A Korean Family of Familial Medullary Thyroid Cancer with Cys618Ser RET Germline Mutation

정진향,Shinya Uchino,이영하,박호용 대한의학회 2010 Journal of Korean medical science Vol.25 No.2

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.

VIPoma와 동반된 다발성 내분비 선종증 1예

이시원,최영식,박요한,오경승,신중우,김일진,Shinya Uchino 대한내분비학회 2005 Endocrinology and metabolism Vol.20 No.1

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 저자들은 부갑상선 아전절제술 이후에도 교정되지 않는 고칼슘혈증과 계속된 수양성 설사로 인한 하지 마비 및 전신 쇄약을 주소로 내원한 70세 남자 환자에서 일반 화학 검사, 호르몬 검사, 방사선 검사 등으로 VIPoma와 동반된 MEN I을 진단하여 외과적 절제술 후 수양성 설사, 저칼륨혈증 및 고칼슘혈증이 호전되었을 뿐아니라 환자와 환자의 아들에게 시행한 DNA 염기서열 분석에서 MEN I 유전자 exon 9의 codon 383에서 GAC가 CAT(Asp→His)로 전이되는 점돌연변이가 확인된 1예를 경험하였기에 문헌 고찰과 함께 보고하는 바이다.

가족성 갑상선 수질암에 대한 RET 유전자의 점돌연변이 분석

이강대,문효성,김주연,정헌,최소희,하남욱,Shinya Uchino 대한이비인후과학회 2004 대한이비인후과학회지 두경부외과학 Vol.47 No.9

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 medulary thyroid carcinoma, which is identified by the family history of an index patient, and to investigate the presence of point mutation cariers among the Subjects and Method:DNA was extracted from the peripheral blod leukocyte of 5 patients who were asumed to have sporadic medulary thyroid carcinoma and 1 patient who was an index of a family line asumed to contain hereditary medullary thyroid carcinoma according to the family history. The PCR amplification of exons, 10, 11, 13, 14, 15, 16 was then caried out, and we investigated point mutations of the RET proto-oncogene using a DNA sequence analyzer. After 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 disection and are now being folowed up;operations are scheduled for two other members later on. Conclusion:test and that more complete aproach through early diagnosis would be posible by carrying out the screning test for point mutation in patients with the hereditary medulary thyroid carcinoma .

제 1 형 다발성 내분비선종증을 가진 한 가계의 유전자 변이 분석

이강대,김주연,문효성,최소희,이환호,최영식,박요한,Shinya Uchino 대한이비인후과학회 2005 대한이비인후과학회지 두경부외과학 Vol.48 No.3

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 scatered 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 screning 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 an-alysis 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 aceptor 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 only in genetic counselling of clinical management of the MEN I families but also in reducing health care expenses and psycho-logical burden of the diseases.

A Case of Medullary Thyroid Carcinoma with de novo V804M RET Germline Mutation

최영식,권혜정,김부경,권수경,박요한,김정훈,정상봉,이창훈,이성근,Shinya Uchino 대한의학회 2013 Journal of Korean medical science Vol.28 No.1

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.