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1 대한내과학회지 : 제 89 권제 4 호 성인에서악성고혈압을동반한누난증후군 1 세종병원심장내과, 2 차의과학대학교분당차병원심장내과 엄문용 1 김원장 2 김경희 1 김유나 1 최웅 1 정영리 1 조현아 1 Case of Noonan Syndrome Presenting with Malignant Hypertension in an dult Moon-Yong Eom 1, Won-Jang Kim 2, Kyung-Hee Kim 1, Yu-Na Kim 1, Woong Choi 1, Young-Lee Jung 1, and Hyun-h Cho 1 1 Division of Cardiology, Department of Internal Medicine, Sejong General Hospital, ucheon; 2 Division of Cardiology, Department of Internal Medicine, CH undang Medical Center, CH University School of Medicine, Seongnam, Korea Noonan syndrome is an autosomal dominant disorder characterized by dysmorphic facial features, congenital heart defects and short stature. To date, renal artery stenosis has not been associated with Noonan syndrome. We report the case of a 27-year old male who presented with malignant hypertension associated with renal artery stenosis, dysmorphic facial features, pectus excavatum, pulmonary stenosis and hypertrophic cardiomyopathy who was diagnosed with Noonan syndrome. (Korean J Med 2015;89: ) Keywords: Noonan syndrome; Renal artery obstruction; Pulmonary valve stenosis; alloon valvuloplasty 서론 Noonan syndrome (NS) 은전형적인얼굴이형성증 (dysmorphic face), 선천성심장질환, 저신장등으로표현되는상염색체우성질환중하나로알려져있는데이는신생아 1,000-2,500명당 1명정도로보고되고있으며이는임상적소견으로진단한다. 이질환의진단은매우까다롭고특히성인에있어서는더욱그러하다 [1]. 대략 80% 정도의환자는심혈관질환을동반한다 [2]. 선천성심장질환중폐동맥판막협착 (pulmonary stenosis) 이가장흔하고 (25-35%) 이는종종심방중격결손증 (atrial septal defect) 을동반한다. 그외비후성심근병증 (hypertrophic cardiomyopathy, HCMP) 과부분방실결손 (partial atrio-ventricular canal defect), 대동맥판막협착 (aortic stenosis), 폐성고혈압 (pulmonary hypertension), 동맥관개존증 (patent ductus arteriosus), 가지폐동맥협착 (branch pulmonary artery stenosis), 이엽성대동맥판막 (bicuspid aortic valve), 심실중격결손증 (ventricular septal defect), 팔로사징후 (Tetralogy of Fallot), 대동맥축착증 (coarctation of aorta) 등도동반되는것으로알려져있다 [2]. 드물지만다른심혈관질환으로는대동맥박리 (aortic dissection), 확장성심근병증 (dilated cardiomyopathy), 승모판막이상 (mitral valve anomalies), 폐동맥판폐쇄 (pulmonary atresia), 대 Received: Revised: ccepted: Correspondence to Won-Jang Kim, M.D., Ph.D. Division of Cardiology, Department of Internal Medicine, CH undang Medical Center, CH University School of Medicine, 59 Yatap-ro, undang-gu, Seongnam 13496, Korea Tel: , Fax: , mdwjkim@cha.ac Copyright c 2015 The Korean ssociation of Internal Medicine This is an Open ccess article distributed under the terms of the Creative Commons ttribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

하지만 NS와동반된신동맥협착 (renal artery stenosis) 에대한보고는아직없으며이에본저자들은성인의악성고혈압에동반된신동맥협착과함께폐동맥판막협착, 얼굴이형성증, 오목가슴 (pectus excavatum) 의임상증상으로진단된 NS의증례를보고한다.

2 - The Korean Journal of Medicine: Vol. 89, No. 4, 동맥뿌리확장 (aortic root dilation), 제한성심근병증 (restrictive cardiomyopathy), 삼첨판막의엡스타인기형 (Ebstein's anomaly of tricuspid valve), 관상동맥이상 (coronary artery anomalies) 등이보고되고있다 [2]. 하지만 NS와동반된신동맥협착 (renal artery stenosis) 에대한보고는아직없으며이에본저자들은성인의악성고혈압에동반된신동맥협착과함께폐동맥판막협착, 얼굴이형성증, 오목가슴 (pectus excavatum) 의임상증상으로진단된 NS의증례를보고한다. 증례환자 : 27세남자주소 : 3년전부터시작되어 1달전부터악화된호흡곤란현병력 : 환자는내원 3년전부터 New York Heart ssociation Functional Class II (NYH Fc II) 의호흡곤란이있었으며최근내원 1달전부터 NYH Fc III로증상이악화되어외래통해내원하였다. 과거병력 : 내원 3년전고혈압을진단받았으나약은복용 하지않고있었다. 가족력및사회력 : 가족중특이병력을가진사람은없었으며주 1회회당소주 1병, 10갑년흡연력이있었다. 약물복용력 : 없음. 신체검진 : 내원당시측정한활력징후는혈압 187/113 mmhg, 맥박수 60회 / 분, 호흡 18회 / 분, 체온 36.7 였으며의식은명료하였다. 흉부청진상수축기심잡음이들렸다. 얼굴이형성증 (hypertelorism, short neck, broad forehead 등 ) 을보였으며 (Fig. 1), 오목가슴 (Fig. 1), 저신장 (161.6 cm, 5 percentile 미만 ) 을보였다 [3]. 검사실소견 : 말초혈액검사소견은정상범위내의 potassium 4.1 mmol/l를포함해 24시간뇨 vanillyl mandelic acid 2.2 mg/day, metanephrine μg/day, normetanephrine μg/day, epinephrine 8.2 μg/day, norepinephrine 46.2 μg/day, 그리고 renin 2.78 ng/ml/hr, aldosterone 11.0 ng/dl 등으로정상범위였고, antinuclear antibody도음성소견을보였다. 갑상선기능검사도정상이었다. 흉부엑스선소견 : 양폐에폐혈관음영의증가소견이관찰되었으며, 왼쪽심장경계의직선화소견을보였다. Figure 1. () Dysmorphic facial features, hypertelorism, short neck and broad forehead. () Pectus excavatum

심초음파소견 : 정상좌심실수축기능을보이며심첨부비후성심근병증 (apical HCMP) 소견에동반된심첨부로전위된유두근 (apically displaced papillary

() Transvalvular flow acceleration with post-stenotic dilation of the main pulmonary artery.

3 - Moon-Yong Eom, et al. Noonan syndrome with hypertension - 심전도소견 : 정상동성리듬이었으며좌심실비대와 I, avl, V3-6에서 T파전위가있었다. 심초음파소견 : 정상좌심실수축기능을보이며심첨부비후성심근병증 (apical HCMP) 소견에동반된심첨부로전위된유두근 (apically displaced papillary muscles) 소견을보였다. 폐동맥판막의비후와함께 main pulmonary artery (MP) 와 left pulmonary artery 가늘어나있었다. 삼첨판역류의최대속도가 4.4 m/s로측정되어우심실의수축기압력은 (4.42 4) + 우심방압력 (5 mmhg) 으로계산하면 82 mmhg 로계산되고폐동맥압력을 15/5 mmhg 로가정하면, 판막을통한압력차 Figure 2. () Transvalvular flow acceleration with post-stenotic dilation of the main pulmonary artery. () Maximal velocity of tricuspid regurgitation (4.4 m/s) and transvalvular gradient (67 mmhg = right atrial pressure - 15 mmhg). Right Figure 3. Renal artery computed tomography angiography showing > 90% stenosis (arrow) at the ostium of the right renal artery (, )

- 대한내과학회지 : 제 89 권제 4 호통권제 662 호 2015 - Figure 4. Percutaneous balloon pulmonary valvuloplasty.

(transvalvular pressure gradient) 는 67 mmhg 로중증의폐동맥판막협착증 (pulmonary valve stenosis, PS) 소견을보였다 (Fig. 2).

신동맥 CT 소견 : 오른쪽신동맥입구에심한국소적협착소견을보이고있으며, 특징적인염주알형태 (string of beads) 의섬유근육이형성증 (fibromuscular dysplasia) 소견을보이고있지는않았다 (Fig. 3).

4 - 대한내과학회지 : 제 89 권제 4 호통권제 662 호 Figure 4. Percutaneous balloon pulmonary valvuloplasty. The waist (white arrows) was well demarcated before full inflation of the balloon (), and disappeared after ballooning (). (transvalvular pressure gradient) 는 67 mmhg 로중증의폐동맥판막협착증 (pulmonary valve stenosis, PS) 소견을보였다 (Fig. 2). 24시간혈압모니터링소견 : Non-dipper 형태의고혈압소견을보였으며낮평균혈압은 167/92 mmhg, 밤평균혈압은 144/85 mmhg, 24시간평균혈압은 156/91 mmhg 로측정되었다. 신동맥 CT 소견 : 오른쪽신동맥입구에심한국소적협착소견을보이고있으며, 특징적인염주알형태 (string of beads) 의섬유근육이형성증 (fibromuscular dysplasia) 소견을보이고있지는않았다 (Fig. 3). 경피적풍선폐동맥판막성형술 (percutaneous balloon pulmonary valvuloplasty): Maxi 풍선 (20 60 mm, Cordis Corporation, ridgewater, NJ, US) 을사용하여판막성형술을시행했으며시술전 MP의압력은 15 mmhg, right ventricle 압력은 65 mmhg 로측정되었고풍선이완전히부풀리기전에좁아진판막에의해풍선중간이잘록해졌다가 ( waist ) 완전히부풀린후잘록한부분이없어진것을확인할수있었다 (Fig. 4). 신동맥혈관확장술 : 신동맥협착소견에대하여시술을시도했으나카테터진입실패로이에대해서는약물치료를계획하였다. 심장 magnetic resonance imaging (MRI) 소견 : HCMP Figure 5. Cardiac magnetic resonance imaging showing that the papillary muscle was apically displaced (*) with a lateral wall thickness of 15 mm. 소견에대한평가를위해 MRI 를시행하였으며전반적인심내막하의조영감소와함께심첨부의비대소견으로 apical HCMP (apically displaced papillary muscle) 에합당한소견을보였다 (Fig. 5). *

5 - 엄문용외 6 인. 성인악성고혈압에동반된누난증후군 - 치과파노라마엑스선소견 : 심한치아상태불량소견을보였다. 유전자검사소견 : NS 진단을위해시행한검사에서핵형 (karyotype) 은 46, XY였으며 NS와연관된유전자중 PTPN11 를분석한결과정상소견을보였다. 고찰 Noonan syndrome은 1962년에처음소개된질환으로독특한얼굴생김새 (dysmorphic face) 와선천성심장질환을포함한다양한비정상소견을그특징으로하였다. NS는비교적흔한선천성유전질환이며남녀모두에서발생가능하다. 소아청소년기에는얼굴생김새및근골격계의형태가특징적으로나타나진단이용이한반면, 이시기를지난성인에는이러한특징들이애매하므로진단을하기어려우며그진단은일반적으로 van der urgt 등 [4] 에의해제안된임상적진단기준에따른다 (Table 1). NS로확진하기위해서는전형적인얼굴이형성증 (typical face) 소견은필수적이며여기에다른 1 가지 major 소견또는 2가지 minor 소견이동반되거나, NS로의심되는얼굴생김새이상 (suggestive face) 과함께 2가지 major 소견또는 3가지 minor 소견이필요하다 [4]. 본증례는전형적인얼굴이형성증, 오목가슴의이학적소견과심초음파상 PS 및 HCMP의소견을동반하여 van der urgt 등 [4] 진단기준에따라 NS로진단하였던증례였다. 본질환은특징적으로 PS를자주동반하는것으로알려져있으며 (25-30%) [5], 본증례에서도 PS가발견되어이를경피적풍선폐동맥판막성형술을시행하여성공적으로압력차를감소시켰다. 일반적으로 7개의유전자 (PTPN11, SOS1, KRS, RF1, NRS, RF 그리고 SHOC2) 가본질환과연관되어있다고알려져 있으며 [5,6], 약 50% 이상의환자에서 PTPN11 변이가있다고알려져있으나이는절대적인진단기준은아니다 [7]. 본증례에서도대표적인유전자인 PTPN11 변이를조사하였으나정상소견을보였다. 한편, NS는자가면역질환과드물게연관되어있다고알려져있어전신홍반성낭창 (systemic lupus erythematosus), 셀리악병 (Celiac disease) 등의증례보고가있으나 [8], 명확한연관관계는아직알수없다. 본증례에서도자가면역질환이나이외의전신질환의증거를찾을수는없었다. 본질환은신장이상을 10-11% 에서동반하는데 [9], 주로단신 (solitary kidney), 신우확장 (renal pelvis dilation), 중복된집뇨계 (duplicated collecting system) 등과관련되어있는것으로알려져있다. 하지만신동맥협착과연관되어있다는보고는지금까지없다. 본증례는신동맥입구에심한협착소견을보이고이로이한악성고혈압을동반하였고이와함께호흡곤란으로내원하게되었으며임상적으로 NS로최종진단되었다. NS와신동맥협착사이의병태생리학적연관성에대해서는보고된바가없고추가적인연구가필요할것으로사료된다. 요약본저자들은호흡곤란과악성고혈압으로내원한 27세남자에대해이차성고혈압을의심하에평가하던중전형적인이학적소견및 PS 및 HCMP 소견을통해 NS로최종진단된환자에서신동맥협착소견이동반된증례를문헌고찰과함께보고한다. 한편환자에게동반된소견중폐협착에대해서는경피적풍선폐동맥판막성형술을통한시술로해결하였으며신동맥협착소견에대해서는약물치료를계획하였다. Table 1. Diagnostic features of Noonan syndrome (adapted from van der urgt et al., m J Med Genet 1994 [4]) Feature = major = minor Facial Typical face (facial features of NS vary over time and may have only Suggestive face subtle difference. Expert assessment is therefore required) Cardiac Pulmonary valve stenosis and/or hypertrophic cardiomyopathy Other cardiac defect Height < 3rd centile < 10th centile Chest wall Pectuscarinatum/excavatum road thorax Family history First-degree relative with definite NS First-degree relative suggestive of NS Other Mild developmental delay, cryptorchidism and lymphatic dysplasia Mild developmental delay, cryptorchidism, or lymphatic dysplasia NS, Noonan syndrome

6 - The Korean Journal of Medicine: Vol. 89, No. 4, 중심단어 : 누난증후군 ; 신동맥협착 ; 폐협착 ; 경피적풍선폐동맥판막성형술 REFERENCES 1. garwal P, Philip R, Gutch M, Gupta KK. The other side of Turner s: Noonan s syndrome. Indian J Endocrinol Metab 2013;17: Romano, llanson JE, Dahlgren J, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 2010;126: Ko G, Moon YJ, Chung DS, et al. The Survey of National Physical Fitness. Sejong (KR): Ministry of Culture, Sports and Tourism, c2011 [cited 2011 Dec 31]. 4. van der urgt I, erends E, Lommen E, van eersum S, Hamel, Mariman E. Clinical and molecular studies in a large Dutch family with Noonan syndrome. m J Med Genet 1994;53: oki Y, Niihori T, Narumi Y, Kure S, Matsubara Y. The RS/MPK syndromes: novel roles of the RS pathway in human genetic disorders. Hum Mutat 2008;29: Lin E, lexander ME, Colan SD, et al. Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MPK pathway syndrome. m J Med Genet 2011;155: Tartaglia M, Kalidas K, Shaw, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. m J Hum Genet 2002;70: lanay Y, alci S, Ozen S. Noonan syndrome and systemic lupus erythematosus: presentation in childhood. Clin Dysmorphol 2004;13: Sharland M, urch M, McKenna WM, Paton M. clinical study of Noonan syndrome. rch Dis Child 1992;67:

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<4D F736F F F696E74202D20BFA1C4DA5FC0D3BBF3C3CAC0BDC6C42E BC8A3C8AF20B8F0B5E55D> 심장 (Heart) 심초음파 서울대병원내과 김용진 심장은평생몇번이나뛸까요? 1) 3 백만번 2) 3 천만번 3) 3 억번 4) 30 억번 30 억박동, 2 억리터의혈액 Cause 심장질환 6.2 12.4 11.1 16.2 뇌졸중 4.3 8.5 7.7 11.3 기타심혈관질환 2.6 5.1 6.0 8.8 심혈관질환 13.1 26.0 24.8 36.3 총사망 50.4