Familial medullary thyroid carcinoma (FMTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. An identifiable RET mutation can be detected in about 85% of FMTC families. The majority of germline mutations in FMTC have been found in exons 10 and 11 of the RET proto-oncogene, specifically within the cysteine codons 609, 611, 618, 620, and 634. We screened members of a large Korean family that had a history of FMTC by genetic analyses, and propose a therapeutic approach for managing the disorder. We report a RET mutation in exon10, codon 618 that causes substitution of a cysteine by a serine in the cysteine-rich domain of the RET receptor in a three-generation FMTC family composed of 30 members with 11 carriers. Nine of the gene carriers were clinically affected. The FMTC with cysteine RET mutations found in the Korean population is consistent with the clinical pattern reported worldwide; to date there have been no ethnic differences identified for FMTC. Our results suggest that this genetic profile might be associated with usually aggressive clinical course with regional lymph node metastasis but late onset of MTC.
Adolescent ; Adult ; Aged ; Amino Acid Substitution ; Carcinoma, Medullary/*genetics/pathology/secondary ; Exons ; Female ; Genetic Predisposition to Disease ; Genetic Testing ; Genotype ; *Germ-Line Mutation ; Humans ; Male ; Middle Aged ; Pedigree ; Proto-Oncogene Proteins c-ret/*genetics ; Republic of Korea ; Thyroid Neoplasms/*genetics/pathology

Many cases of RET proto-oncogene mutations of hereditary medullary thyroid carcinoma (MTC) have been reported in Korea. However, MTC with V804M RET proto-oncogene germline mutations have not been reported in Korea. A 33-yr-old man was diagnosed with a 0.7-cm sized thyroid nodule. Laboratory testing revealed serum calcitonin was elevated. The patient underwent total thyroidectomy with central compartment neck dissection for the thyroid tumor. RET gene analysis was performed in both the index patient and his family. There were no V804M RET mutation and abnormal laboratory findings within his family except the index patient. Therefore, this patient was a de novo V804M RET germline mutation.
Adult ; Calcitonin/blood ; Germ-Line Mutation ; Humans ; Male ; Pedigree ; Proto-Oncogene Proteins c-ret/*genetics ; Sequence Analysis, DNA ; Thyroid Neoplasms/*diagnosis/genetics/ultrasonography ; Thyroidectomy

Multiple endocrine neoplasia I(MEN I) is a genetic disorder that consists of neoplasia of neuroendocrine type in the parathyroid glands, in the islets of Langerhans in the pancreas, and in the anterior pituitary gland. Primary hyperparathyroidism is the most common feature and occurs in approximately 95% of MEN I patients. Pancreatic islet cell tumors occur in 40% of MEN I patients. Most of these tumors produce excessive amounts of hormones, such as gastrin, insulin, glucagon and vasoactive intestinal polypeptide(VIP). VIP-producing pancreatic tumors(VIPoma) associated with MEN I are rare and so far only one has been reported in Korea. Recently, we came across a case of MEN I, associated VIPoma presented persistent hypercalcemia after a parathyroidectomy. A 70 year old man had suffered from large amount of watery diarrhea, severe general weakness and paralysis of lower limbs for 3 months which suggests symptoms of hypercalcemia. Before the patient visited our hospital, he underwent subtotal parathyroidectomy due to hyperparathyroidism. Even though he was operation, there was no subsidization of the symptoms and abnormal findings of blood chemistry such as hypercalcemia, hypocalemia were remained unchanged. However, the parathyroid hormone level was still within normal limits. Abdominal computerized tomography scan demonstrated a mass of 2.5cm diameter in tail of the pancreas. As serum level of VIP hormone was also elevated, distal pancreatectomy was carried out to performed. There was improvement in the symptoms towards the normal condition and the level of biochemical parameters such as serum potassium, calcium and VIP, were also within the normal limits. In a direct sequence analysis, GAC-->CAT(Asp-->His) point mutation, at codon 383 of exon 9 of the MEN I gene was identified in both the patient and his son. The authors report a rare case of VIPoma associated with MEN I with review of literature on MEN I.
Aged ; Calcium ; Chemistry ; Codon ; Diarrhea ; Exons ; Gastrins ; Germ-Line Mutation ; Glucagon ; Humans ; Hypercalcemia ; Hyperparathyroidism ; Hyperparathyroidism, Primary ; Insulin ; Islets of Langerhans ; Korea ; Lower Extremity ; Multiple Endocrine Neoplasia Type 1 ; Multiple Endocrine Neoplasia* ; Pancreas ; Pancreatectomy ; Paralysis ; Parathyroid Glands ; Parathyroid Hormone ; Parathyroidectomy ; Pituitary Gland, Anterior ; Point Mutation ; Potassium ; Sequence Analysis ; Vipoma*

BACKGROUND AND OBJECTIVES: Hereditary medullary thyroid carcinoma is presented as a part of MEN2A (65-75%) or MEN2B, but can also be inherited alone, which is called familial medullary thyroid carcinoma. The author sought to detect point mutations of the RET proto-oncogene using the molecular genetic method on the family line of the familial medullary thyroid carcinoma, which is identified by the family history of an index patient, and to investigate the presence of point mutation carriers among the family members. SUBJECTS AND METHOD: DNA was extracted from the peripheral blood leukocyte of 5 patients who were assumed to have sporadic medullary thyroid carcinoma and 1 patient who was an index of a family line assumed to contain hereditary medullary thyroid carcinoma according to the family history. The PCR amplification of exons, 10, 11, 13, 14, 15, 16 was then carried out, and we investigated point mutations of the RET proto-oncogene using a DNA sequence analyzer. After identifying point mutation of the familial medullary carcinoma with them, the same investigation was carried out with their family. RESULTS: We identified point mutation of TGC (Cys)->CGC (Arg) at codon 618 of the RET proto-oncogene exon 10, using the automatic DNA sequence analyzing method on the index patient and detected the same point mutation with 4 of the 9 family members. Among them, the index patient and her mother who had biochemical and clinical symptoms underwent a total thyroidectomy and neck dissection and are now being followed up ; operations are scheduled for two other members later on. CONCLUSION: With the genetic analysis of RET proto-oncogene, we expect to overcome the limitations of the calcitonin stimulation test and that more complete approach through early diagnosis would be possible by carrying out the screening test for point mutation in patients with the hereditary medullary thyroid carcinoma.
Base Sequence ; Calcitonin ; Carcinoma, Medullary ; Codon ; DNA ; Early Diagnosis ; Exons ; Humans ; Leukocytes ; Mass Screening ; Molecular Biology ; Mothers ; Multiple Endocrine Neoplasia Type 2a ; Multiple Endocrine Neoplasia Type 2b ; Neck Dissection ; Point Mutation* ; Polymerase Chain Reaction ; Proto-Oncogenes ; Thyroid Gland* ; Thyroid Neoplasms* ; Thyroidectomy

BACKGROUND AND OBJECTIVES: MEN I is an autosomal dominant disorder characterized by multiple tumors occurring in the parathyroid, pituitary, and pancreas. There is a variety of mutations in MEN I that are scattered throughout the coding region, thus MEN I family has its unique type of mutations. The aim of this study is to investigate the significance of genetic screening via analyzing the MEN I gene in the MEN I family. SUBJECTS AND METHOD: Three family members related to MEN I were involved for studying the MEN I gene mutation by using single strand conformational polymorphism and DNA sequence analysis of the coding region and the exon-intron boundaries of the MEN I gene. RESULTS: A specific germline mutation of 1023 a to g transition at the splice acceptor site of exon 7 was identified in all three members of the family in the direct sequence analysis of MEN I gene. CONCLUSION: Genetic analysis for mutations in the MEN I family allows identification of individuals predisposed to the disease and enables an early diagnosis and more complete management. Also, this new diagnostic approach is helpful not only in genetic counselling of clinical management of the MEN I families but also in reducing health care expenses and psychological burden of the diseases.
Clinical Coding ; Delivery of Health Care ; Early Diagnosis ; Exons ; Genetic Testing ; Germ-Line Mutation ; Humans ; Male ; Multiple Endocrine Neoplasia Type 1* ; Pancreas ; Polymerase Chain Reaction ; RNA Splice Sites ; Sequence Analysis ; Sequence Analysis, DNA