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1 대한내분비학회지 : 제 21 권제 3 호 2006 증례 VHL 유전자배선돌연변이 (Q73X) 를동반한제 1 형 von Hippel-Lindau 병 1 예 고신대학교의과대학내과학교실, 영상의학과교실 1, 한국유전성종양등록소서울대학교암연구소 2 서정훈 양재홍 최평락 김유리 최영식 박요한 고지호 1 강효정 2 김일진 2 박재갑 2 Case of Type 1 von Hippel-Lindau (VHL) Disease associated with VHL Germline Mutation Jeong Hoon Seo, Jae Hong Yang, Pyoung Lak Choi, Yu Lee Kim, Young Sik Choi, Yo Han Park, Ji Ho Ko 1, Hio Chung Kang 2, IL Jin Kim 2, Jae Gahb Park 2 Departments of Internal Medicine and Radiology 1, Kosin University College of Medicine; and Korean Hereditary Tumor Registry, Cancer Research Institute, Seoul National University 2 STRCT Von Hippel-Lindau (VHL) disease is an autosomal dominant neoplasia syndrome that result from a germline mutation in the VHL gene. Germline mutation in the VHL gene lead to the development of hemangioblastomas of the central nervous system and retina, cysts and clear cell carcinoma of the kidney, cyst adenomas of other organs, and pheochromocytoma. VHL is a tumor suppressor gene on the short arm of chromosome 3. VHL disease has been classified into two main clinical subtypes depending on the presence (type 2) or absence (type 1) of pheochromocytoma. Type 2 has been subdivided into three categories depending on the presence (type 2) or absence (type 2) of renal cell carcinoma, with type 2C being a rare subtype in which pheochromocytoma is the sole manifestation of VHL disease. Recently we experienced a family with VHL type 1 who carry C to T (Q73X) transition in codon 217 nonsense germline mutation in exon 1 of VHL gene. The authors report this case with literature review. (J Kor Soc Endocrinol 21:239~244, 2006) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key Words: VHL germline mutation, Von Hippel-Lindau disease 서론3 1) von Hippel-Lindau (VHL) 병은상염색체우성으로유전하며, VHL유전자의배선돌연변이 (germline mutation) 의결과로발생한다 [1]. VHL유전자의배선돌연변이는중추신경계와내장기관의여러장기에양성및악성종양을초래하는데, 이들종양으로는소뇌, 척수, 뇌간및망막의혈관모세포종, 신세포암, 갈색세포종및췌도종양등이있다. VHL 병은갈색세포종과신세포암의동반유무에따라 4가지의접수일자 : 2005년 11월 25일통과일자 : 2006년 1월 17일책임저자 : 최영식, 고신대학교의과대학내과학교실 표현형으로분류된다. 갈색세포종이동반되지않은경우를 1 형, 갈색세포종이동반된경우 2형으로나뉘며, 2형은각각혈관모세포종과갈색세포종은있으나신세포암이동반되지않은 2형, 신세포암이동반된 2형과혈관모세포종동반없이갈색세포종만있는 2C형으로세분된다 [2,3]. 국내에서도 VHL병에대한보고가있었으며 [4], 최근에는유전자검사를통한 VHL유전자의돌연변이를보고한증례들이보고되고있다 [5,6]. 저자들은췌장과우측신장에종괴를가진환자와소뇌에혈관모세포종을가진환자의딸에서시행한유전자검사상 VHL exon1의 codon 217에서 C T (Q73X) 로무의미 (nonsense) 돌연변이를일으킨증례를경험하였기에보고하는바이다

CT and MR of the patient's daughter show a sharply demarcated and smoothly marginated cystic mass (about 4.5 cm) with a small intensely enhancing mural nodule at posterior fossa.

2 대한내분비학회지 : 제 21 권제 3 호 2006 Fig. 1. family pedigree of the patient. Genetic test of the daughter and son of the patient was done. Three girl's elder brother of the patient had a past history of surgery for kidney tumor. Their genetic test was not done. Fig. 2. CT and MR of the patient's daughter show a sharply demarcated and smoothly marginated cystic mass (about 4.5 cm) with a small intensely enhancing mural nodule at posterior fossa. 증례환자 : 이 O 숙, 여자 41세주소 : 상복부통증현병력 : 내원 1년전상복부통증으로타병원에입원하여서췌장의악성종양이의심되어개복술을시행받았으나종양을절제하지못하였다고함. 대증치료중내원 1개월전부터악화되는상복부통증으로본원에입원하였다. 과거력 : 특이소견없음. 가족력 : 4남 2여중다섯째이며, 가족중오빠 3명이신장의종양으로수술을시행받아 VHL병이의심되나유전자검사는시행하지못하였고, 환자의딸과아들만유전자검사를시행하였다 (Fig. 1). 환자의딸이소뇌종양으로 (Fig. 2) 타병원에서수술을받았다. 신체검사소견 : 내원당시혈압은 130/80 mmhg, 맥박은 72회 / 분, 호흡수 20회 / 분이었다. 복부진찰소견상상복부에 3 4 cm 크기의종괴가촉지되었다. 그외신체검사에특이소견이관찰되지않았다. 검사실소견 : 말초혈액검사에서백혈구 5200/mm 3, 혈색소 12.2 g/dl, 혈소판 18900/mm 3 였고, 혈청생화학검사에서 ST 22 IU/dL, LT 34 IU/dL, UN 9 mg/dl, Cr 0.6 mg/dl, Na 139 meq/l, K 3.8 meq/l, amylase 63 U/L, lipase 31 U/L이었다. 24시간뇨중 metanephrine 45 μg/day (0 300 μg/day), epinephrine 4.5 μg/day (0 20 μg/day), vanillylmandelic acid 2.5 mg/day (2 8 mg/day), norephinephrine 37.4 μg/day (15 80 μg/day), normetanephrine 128 μg/day (0 600 μg/day) 이었다. 방사선학적소견및기타검사 : 복부초음파검사에서췌

서정훈외 9 인 : VHL 유전자배선돌연변이 (Q73X) 를동반한제 1 형 von Hippel-Lindau 병 1 예 Fig. 3. Ultrasound showing 6.

Magnetic resonance cholangiopancreatography showing a pancreatic head mass (5 cm sized) with duct dilatation. 장의두부에 6.

Magnetic resonance cholangiopancreatography (MRCP) 상췌장두부에췌관의확장을동반한약 5 cm 크기의이질성종괴가관찰되었다 (Fig. 4). 뇌전산화단층촬영은시행하지못하였다.

Trizol reagent (Invitrgen, Carlsbad, C, US) 를이용하여게놈 (genomic) DN를분리하였다.

3 서정훈외 9 인 : VHL 유전자배선돌연변이 (Q73X) 를동반한제 1 형 von Hippel-Lindau 병 1 예 Fig. 3. Ultrasound showing 6.3 cm sized mass at pancreatic head and 3.3 cm sized isoechoic mass at right kidney. Fig. 4. Magnetic resonance cholangiopancreatography showing a pancreatic head mass (5 cm sized) with duct dilatation. 장의두부에 6.3 cm 크기의종괴가관찰되었고, 우측신장에 3.3 cm 크기의동일음영의종괴가관찰되었다 (Fig. 3). Magnetic resonance cholangiopancreatography (MRCP) 상췌장두부에췌관의확장을동반한약 5 cm 크기의이질성종괴가관찰되었다 (Fig. 4). 뇌전산화단층촬영은시행하지못하였다. 환자의안저검사는정상소견을보였다. 치료및경과 : 환자는췌장의종양으로이전에수술을시도하였으나실패한과거력이있었기에조직검사후특별한치료를시행하지못하였다. 신장의낭성종양도악성의가능성이있었으나, 조직검사는시행하지못하였다. 대증치료후퇴원하였고외래를통해추적관찰중이다. 유전자검사 : 환자와환자의아들과딸의동의하에 VHL 유전자에대한배선돌연변이유무를조사하기위해말초혈액을 EDT 용기에담아 Ficoll-Plaque (mersham Pharmacia iotech, Uppsala, Sweden) 와 Trizol reagent (Invitrgen, Carlsbad, C, US) 를이용하여게놈 (genomic) DN를분리하였다. VHL 유전자의총 3개의 exon에대하여 6개의 primer를사용하여중합효소연쇄반응 (polymerase chain reaction, PCR) 을시행하였으며, 증폭된 PCR 산물을 I 3100 automated sequencer (pplied iosystems, Foster City, C, US) 를이용하여분석하였다. 저자들은환자와환자의딸에서 VHL exon1의 codon 217에서 C T (Q73X) 로무의미돌연변이를발견하였다 (Fig. 5). 고찰 VHL병은약 36,000명중 1명발생하는비교적드문질환으로, 평균생존율은 50세정도이나최근이질환에대한이해와조기진단으로예후가좋아지고있다. VHL병의주된사망의원인은신세포암과중추신경계의혈관모세포종에의한것으로알려져있다 [7]. VHL병은 VHL병의가족력이있는경우망막, 척수, 소뇌의혈관모세포종중하나가있거나, 그밖에신세포암및갈색세포종등이있을경우에진단이가능하며, 가족력이없는경우망막이나중추신경계에혈관

대한내분비학회지 : 제 21 권제 3 호 2006 C Fig. 5. Direct sequence analysis of exon 1 of the VHL gene. Germline mutation at exon1 codon 217, C T (Q73X).. Wild type (patient's son).. Index patient. C. Her daughter.

4 대한내분비학회지 : 제 21 권제 3 호 2006 C Fig. 5. Direct sequence analysis of exon 1 of the VHL gene. Germline mutation at exon1 codon 217, C T (Q73X).. Wild type (patient's son).. Index patient. C. Her daughter. 모세포종이있거나, 한부분에모세혈관종이있고그외다른장기에특징적인종양이있으면진단이가능하다 [8,9]. 종양억제유전자인 VHL유전자는 3번염색체의단완에위치하며 [10], 213개의아미노산을가진 VHL단백질 (pvhl) 을 encode하며, pvhl은혈관생성및세포외기질 (extracellular matrix) 형성에관여한다 [11]. 정상상황 (normoxia) 에서 pvhl은 elongin 와 elongin C 및 cullin 2 (CUL2) 와복합체 (VC-CUL2) 를형성하여, hypoxia inducible factor (HIF) 1과 2의 α subunit에결합하고, ubiquitin 매개단백질분해를통해 HIF가분해된다. 반면 VHL병과같이 VHL단백질에이상이있거나또는저산소증 (hypoxia) 상황에서는 HIF가분해되지않을뿐아니라, HIF의표적단백질인 vascular endothelial growth factor (VEGF), erythropoietin, tumor growth factor (TGF) α 및 β 등의과증식을유도하여세포증식과혈관형성을일으킨다 [12]. 1988년 Seizinger 등 [13] 에의해 VHL유전자의위치가알려진이후, 500개가넘는배선돌연변이가보고되었다 [14]. 이들 VHL유전자의돌연변이에는유전자의발현을방해하는결손 (deletion), frameshift, 무의미돌연변이, splice site 돌연변이등과비정상단백질의발현을일으키는과오 (missense) 돌연변이등이있다 [15]. 본증례에서는 VHL exon1의 codon 217에서 C T (Q73X) 로무의미돌연변이를 일으켰다. VHL병환자의 60~80% 에서발생하는중추신경계혈관모세포종의주된호발부위는소뇌, 척수및뇌간이나요척추신경근부위와천막상부에도발생한다 [16]. 소뇌의혈관모세포종은 VHL병초기에나타나는소견으로소뇌혈관모세포종의환자의경우에는 VHL병에대한선별검사와함께가족력에대한조사도요구된다. 중추신경계혈관모세포종은내벽에고형성분을가진낭종성병변 ( 벽성결절, mural nodule) 이흔하다 [17]. 소뇌에혈관모세포종을가진본증례의딸의경우도벽성결절이관찰되었다. 임상증상은병변의위치에좌우된다. 천막하종양의경우두통, 구토, 보행장애혹은운동실조가주로나타나며, 천막상부의경우에는병변의위치에따라다르게나타난다. 혈관모세포종은일반적으로천천히자라지만, 종종유두부종을동반한수두증을일으킬정도로급격히커지는낭종이생기기도한다. 중추신경계에동반된혈관모세포종의진단에는자기공명영상이가장좋다. 대부분의중추신경계혈관모세포종은수술로안전하게제거할수있으나, 혈관모세포종이다발적으로발생할수있을뿐아니라새로운병변이발생할수있으므로, 불필요한수술을줄이기위해증상이발현될때까지수술을연기하기도한다. 대부분의중추신경계종양들은결국중재술이필요하게된다. 본증례에서는 15세된환자의딸이소뇌의

5 서정훈외 9 인 : VHL 유전자배선돌연변이 (Q73X) 를동반한제 1 형 von Hippel-Lindau 병 1 예 혈관모세포종으로두차례에걸쳐타병원에서수술을받았다. 내장기관의경우췌장종양이 35~70%, 신장종양이 25~60%, 부고환낭종이 25~60%, 갈색세포종이 10~20% 순으로나타난다 [18]. 췌장병변은대부분단순낭종이나빈번하게다발성으로나타나며 [19], 췌장의두부에생긴낭종이담관폐쇄를일으키기도한다. 췌장의종양의크기가 3 cm 이상일경우악성일가능성이크다 [20]. 본증례에서환자의경우 MRCP상담관의확장은없으면서췌장의두부에췌관확장을동반한 5 cm 크기의종양을확인할수있었으며, 초음파검사에서우측신장에서도종괴를관찰하였다. 병의특성상뇌전산화단층촬영및악성의가능성이있는신장의종괴에대한조직검사가필요하였으나, 환자가더이상의검사는원하지않아서검사를시행하지못하였다. 본연구에서무증상의아들에서는돌연변이가관찰되지않았다. 저자들은본증례를통하여 VHL유전자검사가 VHL병의진단에유용함을알수있었고, 향후환자의나머지가족들에대해서도유전자검사를통해조기진단이필요할것으로생각되었다. 요약 Von Hippel-Lindau (VHL) 병은 VHL유전자의배선돌연변이 (germline mutation) 의결과로발생하며, 상염색체우성으로유전하는질환으로소뇌, 척수, 뇌간의혈관모세포종과망막의혈관종, 신세포암, 갈색세포종및췌도종양등의여러장기에양성및악성종양을초래하는질환이다. 저자들은췌장과신장에종양을가진환자와소뇌의종양을가진딸에서시행한유전자검사상 VHL exon1의 codon 217에서 C T (Q73X) 로무의미돌연변이를경험하였기에문헌고찰과함께보고하는바이다. 참고문헌 1. Maher ER, Yates JR, Harries R, enjamin C, Harris R, Moore T, Ferguson-Smith M: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 77: , Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, Gnarra JR, Orcutt ML, Duh FM, Glenn G: Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat 5:66-75, Zbar, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey P, Webster R, ffara N, Ferguson-Smith M, rauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger, Kley N, Olschwang S, oisson C, Richard S, Lips CH, Lerman M: Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North merica, Europe, and Japan. Hum Mutat 8: , Kim W, Min JK, Chon DS, Chae HS, Han SW, Chung IS, Sun HS: One case of von Hippel-Lindau disease with autosomal dominant inheritance. Korean J Med 44: , Kim JW, Choi SJ, Kim YK, hn SM, Song KE, Jung SH, Kim DJ, Chung YS, Lee KW, Kim IJ, Kang HC, Park JG: case report of von Hippel-Lindau disease manifested in a monozygous twin. J Kor Soc Endocrinol 20: , Yang JH, Choi YS, Park YH, Oh KS, Chun K, Lee SJ, Kim IJ: case of von Hippel-Lindau (VHL) germline mutation associated with familial bilateral pheochromocytoma in the VHL disease. Korean J Med 69:S873-S878, Maher ER, Iselius L, Yates JR, Littler M, enjamin C, Harris R, Sampson J, Williams, Ferguson-Smith M, Morton N: Von Hippel-Lindau disease: a genetic study. J Med Genet 28: , Choyke PL, Glenn GM, Walther MM, Patronas NJ, Linehan WM, Zbar : Von Hippel-Lindau disease: genetic, clinical and imaging features. Radiology 194: , Couch V, Lindor NM, Karnes PS, Michel VV: Review of von Hippel-Lindau disease. Mayo Clin Proc 75: , Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260: , Pause, Lee S, Lonergan KM, Klausner RD: The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl cad Sci US 95: , Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399: , Seizinger R, Rouleau G, Ozelius LJ, Lane H,

6 대한내분비학회지 : 제 21 권제 3 호 2006 Farmer GE, Lamiell JM, Haines J, Yuen JWM, Collins D, Majoor-Krakauer D, onner T, Mathew C, Rubenstein, Halperin J, McConkie-Rosell, Green JS, Trofatter J, Ponder, Eierman L, owmer MI, Schimke R, Oostra, ronin N, Smith DI, Drabkin H, Waziri MH, Hobbs WJ, Martuza RL, Conneally PM, Hsia YE, Gusella JF: von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 332: , Sims K: Von Hippel-Lindau disease: gene to bedside. Curr Opin Neurol 14: , Richard S, Graff J, Lindau J, Resche F: Von Hippel- Lindau disease. Lancet 363: , Filling-Katz MR, Choyke PL, Oldfield E, Charnas L, Patronas NJ, Glenn GM, Gorin M, Morgan JK, Linehan WM, Seizinger R: Central nervous system involvement in von Hippel-Lindau disease. Neurology 41:41-46, Richard S, Campello C, Taillandier L, Parker F, Resche F: Haemangioblastoma of the central nervous system in von Hippel-Lindau disease. French VHL Study Group. J Intern Med 243: , Maher ER, Kaelin WG Jr: von Hippel-Lindau disease. Medicine (altimore) 76: , Neumann HP, Dinkel E, rambs H, Wimmer, Frieburg H, Volk, Sigmund G, Riegler P, Haag K, Schollmeyer P: Pancreatic lesions in the von Hippel- Lindau syndrome. Gastroenterology 101: , Marcos H, Libutti SK, lexander HR, Lubensky I, artlett DL, Walther MM, Lienhan WM, Glenn GM, Choyke PL: Neuroendocrine tumors of the pancreas in von Hippel-Lindau disease: spectrum of appearances at CT and MR imaging with histopathologic comparison. Radiology 225: ,

Lumbar spine

Lumbar spine CT 32 111 DOI : 10.3831/KPI.2010.13.2.111 Lumbar Spine CT 32 Received : 10. 05. 23 Revised : 10. 06. 04 Accepted : 10. 06. 11 Key Words: Disc herniation, CT scan, Clinical analysis The Clinical