Min Jung Kim, et al.:a case Report of Classical C Pediatric Patient in Korea 낭성섬유증유병률은국가, 인종별로큰차이를보이고있다. 낭성섬유증은백인에서가장흔한유전질환중하나로 2,000-4,000 명의출생아중 1명나

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1 소아알레르기호흡기 : 제 21 권제 1 호, pp61~66, 2011 년 1) 반복적인가래기침을주소로내원한 9 세여아에서발견된낭성섬유증 1 례 : CTR 유전자변이 D339Y, Q220X 연세대학교의과대학소아과학교실및알레르기연구소, 약리학교실 *, 영상의학교실 김민정ㆍ강정완ㆍ이지현 * ㆍ김경원ㆍ손명현ㆍ이민구 * ㆍ김명준 ㆍ김규언 A case Report of a Classic Cystic fibrosis Pediatric Patient in Korea Carrying Very Rare CTR Gene Mutations (D993Y and Q220X) Min Jung Kim, M.D., Jung Wan Kang, M.D., Ji Hyun Lee, Ph.D. *, Kyung Won Kim, M.D., Myung Hyun Sohn, M.D., Min Goo Lee, M.D. *, Myung-Joon Kim, M.D., and Kyu-Earn Kim, M.D. Department of Pediatrics and Institute of Allergy, Department of Pharmacology*, Department of Diagnostic Radiology, Yonsei University College of Medicine, Seoul, Korea Cystic fibrosis is the most common autosomal recessive disease in Caucasian. Cystic fibrosis is caused by cystic fibrosis transmembrane conductance regulator (CTR) gene mutations that lead to dysfunction of chloride ion channel regulations in the epithelium. Cystic fibrosis can affect multiple organ functions, resulting in various signs and symptoms. Typically, chronic airway infection, maldigestion, failure to thrive, and male infertility can occur. There are approximately 1800 CTR gene mutations which have been identified thus far. However, there are only a few types of mutations reported in Korea because the prevalence of the disease is different among ethnicitiess and nations. Despite its rarity, reports of CTR mutations or diagnosed patients on the rise. Therefore, we have to detect better outcomes as early as possible based on a precise understanding of the disease entity. We report a 9-year-old girl carrying D339Y and Q220X gene mutations, as the first case report of a D339Y mutation in Korea. [Pediatr Allergy Respir Dis(Korea) 2011;21:61-66] Key Words : Cystic fibrosis, CTR gene mutation, Korea 서 낭성섬유증 (Cystic fibrosis, C) 은상염색체열성유전질환으로 7번염색체장완에위치하는낭성섬유증막전도조절유전자 (cystic fibrosis transmembrane conductance regulator, CTR) 의변이에의해나타난다. CTR 론 접수 : 2010 년 11 월 2 일, 승인 : 2011 년 3 월 9 일책임저자 : 손명현, 서울시서대문구성산로 250 연세대학교의과대학소아과학교실 Tel : 02) ax. : 02) mhsohn@yuhs.ac 유전자는폐, 부비동, 췌장, 생식기내상피세포의염소이온통로 (chloride channel) 기능에관여하는유전자이다. 따라서 CTR 유전자변이로인한낭성섬유증은염소이온통로의양적또는기능적저하로인해땀샘을비롯한호흡기와췌장을포함한소화기계, 생식기계의외분비샘이상을초래하여다양한임상증상을유발하게된다. 1-4) 즉, 반복적인호흡기감염과소화불량, 성장부진및남성불임등의다양한임상경과를보이며, 이중만성기침과가래, 부비동염, 반복되는폐렴등의호흡기증상이가장대표적인증상이며예후에관여하는가장중요한요소로알려져있다. 3)

Min Jung Kim, et al.:a case Report of Classical C Pediatric Patient in Korea 낭성섬유증유병률은국가, 인종별로큰차이를보이고있다. 낭성섬유증은백인에서가장흔한유전질환중하나로 2,000-4,000 명의출생아중 1명나타나신생아선별검사를시행하고있다.

2 Min Jung Kim, et al.:a case Report of Classical C Pediatric Patient in Korea 낭성섬유증유병률은국가, 인종별로큰차이를보이고있다. 낭성섬유증은백인에서가장흔한유전질환중하나로 2,000-4,000 명의출생아중 1명나타나신생아선별검사를시행하고있다. 그러나아시아인에게는매우드물어 90,000 명중 1명으로추정된다. 5) 특히우리나라의경우현재까지몇몇증례보고만있었을정도로드문질환이다 ) 낭성섬유증을진단하기위해서는첫째, 만성호흡기질환이나소화불량에따른성장저하, 남성생식기이상등의특징적인임상경과를보이거나, 둘째, 가족중낭성섬유증환자가있는경우, 또는셋째, 신생아선별검사상양성인경우중한가지를만족해야한다. 여기에 CTR 유전자이상, 땀염소농도 60 meq/l 이상, 또는비강상피세포에서의이온전달이상을확인한경우에낭성섬유증으로진단할수있다. 1-4) 본증례에서는반복되는호흡기증상을주소로내원한 9 세여아에서땀염소농도검사로낭성섬유증을진단받고유전자검사를통해서로다른 2개의 CTR 유전자변이가확인된 1례에대하여문헌고찰과함께보고하고자한다. 증례환아 : 이, 여아, 9년 8개월주소 : 4년전부터반복되는기침, 가래과거력및가족력 : 재태주령 38 주, 출생체중 2.5 kg으로정상질식분만하였으며주산기문제는없었다. 생후 3일경부터반복되는구토로생후 10 일째타병원소아외과입원하 여태변성장폐색증 (meconium ileus) 진단하에장절제술및회장루시행받았다. 생후 1개월경패혈증으로타병원입원치료받았고생후 3개월에는폐렴으로타병원입원하여기도삽관및기계호흡치료받은과거력있으며생후 5개월과 6세, 7세에도 5차례폐렴으로본원에서입원치료받았다. 생후 5개월폐렴입원치료중원인불명의저나트륨혈증및저염소혈증지속되는소견보였으나보존적치료후회복되었다. 환아는이후저신장으로외래추적관찰중이었다. 예방접종은예정대로시행하였으며가족력상특이소견없었다. 현병력 : 4년전천식진단받고외래에서추적관찰중이다가 2년전부터 fluticasone propionate/salmeterol 50/ 100 μg 하루 2회흡입하면서조절하던환아로가래기침이호전과악화가반복되어외부병원에서시행한흉부방사선사진상결핵의심되어내원하였다. 진찰소견 : 내원당시몸무게 24 kg (10-25 백분위수 ), 신장 132 cm (10-25 백분위수 ) 였고활력징후상특이소견없었다. 환아는아파보이지않았고창백하거나청색증도없었다. 흉부소견상호흡음은다소거칠고양측으로경도의천명음이들렸으나흉곽함몰은보이지않았다. 그외다른이상소견은보이지않았다. 검사소견 : 내원당시시행한말초혈액소견상혈색소 14.1 g/dl, 적혈구용적 41%, 백혈구 15500/mm 3 ( 중성구 71%, 림프구 23%, 단핵구 3%, 호산구 0.6%), 혈소판 422,000/mm 3 이었으며일반화학검사상특이소견없었다. 투베르쿨린검사 (Tuberculin test) 는음성이었고결핵균특이항원자극 QuantiERON -TB Gold In Tube (QT-G IT, Cellestis Limited, Carnegie, Victoria, ig. 1. (A) Plain chest X-ray shows diffuse nodular densities in both lungs. (B) Water's view shows both maxillary sinusitis

김민정들 : 반복적인가래기침을주소로내원한 9 세여아에서발견된낭성섬유증 1 례 ig. 2. Multiple tiny air-space nodules are seen in both lung fields. Also bronchiectasis in both lungs are observed on computer tomographic imaging. ig. 3.

(B) There are SNPs in exon 16 of, P, B and S. Abbreviations :, father; M, mother; P, patient; B, brother; S, sister Australia) 결과도음성이었다.

3 김민정들 : 반복적인가래기침을주소로내원한 9 세여아에서발견된낭성섬유증 1 례 ig. 2. Multiple tiny air-space nodules are seen in both lung fields. Also bronchiectasis in both lungs are observed on computer tomographic imaging. ig. 3. Denaturing gradient gel electrophoresis (DGGE) results of the patient and her family. (A) There are single nucleotide polymorphisms (SNPs) in exon 6a of M and P. (B) There are SNPs in exon 16 of, P, B and S. Abbreviations :, father; M, mother; P, patient; B, brother; S, sister Australia) 결과도음성이었다. 가래검사상항산균 (acid fast bacillus, AB) 도말검사음성, 결핵균배양검사도음성으로나타났으나, 세균배양검사상 Staphylococcus aureus와 Stenotrophomonas maltophilia가동정되었다. 방사선학적소견 : 흉부방사선사진상폐는과팽창되어있었으며양측으로미만성결절상음영이관찰되었다.(ig. 1A) 고해상전산화단층촬영에서는폐실질내작은공기음영결절과기관지벽두께증가및기관지확장증이관찰되었다.(ig. 2) 우상엽에서는분절하성무기폐가관찰되었으며우하엽에는점액전형성소견도보였다. 부비동사진에서는양측만성상악동염소견이관찰되었다.(ig. 1B) 땀염소농도검사 : 양측상완에서 30분동안땀을채취하여왼쪽에서 238 μl오른쪽에서 229 μl의땀을채취할수있었다. National Committee for Clinical Laboratory Standards (NCCLS) 에의거하여 5분간 pilocarpine iontophoresis 를시행하였고 Mercuricmetric titration 법으로측정 6) 한결과땀염소농도는왼쪽 71.1 mmol/l, 오른쪽 71.1 mmol/l, 평균 71.1 mmol/l 로낭성섬유증에합당한소견을보였다. 환아오빠의땀염소농도는 37.2 mmol/ L, 아빠는 24.6 mmol/l 로음성이었고, 엄마와여동생은검사하지않았다. 유전학적소견 : 변이유전자를검출하기위한 denatur

4 Min Jung Kim, et al.:a case Report of Classical C Pediatric Patient in Korea ing gradient gel electrophoresis (DGGE) 를시행하여 CTR 변이위치를확인한뒤확인된부분의염기서열을분석하였다.(ig. 3) 12) 본환아의경우, CTR 유전자에서 Q220X와 D993Y, 2개의변이가발견되었다. 부모의 CTR 유전자검사까지함께시행한결과 Q220X 는엄마로부터, D993Y는아빠로부터유전된것을확인할수있었다.(ig. 4) 고 낭성섬유증은미국의경우그수가전체인구중 3만명정도인것으로알려져있으나미국내에서도흑인은 15,000 명에 1명, 아시아계는 30,000 명에 1명꼴로인종에따른차이를보인다. 5) 지역적으로는북미와유럽중심으로나타나고동아시아의경우특히드물어일본에서는이질환 ig. 4. A pedigree of the patient diagnosed as cystic fibrosis. 2 kinds of disease-causing mutations are found in this patient. Q220X mutation is from her mother, and D993Y came from her father. In the other words, her parents are unaffected carriers. She has 2 siblings possessing D993Y. Both of them are not only the unaffected but also carriers. 찰 의유병률을 35,000명에 1명정도로추정 7, 8) 하고있다. 중국의경우, 과거 20년동안불과 20여개의증례보고가있었다. 9) 또한전세계적으로 1800여개의 CTR 변이유전자가보고 11) 되었지만이역시인종별, 지역별로유형및분포에차이가있으며 10-12) 국내에서는현재까지 15개의변이가보고되었다. 이중전세계적으로변이유전자의 70% 이상을차지하는 508 2, 3) 은단 1차례보고되었다. 본증례에서환아는출생직후태변성장폐색증으로수술받았고폐렴으로여러차례입원치료를받은과거력이있었으며천식으로진단받고흡입치료를받는중이었다. 만성적인가래기침외에지방변이나영양불균형소견은없었다. 고해상단층촬영을통하여만성호흡기질환으로진행하고있음을알수있었고땀염소농도검사로낭성섬유증을진단하였다. 추가적인유전자검사를통해 D993Y, Q220X 2개의변이가확인되었다. D993Y 변이유전자는 exon16 에위치하며 1995 년프랑스에서발표 11) 된이후보고된바없고우리나라에서는처음보고되는것으로그의미가있다. 또다른 Q220X변이유전자는 exon6a 에위치하고 1994년영국에서처음보고 13) 된이후프랑스와우리나라에서각각 1차례씩추가보고된바있다. 14) 가족내비슷한증상을보이거나검사결과이상은없었다. 현재까지우리나라에서보고된 7개의증례 14-20) 를검토한결과, 이중 5명은본환아와같이만성호흡기감염을주소로내원하였고이중 1명은태변성장폐색증으로수술받은과거력 18) 도있었다. 대상환아의연령이너무어리거나 17) 전반적인상태가좋지않아 18) 땀염소검사를시행하지않은경우가 2명있었으며임상증상및땀염소농도검사상낭성섬유증으로진단되었으나유전자검사상질병과관련없는다형성만확인 16) 되었거나하나의변이유전자 Table 1. Summary of Cystic ibrosis Pediatric Patients Reported in Korea Case Age at diagnosis Sex Sweat chloride test Genetic analysis Clinical history Mutation 1 15) 2 16) 3 14) 4 17) 5 18) 6 19) 7 20) 4 mo 9 yr 6 yr 15 yr 2 d 4 mo 9 yr 5 yr M M M not evaluated not evaluated not evaluated Meconium ileus, Chronic cough Chronic cough, Poor growth Meconium ileus only Meconium ileus, Respiratory difficulty Pancreatic insufficiency, not evaluated Q1291, IVS8 T5-M470V polymorphism Q98R, Q220X Q98R, Q1352H c.263t>g, c insa c t>c, c.3908dupa L441P in one allele Abbreviations : mo, month; yr, years; d, days; M, male;, female

5 김민정들 : 반복적인가래기침을주소로내원한 9 세여아에서발견된낭성섬유증 1 례 만발견된변이형낭성섬유증환아 20) 도각각 1명씩있었다. 반면, 본증례와같이전형적인임상증상및경과를보이며땀염소농도검사에서낭성섬유증을확진받고서로다른 2개의변이유전자까지확인된경우는 3명 14, 16, 19) 이었다.(Table 1) 낭성섬유증은광범위한장기를침범하여증상을유발하며변이발현시기및진단당시연령, 증상정도에따라다양한예후 4) 를보인다. CTR 변이유전자유형에따라특이장기침범이두드러지게나타나는경우도있지만최근연구에따르면같은유전자변이라하더라도증상의발현정도는지역이나인종, 환자의나이에따라다르며특히질병이진행할수록유전적영향보다는환경, 감염등과같은인자들에따른영향이예후에더크게작용하는것으로나타났다. 26) 전형적인낭성섬유증환자는영아기에는태변성장폐색, 지방변, 성장부전을보이다학동기연령으로성장하면서반복되는호흡감염이나천식증상을보이며청소년기이후에는만성호흡기질환, 인슐린의존성당뇨, 췌장염, 남성불임등으로발현될수있다. 특히, 만성호흡기질환은 S. aureus 나 P. aeuroginosa 같은세균성폐렴이나폐농양, 기관지확장증을동반하고폐섬유화로까지진행할수있어낭성섬유증환자의이환율과사망률에가장큰영향을주는 2, 4) 것으로알려져있다. 발병률이높은미국과유럽에서는이미신생아선별검사를통한조기진단 21, 22) 과변이유형에대한연구 3, 5) 적극적인추적관찰로평균진단연령은 6개월, 평균수명연령은 36.9세 23) 로까지발전하였다. 또한진단된환자및가족은전문화된기관에서정기적인추적관찰을통해영양상태를평가하고 2차적인감염과증상발현을예방하고있으며유전상담을시행 24, 25) 하고있다. 현재우리나라의경우낭성섬유증에대한신생아선별검사를시행하는것은비용-가치측면에서불합리하나최근증례및새로운변이유전자에대한보고가증가하는추세로국내에서도질환에대한이해가필요하며적극적인진단및합병증을예방하려는노력이필요하다. 본증례와같이태변성장폐색등의과거력이있고만성호흡기증상을보이는환아의경우가족력과관계없이땀염소농도검사등의추가검사를통하여낭성섬유증여부를확인해야할것이다. 낭성섬유증에대한적극적인진단을통하여질병의진행을예방하고환자의삶의질및예후향상에도움이될것으로기대된다. 요 낭성섬유증은막전도조절유전자의변이에의해나타나는상염색체열성질환으로국가와인종에따라발병률에차이를보이며우리나라에서는매우드문질환이다. 연령및침범한기관에따라다양한증상및경과를보여반복되는기침이나만성부비동염, 소화불량또는성장부전. 남성불임까지유발할수있으며, 점차말단장기로진행하여만성호흡기질환및췌장기능부전등의치명적인결과를초래하기도한다. 이미미국이나유럽에서는신생아선별검사를통한조기진단및정기적인추적관찰, 유전연구등으로진단및예후에큰변화를보였으나국내의경우몇몇증례보고만있었다. 저자들은반복적인가래기침을주소로내원했던 9세여아에서특징적인임상경과및땀염소농도검사양성을보이며 2개의 CTR 변이유전자 (Q220X,D993Y) 가확인된낭성섬유증 1례를경험하였기에보고하는바이다. 약 참고문헌 1) lume PA, Stenbit A. Making the diagnosis of cystic fibrosis. Am J Med Sci 2008;335: ) Wallis C. Diagnosis and presentation of cystic fibrosis. In: Chernick V, Boat T, Wilmott R, Bush A, editors. Kendig s Disorders of the Respiratory tract in Children. 7th ed. Philadelphia, Pa: Saunders Elsevier, 2007: ) Moskowitz SM, Chimel J, Sternen DL, Cheng E, Gibson RL, Marshall SG, et al. Clinical practice and genetic counseling for cystic fibrosis and CTR-related disorders. Genet Med 2008;10: ) arrell PM, Rosenstein BJ, White TB, Accurso J, Castellani C, Cutting GR, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic ibrosis oundation Consensus Report. J Pediatr 2008;153: S ) Bobadilla JL, Macek M Jr, ine JP, arrell PM. Cystic fibrosis: A worldwide analysis of CTR mutations-correlation with incidence data and application to screening. Hum Mutat 2002;19: ) Legrys VA. Sweat testing for the diagnosis of

6 Min Jung Kim, et al.:a case Report of Classical C Pediatric Patient in Korea cystic fibrosis : practical considerations. J Pediatr 1996;129: ) Imaizumi Y. Incidence and mortality rates of cystic fibrosis in Japan, Am J Med Genet Aug 28;58: ) Yamashiro Y, Shimizu T, Oguchi S, Shioya T, Nagata S, Ohtsuka Y. The estimated incidence of cystic fibrosis in Japan. J Pediatr Gastroenterol Nur 1997;24: ) Li N, Pei P, Bu D, He B, Wang G. A novel CTR mutation found in a Chinese patient with cystic fibrosis. Chin Med J 2006;119: ) Julian zielenski. Geneotype and phenotype in cystic fibrosis. Respiration 2000;67: ) The Cystic fibrosis Genetic Analysis Consortium. Cystic ibrosis Mutation Database ) Lee JH, Choi JH, Namkung W, Hanrahan JW, Chang J, Song SY, et al. A haplotype-based molecular analysis of CTR mutations associated with respiratory and pancreatic disease. Hum Mol Genet 2003:12: ) Shackleton S, Hull J, Dear S, Seller A, Thomson A, Harris A. Identification of rare and novel mutations in the CTR genes of C patients in Southern England. Hum Mutat 1994;3: ) Koh WJ, Ki CS, Kim JW, Kim JH, Lim SY. Report of a Korean patient with cystic fibrosis, carrying Q98R and Q220X mutations in the CTR gene. J Korean Med Sci 2006;21: ) Moon HR, Ko TS, Ko YY, Choi JH, Kim CK. Cystic ibrosis: A case presented with recurrent bronchiolitis in infancy in a Korean male infant. J Korean Med Sci 1988;3: ) Ahn KM, Park HY, Lee JH, Lee MG, Kim JH, Kang IJ, et al. Cystic fibrosis in Korean children: A case report identified by a quantitative pilocarpine inotophoresis sweat test and genetic analysis. J Korean Med Sci 2005;20: ) Hwang IO, Lee ES. A case of cystic fibrosis presented with meconium ileus in a female neonate. Korean J Pediatr 2007;50: ) Ko JM, Kim GH, Kim KM, Hong SJ, Yoo HW. Identification of a novel mutation of CTR gene in a Korean patient with cystic fibrosis. J Korean Med Sci 2008;23: ) Choe YJ, Ko JS, Seo JK, Han JJ, Shim JO, Koh YY, et al. Novel CTR mutations in a Korean infant with cystic fibrosis and pancreatic insufficiency. J Korean Med Sci 2010;25: ) Gee HY, Kim CK, Kim SW, Lee JH, Kim JH, Kim KH, et al. The L441P mutation of cystic fibrosis transmembrane conductance regulator and its molecular pathogenic mechanisms in a Korean patient with cystic fibrosis. J Korean Med Sci 2010;25: ) Ranganathan SC, Stocks J, Dezateux C, Bush A, Wade A, Carr S, et al. The evolution of airway function in early childhood following clinical diagnosis of cystic fibrosis. Am J Respir Cirt Care Med 2004;169: ) Grosse SD, Rosenfeld M, Devine OJ, Lai HJ, arrell PM. Potential impact of newborn screening for cystic fibrosis on child survival: A systematic review and analysis. J pediatr 2006;149: ) Cystic ibrosis oundation. Patient Registry. Annual Data Report Bethesda, Maryland: Cystic fibrosis foundation 2006:17. 23) Grosse SD, Rosenfeld M, Devine OJ, Lai HJ, arrell PM. Potential impact of newborn screening for cystic fibrosis on child survival: A systematic review and analysis. J pediatr 2006;149: ) Proesmans M, Vermeulen, Boeck KD. What's new in cystic fibrosis? rom treating symptoms to correction of the basic defects. Eur J Pediatr 2008;167: ) Mogayzel PJ Jr, lume PA. Update in cystic fibrosis Am J Respir Crit Care Med 2010;181: ) Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration 2000;

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386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon