Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children

BACKGROUND: Patients with multiple endocrine neoplasia (MEN) type 2 are at risk for early medullary thyroid carcinoma (MTC). Recently, the cloning of the ret oncogene has made it possible to identify patients at risk for MEN 2 syndrome with a high degree of reliability before presenting any symptoms. METHODS: Children of families with MEN 2 were screened genetically if one of the parents was a known gene carrier of the RET proto-oncogene. If they were carriers, thyroidectomy was performed. RESULTS: The authors report five children with MEN 2 who underwent prophylactic thyroidectomy irrespective of the results of calcitonin screening tests after genetic screening had shown that they were carrier of the RET proto-oncogene. Apart from a temporary hypocalcemia in one, the operations were uneventful. Pathology results showed MTC in three children of one family with MEN 2A at age 2, 3, and 6 years. In two families with MEN 2B the thyroidectomy specimen showed bilateral MTC in a 1-year-old and a 3-year-old child. CONCLUSIONS: These findings show that MTC occurs at very young age in children with MEN 2. The authors advocate performing prophylactic thyroidectomy in the first year of life in children with MEN 2B and at age 2 years in children with MEN 2A to obtain an optimal cure rate.     

Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma (FMTC) are autosomal dominantly inherited cancer syndromes that predispose to C-cell hyperplasia and MTC. MEN 2A and FMTC are caused by mutations in the RET proto-oncogene. METHODS: We used a multiplex polymerase chain reaction-based assay to screen exons 10, 11, 13, and 14 of RET for mutations in 2 families with FMTC. We correlated mutation status with calcitonin and pathologic studies to determine genotype-phenotype correlations. RESULTS: We identified a mutation in codon 804 in exon 14 (GTG-->ATG; V804M) in both families. An 86-year-old person who was a gene carrier and other individuals over age 70 who were suspected by pedigree analysis to be gene carriers had no overt clinical evidence of MTC. Four of 21 patients who underwent a thyroidectomy also had papillary thyroid cancer. One individual in each family had metastatic MTC at age 30 and 32 years, and all 26 people having thyroidectomies had either MTC or C-cell hyperplasia, leading us to continue to recommend prophylactic thyroidectomy for all identified patients who were gene carriers. CONCLUSIONS: Because of active MTC in younger members of these families, including metastases, we have continued to advocate thyroid surgery in mutation-positive individuals. While DNA diagnosis of gene carriers and subsequent genetic counseling was relatively straightforward, the acceptance of surgical recommendations was more difficult for some individuals. These families demonstrate that the search for RET mutations should include exons 13, 14, 15, and 16 in patients whose studies in exons 10 and 11 are negative.     

Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A.

BACKGROUND: Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. METHODS: A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. RESULTS: Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. CONCLUSION: The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.     

RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease

BACKGROUND: RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene. METHODS: Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients. RESULTS: A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2. CONCLUSIONS: This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.     

Prediction of affected MEN2A gene carriers by DNA linkage analysis for early total thyroidectomy: a progress in clinical screening program for children with hereditary cancer syndrome.

The gene predisposing to multiple endocrine neoplasia type 2A (MEN 2A) has been assigned to chromosome 10, and affected gene carriers can be identified before the development of associated malignancy in some informative families. We applied these advances in gene mapping to clinical screening for possible pediatric surgery. A family with MEN 2A, consisting of 88 members and their spouses, was studied to test the reliability of the provocation of plasma calcitonin with pentagastrin and the possibility of DNA diagnosis of mutated gene carriers with DNA probes closely linked to the MEN2A gene including RBP3 and FNRB genes. Nineteen of the 88 were diagnosed as MEN 2A carriers. Twelve of them were treated surgically and the others died of medullay thyroid carcinoma (MTC) or pheochromocytoma. A strikingly sensitive response of calcitonin was observed in all those with MTC. The genotypes cosegregating with the abnormal allele at MEN2A in this family could be deduced from clinically established affected members. The early detection of gene carriers allows us to concentrate our screening efforts on children at high risk and to release non gene carriers from repeated unnecessary testing. MEN2A is one of the first cancer syndromes for which DNA screening permits early detection of members at high risk.     

Medullary thyroid carcinoma. Genetic screening and prophylactic thyroidectomies

Medullary thyroid cancer is a rare, neuroendocrine, tumor. It arises from parafollicular or C-cells with the ability to produce and secrete different bioactive substances like calcitonin (TC) and CEA (1-5) TC is ideal tumor marker in early diagnosis, in patents' follow up and in evaluation of their treatment. TC determinations after ca/pentagastrine stimulation test give us even more accurate results and the procedure is used for biochemical family screening. MTC occurs as a sporadic tumor or in hereditary settings MEN 2A, MEN 2B and FMCT. Germ/line point mutations in RET proto/onkogene are responsible for tumor arise and inheritance of settings. Genetic screening provides information of these RET mutations in family members even before pathologic changes occur. These individuals with MEN 2A, 2B and FMCT characteristic RET mutations are almost certain to acquire MTC (95% penetrance) in their lives and are candidates for preventive total thyroidectomy (TT), with or without central neck dissection (CND). Surgery is still the treatment of choice for MTC and only C-cell hyperplasia and early stage of MTC can be cured. Prophylactic thyroid surgery eliminates the possibility of MTC but doesn't influence appearance of other diseases (PHEO, HPTH) of MEN 2 syndromes.     

多发性内分泌肿瘤2型的诊断和外科处理

目的 探讨多发性内分泌肿瘤2型（multiple endocrine neoplasia,MEN2）的诊断和外科处理方法.方法 回顾性研究1997年6月至2006年6月我院诊断和治疗的MEN2患者28例的临床资料.结果 MEN2a型25例,其中23例分属7个家系,均有RET基因11外显子634编码子突变;MEN2b型3例,无家族史,为RET基因16外显子918编码子突变.MEN2a型中22例有甲状腺肿物伴降钙素升高,其中17例经病理证实为甲状腺髓样癌;12例合并嗜铬细胞瘤,其中5例为多发性,2例恶性;5例合并甲状旁腺功能亢进症,3例无临床症状及生化改变.3例MEN2b型均为甲状腺髓样癌合并黏膜神经瘤病和马凡样体形,其中1例伴双侧肾上腺嗜铬细胞瘤.MEN2a型中12例接受双侧甲状腺全切除＋双侧颈淋巴清扫,5例行甲状腺肿物切除;甲状旁腺病变在甲状腺手术时一并处理;9例接受11次肾上腺肿瘤摘除术,3例为双侧肾上腺手术.3例MEN2b型均行双侧甲状腺全切除＋双侧颈淋巴清扫.结论 MEN2型以甲状腺髓样癌为主要病变,基因筛查可帮助早期诊断.根治性甲状腺切除能预防和治疗甲状腺髓样癌.     

Medullary thyroid carcinoma in Northern Ireland, 1967-1997

BACKGROUND: The experience of managing medullary thyroid carcinoma (MTC) in a specialist endocrine surgery unit was reviewed. METHODS: The case records of 38 patients (19 male, 19 female) treated over a 30 year period were studied. RESULTS: There were 23 (60.5%) patients with sporadic MTC while the remainder had familial MTC--12 multiple endocrine neoplasia (MEN) type 2A, two MEN type 2B, one non-MEN familial medullary thyroid carcinoma (FMTC). Sporadic MTC patients were significantly older at presentation (median 56 years, interquartile range 41.5-61.3 years) compared to MEN 2A patients (median 26 years interquartile range 17.5-34 years) and had more advanced stage of disease. Survival of MTC patients was significantly worse in sporadic disease than in those with MEN 2A (P < 0.0001). All familial cases had bilateral multifocal tumour whereas in sporadic patients only unilateral disease was seen. The availability of genetic testing now allows early identification of affected members of familial MTC kindreds. This has led to total thyroidectomy being performed on the basis of positive genetic screening alone in three patients (two MEN 2A, one FMTC), in all of whom widespread C-cell hyperplasia and microscopic multifocal invasive MTC were identified histologically. CONCLUSIONS: The management of MTC has changed during the study period with total thyroidectomy recommended as the primary procedure of choice for all patients. In the familial setting, positive genetic testing now allows thyroidectomy to be performed at an early pre-clinical stage, with the hope of permanent cure.     

Presentation of a medullary endocrine neoplasia 2A kindred with Cushing's syndrome

Although medullary thyroid cancer (MTC) can produce adrenocorticotropic hormone (ACTH) in up to 40 per cent of cases as determined by immunohistochemistry, clinical hypercortisolism is rarely seen. We report a medullary endocrine neoplasia 2A (MEN 2A) kindred whose proband case presented with Cushing's syndrome (CS). This 51-year-old woman presented with debilitating weakness, exertional dyspnea, 50 pound weight gain, moon facies, worsening hypertension, striae, and hirsutism. A comprehensive evaluation diagnosed ectopic ACTH production from unresectable metastatic MTC to the liver. Genetic testing revealed a germline RET proto-oncogene mutation at codon 609. Further genetic testing identified six family members with the same mutation. The patient underwent palliative bilateral laparoscopic adrenalectomies with significant improvement in major comorbidities. Overall CS resulting from ectopic ACTH overproduction by MTC is rare, occurring in 0.6 per cent of all patients with medullary thyroid carcinoma. About 50 cases have been previously reported in the literature, but only three in families with MEN 2A. We describe the first case of a MEN 2A kindred presenting with CS from ectopic ACTH production by metastatic medullary thyroid carcinoma. We advocate consideration of early bilateral laparoscopic adrenalectomies in patients with symptomatic hypercortisolism from unresectable metastatic medullary thyroid carcinoma.     

Mutational analysis of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease.

BACKGROUND/PURPOSE: Germline mutations of the RET proto-oncogene (RET; 10q11.2) have been reported in multiple endocrine neoplasia type 2A (MEN 2A) and Hirschsprung's disease. The authors investigated a Japanese kindred in which MEN 2A and Hirschsprung's disease frequently have been found. METHODS: The pedigree consisted of 28 members (11 boys and 17 girls) spanning 4 generations, of whom, 8 were affected with MEN 2A or Hirschsprung's disease. RESULTS: Direct sequence DNA analysis of the RET proto-oncogene showed a heterozygosity for a G to C transition at the second nucleotide of codon 620 (exon 10) in the patients, resulting in the replacement of cysteine by a serine residue in the affected Ret protein. This family added a novel RET missense mutation (C620S) predisposing to the association of MEN 2A and Hirschsprung's disease. CONCLUSION: Detection of the mutated RET gene carriers may be used for genetic counseling of potential risk for Hirschsprung's disease as well as MEN 2A in the affected families.     

Prophylactic thyroidectomy in MEN 2A syndrome: experience in a single center

BACKGROUND: Genetic study of the RET proto-oncogene has modified the management, treatment, and prognosis of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia 2A (MEN 2A), for patients with less advanced tumor stages. Classically, the diagnosis was based on an increase in basal and poststimulus peak calcitonin (bCT and pCT). Prophylactic thyroidectomy, based on results of genetic testing, may reduce recurrences in MTC. STUDY DESIGN: Of 82 MTC (MEN 2A) patients genetically diagnosed and surgically treated at our center, 22 received a prophylactic thyroidectomy (RET +, bCT and pCT with normal values and asymptomatic). We analyzed age, gender, phenotype, RET mutation, cervical ultrasound, laboratory tests (bCT, pCT, and CEA), surgery, histologic data, TNM, and followup. RESULTS: The 22 patients belonged to 8 families with MTC (MEN 2A). Mean age was 15.2 years (range 5 to 36 years). The RET mutation in 21 patients was Cys-->Tyr and in the remaining patient both in codon 634 in exon 11. The median values of bCT and pCT were 38 pg/mL (range < 15 to 75 pg/mL) and 148.5 pg/mL (range < 15 to 250 pg/mL), respectively. Total thyroidectomy was performed in 8 patients (age < or = 10 years) and associated central neck dissection in 14 patients (age> 10 years). Histologic study showed 7 C-cell hyperplasias and 15 MTCs (8 bilateral); the median size was 0.2 cm (range < 0.1 to 0.7cm); 1 patient had metastatic adenopathies. According to TNM, 7 were stage 0, 14 were stage I, and 1 was stage III. Postsurgery bCT and pCT values were normal in all patients, with a curative rate of 100%. MTC patients compared with C-cell hyperplasia patients were older on average, had higher mean bCT, mean pCT, and mean CEA. CONCLUSIONS: Prophylactic thyroidectomy based on genetic testing allows identification and treatment of patients at an early stage of the disease and decreases recurrence rates. pCT values above the upper limit of normal may be markers for the presence of MTC and should be considered in selecting operative procedures for these patients.     

Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship

HYPOTHESIS: Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC. DESIGN: Review of endocrine surgery database from 1951 through 2002. SETTING: Tertiary referral center. PATIENTS: Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918). MAIN OUTCOME MEASURES: Stage of MTC at diagnosis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism. RESULTS: RET analysis was complete for 71 patients from 39 kindreds. Multivariate analysis identified an increased likelihood of stage III or IV MTC at diagnosis with increasing age (odds ratio, 1.12 per year of age at thyroidectomy; 95% confidence interval, 1.07-1.17; P<.001) and increasing risk group (odds ratio, 14.23 per incremental increase in MTC risk group from 1 to 3; 95% confidence interval, 3.05-66.55; P<.001). Pheochromocytomas were found in 21 patients from 12 kindreds; 20 of 21 patients had codon 634 or 918 mutations. Hyperparathyroidism was found in 10 patients from 7 kindreds; 7 of 10 patients had codon 634 mutations. CONCLUSION: Specific RET mutations predict the phenotypic expression of disease and the MTC aggressiveness in patients with MEN 2, guiding the timing of thyroidectomy and screening for pheochromocytoma.     

Prophylactic thyroidectomy in multiple endocrine neoplasia: the impact of molecular mechanisms of<Emphasis Type="Italic"> RET</Emphasis> proto-oncogene

BACKGROUND: Multiple endocrine neoplasia (MEN) type 2, a cancer syndrome inherited in the dominant fashion, is defined by the occurrence of medullary thyroid carcinoma (MTC), either as a singular lesion (familial medullary thyroid carcinoma, FMTC) or with the variable expression of pheochromocytoma, hyperparathyroidism (MEN 2A), ganglioneuromas, buccal neuromas and Marfanoid-like phenotype (MEN 2B). DISCUSSION: Germline mutations of the RET proto-oncogene, localized on chromosome 10q11.2, have been identified as the underlying genetic cause of the disorder. In the majority of patients with MEN 2A/FMTC missense mutations at exon 10 or exon 11 are identifiable. Cysteine to arginine exchange at codon 634 is the mutation most frequently found. In MEN 2B approximately 95% of patients present with a mutation at codon 918 (exon 16). Additionally, less frequent mutations in other codons have been found in both syndromes. The DNA-based genotype analysis enables the identification of gene carriers at risk of developing MTC and offer them prophylactic thyroidectomy prior to development of any thyroid pathologies. Prophylactic surgery is generally recommended for MEN 2A/FMTC gene carriers at the age of 4-6 years. Due to the aggressiveness of the MEN 2B syndrome gene carriers should be operated by the age of 1 year. Presumably some less virulent mutations allow postponement of the prophylactic treatment to the second to fourth decade of life. CONCLUSIONS: Compared to standard presymptomatic biochemical screening, genetic testing and consecutive prophylactic treatment contribute to better outcome of individuals at risk for MTC.     

Hereditary medullary thyroid carcinoma in patients greater than 50 years old

BACKGROUND: Despite near complete penetrance and frequent early evaluation of medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia 2 (MEN 2) variants, a significant minority of patients are evaluated later in life. METHODS: With the aim of characterizing the expression of hereditary MTC in an older cohort, MEN 2 patients from our institutional database who were evaluated after age 50 years were identified, and clinical data were reviewed. RESULTS: Thirty-nine patients (36 MEN 2A, 3 FMTC, and no MEN 2B) who were evaluated after age 50 years were identified; they represented 9% of all MEN 2 patients who were enrolled in our program. Most of the patients (79%) had abnormal screening examinations, and the AJCC staging was significantly higher in this cohort compared with younger patients. Overall, 43% of the patients had normal calcitonin levels after operation. There were 3 observed MTC-related deaths, all from distant metastases; the overall survival rate was 86% at 5 years and 74% at 10 years. The distribution of RET mutations in this cohort was similar to younger patients. CONCLUSIONS: These results suggest the presence of modifiers of MTC expression. Despite the tendency of older patients with hereditary MTC to have advanced stage disease at evaluation, they have high rates of biochemical cure, and the overall survival is excellent.     

Surgical Strategy in a Kindred with a Rare RET Protooncogene Mutation of Variable Penetrance with Regard to Multiple Endocrine Neoplasia

Prophylactic thyroidectomy is recommended for carriers of RET protooncogene mutations owing to their nearly complete penetrance for medullary thyroid carcinoma (MTC). However, this guideline is challenged by mutations exhibiting variable penetrance of C-cell pathology. A 38-year-old woman presented with pathologic basal and pentagastrin-stimulated calcitonin levels. Genetic analysis revealed a heterozygous RET protooncogene germline mutation in codon 791 (exon 13) (TAT(Tyr)-->TTT(Phe)), followed by thyroidectomy and systematic central lymph node dissection. Histology showed C-cell hyperplasia (CCH) only. Three additional carriers were identified among family members. The 71-year-old father refused surgery despite pathologic calcitonin levels. The index patient's 37-year-old sister had normal basal and stimulated calcitonin levels, and her 6-year-old son had a 10-fold rise of calcitonin after pentagastrin stimulation. Both patients underwent the same operation as the index patient. The sister had 25 hyperplastic C-cells, but the her son had extensive CCH without MTC. The eldest uncle of the index patient had died of metastatic MTC at the age of 52 with unknown carrier status. Despite variable penetrance, each carrier of a RET protooncogene germline mutation should undergo thyroidectomy, even if basal and stimulated calcitonin levels are normal because at present no test can exclude or predict the age of development of MTC. Moreover, pathologic calcitonin levels cannot differentiate between CCH and MTC. Central lymph node dissection is recommended, as lymph node metastases occur early, significantly worsening the prognosis.     

Sporadic medullary thyroid carcinoma with a pedunculated intraluminal internal jugular vein recurrence: A case report and literature review

Medullary thyroid carcinoma (MTC) is an uncommon usually slowly progressing neuroendocrine tumour that arises from calcitonin (CT) producing parafollicular C cells of the thyroid gland. It accounts for approximately 5% of all thyroid cancers. The majority of MTCs are sporadic (75%) whilst 25% are part of the MEN 2 hereditary syndrome (MEN 2A and MEN 2B and familial MTC). Mutations of the proto-oncogene, RET (Rearranged during Transfection), found on chromosome 10q11, are present in more than 95% of hereditary MTCs and about 25% of sporadic MTCs. MTC metastasizes primarily via lymphatic spread, to central, and lateral nodal neck compartments and the anterior and superior mediastinum. Distant haematogenous spread targets the lungs, liver, bone and brain, and is presumed to be secondary to a lymphatic pathway. There are no previously documented reports of a focal pedunculated metastases located within the jugular vein. We present the first reported case of a metastatic MTC lesion found in the right internal jugular vein in a man with recurrent MTC.     

Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre

BACKGROUND: Evidence that germline mutations in the RET proto-oncogene are the underlying cause of the familial form of medullary thyroid carcinoma (MTC) made it possible to identify gene carriers with a very high degree of accuracy. Aiming to define the mutational profile observed in our patients and to assess gene carriers' compliance with an early surgery, we reviewed results of molecular analysis of RET performed at our institution since 1994. METHODS: One hundred fifty-eight individuals were screened for germline mutations of the RET proto-oncogene. Seventy-seven patients had apparently sporadic MTC; 8 patients had both MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B despite a negative family history; 8 patients were known to belong to affected kindreds; and 65 individuals were at-risk individuals to develop MTC. RESULTS: A germline mutation in RET was identified in 4% of apparently sporadic MTC patients, in 100% of patients with MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B, and in 100% of probands of clinically established kindreds. The most affected codon was 634 (58%) followed by codon 804 (16%). Among at-risk individuals, 49% were identified as gene carriers. Seven individuals were submitted to prophylactic thyroidectomy (mean age, 17.7 +/- 12.5 years; range: 3-42 years), and all but 1 had MTC. CONCLUSIONS: RET mutational spectrum observed in the present population disclosed a higher frequency of codon 804 mutations than expected. Compliance with an early prophylactic surgery seemed to be influenced not only by medical advice and cultural factors but also by the aggressiveness of disease in gene carriers' families.     

Long-term follow-up of a large North American kindred with multiple endocrine neoplasia type 2A.

BACKGROUND. Sixty-one patients with multiple endocrine neoplasia (MEN) type 2A (27 men; 34 women; mean age, 39 years) from a single kindred (76 affected, 49 at risk) were followed 1 month to 33 years (median, 14 years) after diagnosis for disease expression. METHODS. Peripheral basal and pentagastrin-stimulated calcitonin, parathyroid hormone, and calcium levels were measured in 60 patients, 58 of whom had undergone previous thyroidectomy; the calcitonin concentration in four patients was concomitantly determined in the hepatic and internal jugular veins. Biochemical or radiographic screening for pheochromocytoma was performed in 58 patients. RESULTS. Recurrence of medullary thyroid carcinoma (MTC) developed in nineteen (33%) of 58 patients after they underwent thyroidectomies. In 14 of 19 patients regional metastases were inapparent at initial operation, and lymphadenectomy was not undertaken. Three patients underwent neck reexploration with removal of micrometastases after selective venous studies were performed. One patient, 33 years of age, died of MTC, and two patients who refused thyroidectomy are alive at 76 and 83 years of age. Fifteen patients are alive with disease 8 to 33 years after they underwent thyroidectomies. All patients identified by prospective screening remain pentagastrin negative. Pheochromocytoma developed in six patients (10%), and four patients have Hirschsprung's disease. Hyperparathyroidism was present in seven patients and did not occur in those with minimal MTC. CONCLUSIONS. These observations suggest that (1) the course of MTC in MEN 2A is highly variable, (2) early treatment of C-cell disease can be curative, (3) routine lymphadenectomy for occult micrometastases may be necessary for cure of MTC, and (4) the hyperparathyroidism of MEN 2A may not be a primary genetic event.     

Polyadenomatoses: type 2 multiple endocrine neoplasms

FROM A CLINICAL POINT OF VIEW: Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant, inherited multiglandular disease with familial and individual age-related penetration and variable expression. A medullary thyroid carcinoma (MTC) is always concomitant to MEN2 and associated in varying proportion with pheochromocytoma (50%) and hyperparathyroidism (5 to 20%). PROGNOSTIC DATA: The prognosis of MEN2 is related to the carcinological evolution of MTC, which depends mainly on the stage of discovery and the quality of the first surgical treatment, emphasizing the need for early diagnosis. THE IMPORTANCE OF THE ERT GENE: The identification of mutations in proto-oncogene RET, responsible for the various forms of the disease allows subjects at risk in a family circle to be identified and early screening of various endocrine damage, notably MTC, should be performed. Biological explorations in all persons carrying this mutation would permit diagnosis and surgical treatment of the endocrine lesions, before their clinical manifestation.     

Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity

In an evaluation of 213 patients from 15 kindreds with familial medullary thyroid carcinoma (MTC), we detected 41 subjects from two kindreds (L and O) who had MTC but no extra-thyroidal manifestations (hyperparathyroidism, phaeochromocytomas or mucosal neuromas) of multiple endocrine neoplasia (MEN) type IIa or IIb. In screening 178 members of the L and O kindreds, we found no evidence that any of them had died from MTC. To assess whether the malignancy was relatively indolent in these families, 20 selected subjects from the two kindreds were compared with 33 MEN IIa subjects. Both groups had clinically occult disease which was diagnosed biochemically by documenting elevated plasma calcitonin (CT) levels following stimulation with intravenous calcium and pentagastrin. There were no differences in the peak stimulated plasma CT levels at the time of diagnosis (1055 +/- 236 pg/ml versus 1096 +/- 191 pg/ml) or the incidence of regional lymph node metastases (0/20 versus 1/33) in the two groups. The mean age at diagnosis, however, was significantly higher in patients of the L and O kindreds than in patients with MEN IIa (43.1 +/- 3.4 years versus 21.1 +/- 2.2 years; P less than 0.001) indicating that in the two kindreds the MTC either developed at a later age or grew more slowly. This study demonstrates that MTC may occur in a familial pattern distinct from its presentation as MEN IIa or MEN IIb. In this setting it appears to be the least aggressive form of MTC yet described.