasia type 2A (MEN2A) families using a cosmid clone containing the ret proto-oncogene as probe. Two polymorphic alleles (A1 and A2) could be detected by digesting DNA with EcoRI: allele A1 was detected as a 10 kb fragment and A2 as 5.4 and 4.6 kb fragments. Of 11 Japanese MEN2A families analysed, four were informative, and the maximum lod score was 4.23 at a recombination fraction of 0.00. This result suggests the ret proto-oncogene to be close to the MEN2A gene and therefore possibly to be a useful DNA marker for cloning the latter.     

Acceptable age for prophylactic surgery in children with multiple endocrine neoplasia type 2a.

AIMS: Germline mutated RET proto-oncogene, causing multiple endocrine neoplasia (MEN)-2a syndrome is the indication for prophylactic total thyroidectomy. Literature regarding the risk and the extent of early surgical intervention is scarce and the optimum age for surgery is still controversial. To optimize management in these young children we evaluate our experience and results. PATIENTS AND METHODS: From 1990 to 2001 preventive total thyroidectomy was performed in 13 MEN-2a gene carriers (4 boys and 9 girls; median age 7 (4-14) years). Preoperative assessment, surgical procedure, pathological examination, postoperative complications and treatment results were studied. RESULTS:Surgery existed of a total thyroidectomy alone (n=3) in children with normal basal calcitonin and in combination with tracheo-esophageal exploration (n=6) or central compartment dissection (n=4) in case of abnormal calcitonin levels. Eight children presented with medullary thyroid cancer (MTC), three (median: 5 (4-12) years) with microscopic MTC and five (median 6 (4-14) years) with frank invasive MTC. Four of these five patients were younger than 6 years. Except for long-lasting hypoparathyroidism in one patient there were no complications. At a median follow-up of 6.5 years all patients are disease free. CONCLUSION: MTC in RET mutated MEN-2a gene carriers in childhood are found at the age of 4 years. Therefore, DNA testing should be done preferably before that age. Preventive surgery can be performed safely at that age and may be limited to total thyroidectomy when baseline calcitonin levels are normal.     

Evaluation of potential mechanisms underlying genotype-phenotype correlations in multiple endocrine neoplasia type 2

Distinct dominant activating mutations in the RET proto-oncogene are responsible for the development of multiple endocrine neoplasia type 2 (MEN 2). Concise examination of the mutated codons led to the detection of a striking genotype-phenotype correlation between the mutated codon and the MEN 2 phenotype in terms of onset and aggressiveness of the disease, suggesting that manifestation and clinical progression is conditioned by the type of mutation. To gain insight into the molecular basis for this genotype-phenotype correlation, we analysed the impact of common and rare mutations identified in MEN 2A (C609Y, C634R), MEN 2B (A883F, M918T) and familial medullary thyroid carcinoma (Y791F) patients on several aspects of cell transformation, including proliferation, apoptosis, anchorage-independent growth and signaling. We found that tumor cells arising from distinct extracellular or intracellular MEN 2 mutations clearly differ in their proliferation properties owing to the activation of different molecular pathways, but importantly, also in resistance to apoptosis. Whereas MEN 2A mutants resulted in accelerated cell proliferation, MEN 2B-RET mutants significantly enhanced suppression of apoptosis, which may account, at least partially, for some of the clinical differences in MEN 2 patients.     

RET oligonucleotide microarray for the detection of RET mutations in multiple endocrine neoplasia type 2 syndromes.

Multiple endocrine neoplasia type 2 (MEN2) syndromes are inherited in an autosomal dominant fashion with high penetrance. There are three subtypes, namely, MEN2A (multiple endocrine neoplasia type 2A), MEN2B (multiple endocrine neoplasia type 2B), and familial medullary thyroid carcinoma. The variations in the RET gene play an important role in the MEN2 syndromes. In this work, we have developed a RET oligonucleotide microarray of 67 oligonucleotides to quickly detect RET mutations in MEN2 syndromes. The predominant RET mutations are missense mutations and are restricted to nine codons (codons 609, 611, 618, 620, 630, 634, 768, 804, and 918) in MEN2 syndromes. Missense mutations at codons 609, 611, 618, 620, and 634 have been identified in 98% of MEN2A families and in 85% of familial medullary thyroid carcinoma families. More than 95% of MEN2B patients also had a predominant mutation type at codon 918 (Met-->Thr). RET oligonucleotide microarray can detect RET missense mutations at these nine codons. Theoretically, a total of 55 missense mutation types can occur at eight codons (codons 609, 611, 618, 620, 630, 634, 768, and 804). RET oligonucleotide microarray is designed to detect all of these 55 missense mutation types at these eight codons and one predominant type at codon 918. Fifty-six oligonucleotides were designed for the 56 mutation types at nine codons, and 11 oligonucleotides were designed for the wild types and positive controls. We found RET mutations in all eight of the Korean MEN2A families (a total of 75 members; 27 affected members, 19 gene carriers, and 29 unaffected members) using the developed RET oligonucleotide microarray and an automatic sequencing. Because we found only five mutation types from eight MEN2A families, the international collaborations are required to see whether the RET oligonucleotide microarray may be used as a genetic diagnostic tool. Taken together, the RET oligonucleotide microarray can function as a fast and reliable genetic diagnostic device, which simplifies the process of detecting RET mutations.