Pedigree screening of a Chinese multiple endocrine neoplasia type 2A family and prophylactic total thy-roidectomy / 中华内分泌外科杂志

Objective To explore the clinical significance of integrated screening of RET in a Chinese multiple endocrine neoplasia type 2A(MEN 2A)family and to evaluate the feasibility and effectiveness of prophy-lactic total thyroidectomy to MEN 2A-related medullary thyroid carcinoma ( MTC).Methods Medical history was obtained from 10 family members in a 3-generation south China family .Systemic investigations including bio-chemical tests, imaging examinations and germline RET screening were performed .3 asymptomatic mutation car-riers underwent prophylactic total thyroidectomy .Results RET screening showed a heterozygous missense muta-tion of TGC to CGC at codon 634 on exon 11 in 6 members(p.C634R), which was completely consistent with the clinical manifestations.There were 4 males and 2 females.The initial mean diagnostic age of 33.5 years(ranging from 19 years to 65 years) and the mean maximum diameter of MTC was 2.3 cm(ranging from 0.7 cm to 5.2 cm). Among them 3 members had palpable neck masses (1 case with diarrhea).Right total thyroidectomy +right level Ⅵlymph-node dissection with modified right neck dissection in one case , and bilateral total thyroidectomy +bilat-eral level Ⅵlymph-node dissection in 2 were performed .In other 3 asymptomatic mutation carriers , prophylactic total thyroidectomy +bilateral level Ⅵ lymph-node dissection were also performed .Among them, 1 case of a-symptomatic pheochromocytom ( PHEO) underwent cortical-sparing adrenalectomy before MTC .After the first op-eration, 4 patients still presented a high value of calcitonin , among whom 1 patient( T3N 1bM 0-1) underwent re-operation for 3 times after the initial operation and presented metastasis to bone after 130 months, taking vandet-anib orally up to now;2 patients underwent reoperation at 6 and 7 months after initial operation respectively (T1N 1bM0 and T2N 1bM0), and the other one patient was closely monitored and followed up for 22 months(T2N 1b M0).Moreover, The calcitonin levels dropped to normal in the other 2 asymptomatic cases(T1N0M0) who were followed up for 20 months.Conclusions Pedigree screening can work up an early diagnosis and improve the prognosis of MEN 2A.Integrated screening of RET and pre-operative calcitonin level measurement and prophylac-tic thyroidectomy for asymptomatic RET mutation carriers are reasonable and effective .

Genotype-phenotype correlation in multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 is an autosomal-dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the rearranged during transfection proto-oncogene, which encodes the receptor tyrosine kinase, on chromosome 10. It has a strong penetrance of medullary thyroid carcinomas and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Multiple endocrine neoplasia type 2 is divided into three varieties depending on its clinical features: multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma. The specific rearranged during transfection mutation may suggest a predilection toward a particular phenotype and clinical course of medullary thyroid carcinoma, with strong genotype-phenotype correlations. Offering rearranged during transfection testing is the best practice for the clinical management of patients at risk of developing multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2 has become a classic model for the integration of molecular medicine into patient care. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on the classification of rearranged during transfection mutations into risk levels according to genotype-phenotype correlations. Earlier identification of patients with hereditary medullary thyroid carcinoma can change the presentation from clinical tumor to preclinical disease, resulting in a high cure rate of affected patients and a much better prognoses.

A Case of Multiple Endocrine Neoplasia Type 2B early Diagnosis by RET Proto-oncogene Analysis and Prophylactic Total Thyroidectomy / 대한소아내분비학회지

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare autosomal-dominant hereditary syndrome which includes medullary thyroid carcinoma (MTC), pheochoromocytoma, multiple ganglioneuromas, gastrointestinal disorders and marfanoid face. MTC is the main cause of death in patients that have not received early and prophylactic treatment. Clinically useful direct DNA tests have recently been available to identify gene carriers before any clinical or biochemical abnormalities are present. Prophylactic total thyroidectomy is recommended to affected children at an early stage of the disease to prevent the development of metastases of MTC. We report a case of MEN 2B patient who was diagnosed by RET proto-oncogene analysis and performed prophylactic total thyroidectomy.

Early Detection of Medullary Thyroid Cancer by Screening of the RET Proto-oncogene Germ Line Point Mutation in Family Members Affected with Hereditary Medullary Thyroid Cancer / 대한내분비학회지

BACKGROUND: Conventional biochemical screening for family members with hereditary medullary thyroid cancer (MTC) is associated with problems of sensitivity and, specificity and it frequently detects gene carriers only after disease progression. Molecular genetic screening tests that detect germ-line point mutations of the RET proto-oncogene has changed our approach to hereditary MTC. In this study we screened members of a large Korean family that had a history of hereditary MTC by a molecular genetic method and propose a therapeutic approach in managing the disorder. METHODS: Using DNA acquired from peripheral blood leukocytes of the index patient, we performed PCR and direct sequencing of exon 10 of the RET proto-oncogene. PCR-RFLP using an Mbo II restriction enzyme was performed on family members who were at risk of MTC according to the family pedigree. Basal serum calcitonin level was determined in family members who had a point mutation of the RET proto-oncogene and a pentagastrin stimulation test was performed in 3 members. RESULTS: Genetic analysis in the index case revealed a mutation in exon 10, codon 618 of the RET proto-oncogene (TGC to AGC). Out of 28 members who were at risk of MTC, 24 members participated in the screening test. 9 members tested positive for a mutation in the same chromosomal location as the index patient by PCR-RFLP. Basal serum calcitonins were above 100 pg/mL in 2 members. 3 members who had a RET point muatation but a normal basal serum calcitonin level participated in the pentagastrin stimulation test and the results were negative in all members. We found a small medullary thyroid carcinoma that had a diameter of 0.2 cm in a 16 years old boy according to a negative pentagastrin stimulation test and who had received a prophylactic total thyroidectomy. He had no evidence of a lymph node metastasis. CONCLUSION: We detected a germ-line mutation of the RET proto-oncogene in codon 618 of Exon 10 by a molecular genetic method in a family with a hereditary MTC and found 9 members that had a negative history of MTC but had a RET point mutation. There was a very small MTC found in a 16 years old boy who had a normal pentagastrin stimulation test result. Therefore, It is recommended that a prophylactic total thyroidectomy be performed as well as in members that have a mutation of the RET proto-oncogene because MTC can metastasize early in its disease course.'