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1 pissn: eissn: (4): , July CASE REPORT 심부전과과다호산구증가증으로내원한 PDGFRB 유전변이가동반된골수성종양 권재우, 1 권지현, 2 허애영 3 1 강원대학교의학전문대학원알레르기내과학교실, 2 충북대학교의과대학내과학교실, 3 강원대학교의학전문대학원심장내과학교실 Myeloid and lymphoid neoplasm with eosinophilia and abnormalities of PDGFRB presenting as congestive heart failure and hypereosinophilia Jae-Woo Kwon, 1 Ji-Hyun Kwon, 2 Ae-Young Her 3 1 Department of Allergy and Clinical Immunology, Kangwon National University School of Medicine, Chuncheon; 2 Department of Internal Medicine, Chungbuk National College of Medicine, Cheongju; 3 Division of Cardiology, Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea Hypereosinophilic syndrome (HES) is a heterogeneous disorder characterized by persistent hypereosinophilia with the evidence of organ dysfunction caused by eosinophilic involvement. HES can be induced by various secondary causes, including helminthic infections, adverse drug reactions, and allergic diseases. Primary/clonal bone marrow disease, including genetic mutations in platelet driven growth factor receptor alpha (PDGFRA), platelet driven growth factor receptor beta (PDGFRB), and fibroblast growth factor receptor 1 (FGFR1) could be its causes. Although corticosteroids are the mainstay of therapy in confirmed HES, imatinib is considered a definitive treatment for HES with these mutations. However, there have been few reports about HES with these genetic mutations in Korea. Here, we report a patient who presented with sudden onset of congestive heart failure and hypereosinophilia, proved to have PDGFRB rearrangement, and was controlled successfully with imatinib after left ventricle thrombectomy. (Allergy Asthma Respir Dis 2017;5: ) Keywords: Hypereosinophilic syndrome, PDGFRB, Imatinib, Eosinophilia 서론호산구증가증 (eosinophilia) 은말초혈액내호산구가 500 cells/μl 이상인경우로정의한다. 특히 1,500 cells/μl 이상인경우호산구의조직침범이증가하는것으로알려져있으며과다호산구증가증 (hypereosinophilia) 이라한다. 또한과다호산구증가증이있으면서단일장기에만국한되지않는명확한조직침범이발생하는경우를과다호산구증가증후군 (hypereosinophilic syndrome, HES) 이라한다. 호산구증가증의원인은기생충, 약물, 알레르기질환에의한이차적인반응이가장흔한것으로알려져있어, 호산구증가증이관찰된경우는병력청취와이학적검사, 영상학적검사등을통하여이차적호산구증가증여부를먼저확인해야한다. 그러나이러한원인이뚜렷하지않으면서 6개월이상과다호산구증가증이 지속되는경우특발성과다호산구증가증후군 (idiopathic HES) 이라하며골수검사및염색체검사등을고려할수있다. 최근의연구를통하여호산구증가증과연관된염색체이상및새로운유전자변이가밝혀지고있으며, 대표적인유전자로는 platelet driven growth factor receptor alpha (PDGFRA), platelet driven growth factor receptor beta (PDGFRB), fibroblast growth factor receptor 1 (FGFR1) 등이있다. 2008년 World Health Organization에서는조혈세포종양의분류에서이러한유전자이상과연관된클론성호산구증가증을 PDGFRA, PDGFRB, FGFR1 유전자변이와호산구증가증이동반된골수성 / 림프구성종양 이라는새로운범주로추가하였다. 그러나실제과다호산구증가증후군환자에서이러한유전자변이가발견되는경우는매우드물다. 저자들은갑작스러운호흡곤란, 기좌호흡등을주소로내원한 Correspondence to: Jae-Woo Kwon Department of Internal Medicine, Kangwon National University Hospital Kangwon National University School of Medicine, 156 Baengnyeong-ro, Chuncheon 24289, Korea Tel: , Fax: , legent@hanmail.net Received: January 4, 2017 Revised: January 22, 2017 Accepted: April 26, The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (

권재우외 PDGFRB 유전자재배열과다호산구증가증 환자에서 PDGFRB 재배열을동반한과다호산구증가증의심근침범을진단하고, 성공적으로치료한 1예를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 42세, 남자주소 : 1주일전부터심해진호흡곤란현병력 : 이전특이병력없던환자로 6개월전부터야간에기침을하였으며, 최근 2개월간 7 kg 가량의체중감소가있었다.

진찰소견 : 혈압 130/80 mmhg, 분당맥박수 118회, 분당호흡수 22회, 체온 36.9 C, 산소포화도 (SpO 2) 91% 였으며, 만성병색이었고의식은명료하였다. 두경부검진상특이소견없었고, 흉부청진에서호흡음은정상이었고심음은규칙적이었으나이완기심잡음이청진되었다.

2 g/dl, 혈소판 40,000/μL였으며, 백혈구감별계산에서호중구 41%, 림프구 6%, 단핵구 1%, 호산구 24% ( 계산된값 : 13,200/μL), 호염구 1%, 모세포 27% (promyelocyte 1%, myelocyte 20%, metamyelocyte 3%, band form 3%) 였다. 동맥혈가스분석에서 ph 7.

2 권재우외 PDGFRB 유전자재배열과다호산구증가증 환자에서 PDGFRB 재배열을동반한과다호산구증가증의심근침범을진단하고, 성공적으로치료한 1예를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 42세, 남자주소 : 1주일전부터심해진호흡곤란현병력 : 이전특이병력없던환자로 6개월전부터야간에기침을하였으며, 최근 2개월간 7 kg 가량의체중감소가있었다. 1개월전부터가슴답답함과운동시호흡곤란이있었으며 1주일전부터호흡곤란과기좌호흡이심해졌고, 누웠을때가슴을누르는듯한통증이있어응급실로내원하였다. 과거력 : 특이병력없었고, 비염이나천식, 기타알레르기질환의병력은없었다. 최근복용한약물은없었고, 생식력은뚜렷하지않았다가족력 : 특이사항없었다. 사회력 : 15갑년의흡연자였으며, 직업은영업직사원이었다. 진찰소견 : 혈압 130/80 mmhg, 분당맥박수 118회, 분당호흡수 22회, 체온 36.9 C, 산소포화도 (SpO 2) 91% 였으며, 만성병색이었고의식은명료하였다. 두경부검진상특이소견없었고, 흉부청진에서호흡음은정상이었고심음은규칙적이었으나이완기심잡음이청진되었다. 경부, 액와부및서혜부에서림프절은촉진되지않았고, 복부검진에서장음은정상이었고, 압통이나반발통은없었으며, 간이나비장의비대도없었다. 피부의이상소견은없었으며하지의함요부종이나늑골척추각압통은없었다. 검사소견 : 내원시시행한말초혈액검사에서백혈구 55,000/μL, 혈색소 10.2 g/dl, 혈소판 40,000/μL였으며, 백혈구감별계산에서호중구 41%, 림프구 6%, 단핵구 1%, 호산구 24% ( 계산된값 : 13,200/μL), 호염구 1%, 모세포 27% (promyelocyte 1%, myelocyte 20%, metamyelocyte 3%, band form 3%) 였다. 동맥혈가스분석에서 ph 7.400, PaCO mmhg, PaO mmhg, HCO mmol/l였으며, 아스파르테이트아미노전달효소 16 IU/L, 알라닌아미노전달효소 13 IU/L, 총빌리루빈 1.3 mg/dl, 혈액요소질소 13.2 mg/dl, 크레아티닌 1.0 mg/dl, 젖산탈수소효소 (lactate dehydrogenase) 505 U/L, B형나트륨이뇨펩티드 (B-type natriuretic peptide) 914 pg/ml였다. 기생충분변검사와간흡충, 폐흡충, 유구낭미충, 스파르가눔, 개회충항체검사는모두음성이었으며, 혈청검사상총혈청면역글로불린 E는 85.8 IU/mL, 트립신분해효소 (tryptase) 14.6 μg/l, 비타민 B 12 >2,000 pg/ml였다. 트로포닌-I ng/ml, creatine kinase-myocardial band (CK-MB) 1.12 ng/ml로정상이었고, 내원당시심전도는동성서맥외이상소견없었다. 폐색전증평가를위한흉부전산화단층촬영소견에서폐색전은없었으나호산구의심장침범이의심되었고, 심초음파에서심박출율은 45% 가량이고, 좌심실내막을따라앞쪽, 중격, 뒤쪽벽에걸쳐유두근을포함하여 1.5 cm 두께의고에코 (hyperechoic) 병변이관찰되어침윤성심질환이의심되는소견과함께좌심실의광범위한혈전형성이관찰되었다 (Fig. 1). 말초혈액도말검사에서호산구증가증 (37%, 20,272/μL) 과뚜렷한혈소판감소증이있었으며, 적혈구부동증이있는정적혈구성정색소성빈혈 (normocytic normochromic anemia with anisocytosis), 백적혈구모세포반응 (leukoerythroblastic reaction; myelocyte 7%, metamyelocyte 3%, band form 8%) 이있었다. 이에골수검사와함께염색체이상과유전자변이에대한검사를시행하였다. 골수검사와유전자변이검사결과에서골수의세포충실도는 90% 이상으로증가된소견이었으며, 골수염색체검사에서분석한 20개중기세포모두에서 t(5; 12)(q33;p13) 염색체이상이관찰되었다. 염색체이상을 200개세포에서관찰한바 86.5% 인 173개세포에서 5q33 (PDGFRB) FISH: nuc ish(pdgfrb 2)(3'PDGFRb sep 5'PDGFRb 1) 양성으로확인하여 PDGFRB 재배열을동반한골 A B C Fig. 1. Transthoracic echocardiography image showing cardiac involvement of hypereosinophilia. (A) Parasternal long-axis view demonstrates a hyperechoic mobile mass ( cm size) suggesting thrombus (white arrow) at the postero-lateral myocardial wall. (B) Apical 4-chamber view demonstrates a large thrombus filling the left ventricular cavity (yellow arrows) and a hyper-mobile thrombus (white arrow) at the myocardial wall. This view also shows the endomyocardial fibrosis extending along lateral wall of the ventricle (arrowheads). (C) The posterior mitral valve leaflet has suffered tissue injury and it has developed moderate to severe eccentric mitral regurgitation (color doppler)

3 Kwon JW, et al. Hypereosinophilia with PDGFRB rearrangement Eosinophilia (/μl) 16,000 14,000 12,000 10,000 8,000 6,000 4,000 2, Troponin-I (ng/ml) Day Right ankle pain Right femoral~foot pain LV Thromboembolectomy Methylprednisolon 120 mg/day (2 mg/kg) 500 mg/day 250 mg/day 20 mg/day Hydroxyurea 1,000 mg/day Imatinib 100 mg/day Fig. 2. Clinical course and medications. LV, left ventricle. 수종양 (myeloid and lymphoid neoplams with eosinophilia and abnormalities of PDGFRb) 으로진단하였다. PDGFRA FISH, BCR-ABL(9:22) FISH 검사는모두음성이었다. 임상경과및치료 : 환자는중환자실에서심부전에대한치료와헤파린정주를시작하였으며, 전신스테로이드 methylprednisolone 2 mg/kg/day 를투약하였다. 전신스테로이드투약다음날, 말초혈액호산구는백혈구 65,300/μL, 호산구 5% (3265/μL) 로감소하였으나 Troponin-I 와 CK-MB 수치가상승하여 3일후감소하였고, 심전도의변화는뚜렷하지않았다 (Fig. 2). 환자의호흡곤란은비슷하였고가슴통증은없었으나, 원인이뚜렷하지않은오른쪽발목부위의심한통증을갑작스럽게호소하였는데, 부종이나피부변화등은없었으며, 신체검진과방사선사진에서도이상소견을찾을수없었다. 헤파린정주지속하며보던중오른쪽다리의저린양상의통증을호소하여시행한혈관조영방사선단층활영에서복부대동맥과슬와동맥의혈전소견이관찰되어좌심실혈전제거술과복부대동맥, 우측신동맥과슬와동맥혈전제거술을시행하였다. 골수검사에서 PDGFRB 재배열확인후 imatinib 100 mg/day 투약을시작하였고, 전신스테로이드는서서히감량하여 2개월가량사용후중단하였다. 이후에는 imatinib 100 mg/day 투약만으로말초호산구수치가정상범위로유지되고있으며, 1년마다중합효소연쇄반응 (polymerase chain reaction, PCR) 을통해 FIP1L1-PDG- FRB 돌연변이가음전됐음을확인하고있다. 고찰과다호산구증가증은대부분이차적호산구증가증이원인이며, 원인을알수없는호산구증가증환자에서도실제 PDGFRA, PDGFRB, FGFR1 유전자변이는매우드문것으로알려져있다. 이 중비교적가장흔한것으로알려진염색체이상은염색체 4q12의결손에의한 FIP1L1-PDGFRA(F/P) 융합이며, 이외 PDGFRB와 FGFR1의유전자변이는보다희귀한것으로알려져있다. 1 국내사례로는 PDGFRA 재배열호산구증가증이 5건, 2 PDGFRB 재배열호산구증가증이본사례를포함하여 3건, 3,4 FGFR1 변이가 4건보고되어있다. 5 PDGFRB 재배열에의한호산구증가증은 1987년 Keene 등 6 에의해처음보고된이후, Golub 등에의하여 ETV6-PDGFRB 융합유전자가밝혀졌다. 7,8 발생연령은다양하지만중앙값으로는매우젊은나이에나타나며, 남성에서휠씬호발하는것으로알려져있다. 8 말초혈액의호산구증가증의정도는다양한것으로알려졌으며빈혈이나혈소판감소를동반하기도한다. 8 또한호산구의심장침범으로인한심부전도보고되고있다. 9,10 국내사례의경우이번증례의 43세남자외에, 피로감을주소로내원한 82세여자와심부전과뇌경색을보여사망한 50세남자의사례가각각보고되었다. 3,4 국내사례에서호발하는연령이나성별은해외문헌에알려진것과는다소차이가있는것처럼보이는반면, 5 심장침범은비교적흔한것으로생각된다. 이러한 PDGFRB 재배열에의한클론성호산구증가증의진단은호산구가증가된상태의만성골수성종양에서 t(5;12)(q31-q33;p12) 혹은다양한전위가존재하거나, ETV6-PDG- FRB 융합유전자혹은 PDGFRB 재배열을증명하여진단한다. 4,8 이러한진단이중요한이유는 PDGFRA 재배열과마찬가지로 11 PDGFRB 재배열에의한골수종양도 imatinib 치료가매우성공적이기때문이다. 12 Imatinib 사용전에는중앙생존기간 (median survival time) 이 2년이내였으나 imatinib 도입이후에는중앙생존기간이 65개월로보고된바있다. 12 PDGFRB 유전변이가동반된골수성종양은드문질환으로아직치료와평가방법이표준화되어있지않다. 그러나호산구증가증을동반한만성골수증식성종양 234

4 권재우외 PDGFRB 유전자재배열과다호산구증가증 의경우 imatinib 중단하면많은수에서재발 (molecular relapse) 한다고알려져있어반응을유지할수있는최소용량을지속적으로투약하는것이일반적이다. 13,14 또한치료의평가는일반혈액검사와 PCR를통한 FIP1L1-PDGFRB 음전을확인하는것으로평가주기등은환자개개인의상태에따라다를수있다. 12 과다호산구증가증후군의장기침범은보고마다차이를보이지만, 피부, 심장, 신경, 호흡기, 비장, 간, 소화기등의순으로보고되었다. 15 특히, PDGFRA, PDGFRB, FGFR1 등의유전자변이를동반한클론성호산구증가증및골수증식형과다호산구증가증후군 (myeloproliferative HES) 에서심장침범을잘하는것으로알려져있으며, 과다호산구증가증후군에의한사망의가장중요한원인으로알려져있다. 15 호산구에의한심장손상은 3단계로나타나는데, 16 급성괴사성단계는초기수주간에발생하며심내막손상, 호산구및림프구의심근침윤, 심근괴사, 호산구탈과립과미세농양형성이나타난다. 급성기에는환자가정상적인심장소견을보이거나심장초음파검사가정상일수있다. 반면, 혈청트로포닌상승은심근병증을조기에발견할수있는방법이며심근괴사의발생의지표로알려져있다. 17 두번째단계는손상된심실내막을따라혈전이형성되는단계이며, 세번째단계는섬유화단계로힘줄끈 (chordae tendineae) 의섬유화에따른움직임제한으로판막역류증이나타나고, 심내막의섬유화로제한성심근병증이나타난다. 과다호산구증가증후군환자는종종혈전이형성되고섬유화된단계로내원하는데, 주로호흡곤란, 가슴통증, 심부전증상, 심잡음, 심비대등의임상증상을보이며, 심초음파와심장자기공명영상을통하여심내혈전과심내막의섬유화를관찰할수있다. 후기단계호산구성심질환환자는심부전에대한치료와필요시밸브교체수술등을시행한다. 이번증례의환자의경우내원당시급성기를지나혈전이형성된상태로트로포닌이정상범위였던것으로생각하며, 이후치료과정에서단기간의상승을보였다. 심장침범외좋지않은예후를시사하는인자로는높은백혈구수 (> 90,000 cells/μl), 빈혈및혈소판감소증등이있으며이는골수증식성질환을시사하고, 18 혈중비타민 B 12, 트립신분해효소의증가도나쁜예후인자로알려져있다. 5 한편, 혈관부종과스테로이드에대한반응, 혈중 IgE 증가는좋은예후인자로알려져있다. 19,20 이증례는심장을침범한과다호산구증가증후군으로내원한환자에서골수검사와유전자변이검사를통하여 PDGFRB 재배열을동반한골수종양으로진단하고, 심실혈전절제술과판막치환술을시행하였으며 imatinib 치료를통하여잘조절된사례이다. PDFGRB 변이를동반한과다호산구증가증은매우드물며, 심장을침범한환자에서심장수술과 imatinib 치료를통하여잘조절된첫번째국내사례로서문헌고찰과함께보고하는바이다. REFERENCES 1. Haferlach T, Bacher U, Kern W, Schnittger S, Haferlach C. The diagnosis of BCR/ABL-negative chronic myeloproliferative diseases (CMPD): a comprehensive approach based on morphology, cytogenetics, and molecular markers. Ann Hematol 2008;87: Kim TH, Gu HJ, Lee WI, Lee J, Yoon HJ, Park TS. Chronic eosinophilic leukemia with FIP1L1-PDGFRA rearrangement. Blood Res 2016;51: Kim M, Lim J, Lee A, Park G, Kim Y, Han K, et al. A case of chronic myelomonocytic leukemia with severe eosinophilia having t(5;12)(q31;p13) with t(1;7)(q10;p10). Acta Haematol 2005;114: Jang SE, Kang HJ, Chang YH, Lee DS, Kim HT, Koh KW, et al. A case of myeloid neoplasm with the PDGFRB rearrangement and eosinophilia. Korean J Med 2010;78: Shin SY, Jung CW, Choi DC, Lee BJ, Kim HJ, Kim SH. Chronic eosinophilic leukemia with a FIP1L1-PDGFRA rearrangement: Two case reports and a review of Korean cases. Blood Res 2015;50: Keene P, Mendelow B, Pinto MR, Bezwoda W, MacDougall L, Falkson G, et al. Abnormalities of chromosome 12p13 and malignant proliferation of eosinophils: a nonrandom association. Br J Haematol 1987;67: Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994;77: Bain BJ, Fletcher SH. Chronic eosinophilic leukemias and the myeloproliferative variant of the hypereosinophilic syndrome. Immunol Allergy Clin North Am 2007;27: Walz C, Metzgeroth G, Haferlach C, Schmitt-Graeff A, Fabarius A, Hagen V, et al. Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor beta gene. Haematologica 2007;92: Wittman B, Horan J, Baxter J, Goldberg J, Felgar R, Baylor E, et al. A 2-year-old with atypical CML with a t(5;12)(q33;p13) treated successfully with imatinib mesylate. Leuk Res 2004;28 Suppl 1:S Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348: David M, Cross NC, Burgstaller S, Chase A, Curtis C, Dang R, et al. Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders. Blood 2007;109: Jovanovic JV, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G, et al. Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood 2007; 109: Klion AD, Robyn J, Maric I, Fu W, Schmid L, Lemery S, et al. Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDG- FRA-positive chronic eosinophilic leukemia: implications for optimal dosing. Blood 2007;110: Ogbogu PU, Bochner BS, Butterfield JH, Gleich GJ, Huss-Marp J, Kahn JE, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 2009;124: e Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994;83:

5 Kwon JW, et al. Hypereosinophilia with PDGFRB rearrangement 17. Pitini V, Arrigo C, Azzarello D, La Gattuta G, Amata C, Righi M, et al. Serum concentration of cardiac Troponin T in patients with hypereosinophilic syndrome treated with imatinib is predictive of adverse outcomes. Blood 2003;102: Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975;54: Lefebvre C, Bletry O, Degoulet P, Guillevin L, Bentata-Pessayre M, Le Thi Huong Du, et al. Prognostic factors of hypereosinophilic syndrome. Study of 40 cases. Ann Med Interne (Paris) 1989;140: Podjasek JC, Butterfield JH. Mortality in hypereosinophilic syndrome: 19 years of experience at Mayo Clinic with a review of the literature. Leuk Res 2013;37:

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7.Æ¯Áýb71ÎÀ¯È« š J KMA Special Issue Myelodysplastic Syndrome June Won Cheong, MD Yoo Hong Min, MD Department of Internal Medicine, Yonsei University College of Medicine E mail : jwcheong70@yumc.yonsei.ac.kr minbrmmd@yumc.yonsei.ac.kr