Case Report pissn 2287-9412. eissn 2287-9803 Autosomal Recessive Polycystic Kidney Disease Confirmed to PKHD1 Gene Mutation: A Case of PKHD1 Gene Mutation Jae Eun Baek, M.D., Soon Min Lee, M.D., Ho Seon Eun, M.D., Min Soo Park, M.D., Kook In Park, M.D., Ran Namgung, M.D., and Chul Lee, M.D. Division of Neonatology, Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea ABSTRACT Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of polycystic kidney disease that is characterized by enlarged kidneys and congenital hepatic fibrosis. The clinical spectrum of this condition shows wide variation. Approximately 30-50% of affected individuals die in the neonatal period, while others survive into adulthood. ARPKD is caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene on chromosome 6p12, which consists of 86 exons variably assembled into many alternatively spliced transcripts. We report a case of a pathogenic PKHD1 frameshift mutation, c.889_931del43, which was identified using direct full sequencing, associated with enlarged cystic kidneys and dilatation of intrahepatic bile duct, as observed on imaging studies. Received: 5 September 2013 Revised: 23 September 2013 Accepted: 2 October 2013 Correspondence to: Min Soo Park, M.D. Division of Neonatology, Department of Pediatrics, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea Tel: +82-2-2228-0400 Fax: +82-2-393-9118 E-mail: minspark@yuhs.ac Key Words: Autosomal recessive polycystic kidney disease, ARPKD, PKHD1 서론 상염색체열성다낭신질환 (autosomal recessive polycystic kidney disease, ARPKD, MIM# 263200) 은신생아기에전형적으로나타나는심한유전성신질환중하나로, 1:20,000 에서 1:40,000 정도의빈도로발생한다 1,2). 이질환은양쪽신장의 collecting duct 가방사형으로팽창되는소견을보이며, 담관의과형성과선천적간섬유화를보이는간삼각 (hepatic portal triad) 의발생부전이동반된다. 또한호흡곤란, 고혈압, 요로감염이흔히나타난다 3). ARPKD 는염색체 6p21 의 PKHD1 (polycystic kidney and hepatic disease 1, MIM# 606702) 유전자의변이와관련되며, 산전초음파와함께 ARPKD 의산전진단에사용되고있으며 4) 현재까지 263 개의유전자변이가 PKHD1 database 에등록되어사용되고있다. 국내에는 ARPKD 의임상증상및산전검사상초음파와부모의유전자검사에의한진단보고들은있으나출생후 PKHD1 유전자검사로확진된보고는없었다 5,6). 본저자들은출생시부터호흡곤란증상과함께 ARPKD 소견을보이고, PKHD1 유전자돌 Copyright(c) By Korean Society of Neonatology. All right reserved. This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0), which permits unrestricted non-commercial use, distribution, and repro duction in any medium, provided the original work is properly cited.
65 연변이 (c.889_931del43) 를확인하였기에이에보고하는바이다. 증례 재태주령 38+5 주, 출생체중 3.28 kg (25-50 백분위 ) 으로출생한남아로출생시산전진찰상양수과소증보여타병원에서유도분만시행하였으며출생직후빈호흡, 경미한흉곽함몰을보이는호흡부전을주소로신생아집중치료실에내원하였다. 1분 APGAR 점수 9점, 5분 APGAR 점수 10점으로질식분만하였다. 산모는특이과거력없었으나본환아가세번째임신으로, 두번째아이는생후 3개월째원인불명으로사망한가족력이있었다. 신생아집중치료실내원시혈압 85/54(68) mmhg, 심박수 118 회 / 분, 호흡수 68회 / 분, 체온 37, 산소포화도 88% 였다. 환아는출생직후호흡부전증세로산소투여받았으며, 신생아집중치료실내원당시움직임, 울음소리는활발했으며, 피부색은분홍이었다. 환아는생김새상이상소견은보이지않았다. 입원시정맥혈가스소견상 ph 7.33, 산소분압 57 mmhg, 이산화탄소분압 40 mmhg, tco 2 23 mm/l 였으며, 말초혈액검사상혈색소 15 g/dl, 백혈구 12,940/mm 3, 혈소판 285,000/mm 3 였다. 혈중총단백 / 알부민은 5.2/3.5 g/dl, AST/ALT 55/8 IU/L, 혈청빌리루빈 ( 총 / 직접 ) 3.9/0.5 g/dl, BUN/Cr 10.5/0.7 mg/dl 이었다. 방사선소견상입원당시흉부소견은특이소견없었으며, 입원 2일째시행한심장초음파에서동맥관개존증 (3.5 mm), 심방중격결손 (5 mm), 중등도의폐고혈압소견이있었다. 입원 3일째시행한뇌초음파 Figure 1. (A, B) Both kidneys are enlarged and cystic in the abdominal ultrasonography. Figure 2. (A, B) MRI shows mild dilatation of calyceopelvis and dilatation of intrahepatic bile ducts.
66 Jae Eun Baek, et al. A Case of PKHD1 Gene Mutation 상특이소견없었고, 복부초음파상간의불균질한음영증가와 2 개의작은낭종이보이고, 양쪽신장의크기증가와함께피질- 수질의미분화소견, 여러개의낭종이관찰되었다 (Figure 1). 입원 8일째시행한복부 MRI 상다낭성신소견과, 간내담관의확장소견이보였다 (Figure 2). 입원당시에는빈호흡과경미한흉곽함몰이관찰되었으나보존적치료이후증상호전되었으며, 위장관수유와경구수유를병행하다가경구수유로진행하였으며다낭성신질환은경과관찰하기로하고퇴원하였다. 환아의혈액샘플을채취하여 DNA 를추출한뒤 PKHD1 유전자의양방향 sequencing 분석을시행하였으며, 분석은 Medical Genomics Laboratory 에서시행하였다. 환아는 c.889_931del43 의 frame-shift 유전자변이가확인되었다 (Figure 3). 환아는생후 6개월까지추적관찰되었으며, 다낭성신질환의악화소견은관찰되지않고약물복용으로신성고혈압은안정적으로조절되는상태였다. 고찰 상염색체열성다낭신질환 (autosomal recessive polycystic kidney disease, ARPKD) 은양측신장을광범위하게침범하는유전질환으로서, 태아기에신세뇨관의발육이상으로발생하며 20,000-40,000 명의한명정도로발생한다 1,2). 산전에양수과소증으로인하여 Potter 증후군이나폐발육부전을보이기도하며, 출생후호흡곤란을보이기도하고고혈압이나요로감염을보이기도한다3). 양쪽신장의 collecting duct 가방사형으로팽창되고담관의과형성과선천적간섬유화를보이나기능적으로는출생직후특이소견을보이지않다가 2-3 년후신기능저하와신부전이발생할수있으며, 이후간섬유화가진행하여아동기이후간경화, 문맥압항진증과식도정맥류출혈등이발생할수있다 3,7). 대 부분의경우에서임신후반기나신생아기에발견되며, 산전초음파에서신장크기의증가를동반한음영증가나, 양수과소증을확인한다하더라도 ARPKD 를진단하기는어렵다 8-10). 30-50% 의환아들이출생직후신장문제가아닌폐이형성증에의한호흡부전으로사망하며, 연령이증가함에따라서서히신부전이진행된다 7). 신부전에대한적극적인치료는 ARPKD 환아의생존율을향상시키며성인까지생존이가능하게하지만, 궁극적인치료는신이식이며그전까지복막투석이나혈액투석을병행하며합병증의보존적치료를진행하여야한다. ARPKD 의염색체진단은 1994 년처음시작되었으며, 염색체 6p21 의 PKHD1 유전자와관련된다 11). PKHD1 유전자는거대유전자중하나로, 470 kb의유전자분절 (genomic segment) 까지걸쳐있으며 67 cording exon 을포함하고있다. 복잡한 PKHD1 의변이는 29개의다른돌연변이와 40개의변이유전자들 (alleles) 로설명할수있으며 12), 주요변화들로 missense, frame shifting insertion, deletion, nonsense mutation 이있다 13). 방사선검사상복부초음파에서신피질과신수질의구분없이미만성으로확장된신장이관찰되고대체로크기가 2 cm 미만의낭으로구성된다. 간은간내담관확장과간문맥주위섬유화소견을보인다. 국내에서는출생직후사망한 3례의 ARPKD 보고가있었으며 5), ARPKD 와 Caroli s Syndrome 이동반된보고가있었고 14), 그외산전진단과관련된보고가있었다 15). 국내 ARPKD 의보고는초음파로진단된경우가가장많고 5,16), 복부종괴나다른동반기형에대한검사중발견된경우로임상적보고가대부분이며, 산전부모의유전자검사로진단된경우는있으나출생후환아의유전자검사결과의보고는없는상태이다 6,14). ARPKD 는신생아시기에높은사망률을보이는질환으로서초기생존후임상경과는다양하다. 장기예후에관련된연구로는 1년생존율이 85%, 10년생존율이 82% 로보고되며 17), 만성신부 Figure 3. Nucleotide sequencing. This figure shows the frame shift mutation as c.889_931del43(p.cys296fs).
67 전이이르면 4 세경부터확인될수있다. 대부분의경우신장의크 기가나이대비 97 백분위이상으로측정되며, 75% 에서고혈압 이관찰되고 44% 에서간섬유화및간문맥고혈압의후유증을보 이게된다. 유전형과임상양상과의연관성에관한연구가이루어 지고있으며, missense 변이는경한임상경과를보이는반면에 frame shifting insertion, deletion 등은중한임상경과를보여예 후의차이를보고하기도한다 17). 본증례는출생직후호흡곤란증상을보이고, 이후수유곤란 과고혈압소견을보였으며, 영상의학적으로팽창된신장과담관 의확장을보여임상적으로 ARPKD 에합당하며, 유전자검사로 PKHD1 유전자의돌연변이를확인하여국내에서처음으로보고 하기에의미가있을것으로사료된다. REFERENCES 1) Zerres K, Rudnik-Schoneborn S, Steinkamm C, Becker J, Mucher G. Autosomal recessive polycystic kidney disease. J Mol Med (Berl) 1998;76:303-9. 2) Zerres K, Rudnik-Schoneborn S, Senderek J, Eggermann T, Bergmann C. Autosomal recessive polycystic kidney disease (ARPKD). J Nephrol 2003;16:453-8. 3) Guay-Woodford LM, Desmond RA. Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics 2003;111:1072-80. 4) Bergmann C, Senderek J, Kupper F, Schneider F, Dornia C, Windelen E, et al. PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat 2004;23:453-63. 5) Choi WK, Lee SC, Park YW, Lee CG. Four cases of autosomal recessive polycystic kidney disease. J Korean Soc Pediatr Nephrol 1997;1:91-6. 6) Jang DG, Chae H, Shin JC, Park IY, Kim M, Kim Y. Prenatal diagnosis of autosomal recessive polycystic kidney disease by molecular genetic analysis. J Obstet Gynaecol Res 2011;37: 1744-7. 7) Roy S, Dillon MJ, Trompeter RS, Barratt TM. Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors. Pediatr Nephrol 1997;11:302-6. 8) Zerres K, Mucher G, Becker J, Steinkamm C, Rudnik-Schoneborn S, Heikkila P, et al. Prenatal diagnosis of autoso mal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology. Am J Med Genet 1998;76:137-44. 9) Reuss A, Wladimiroff JW, Stewart PA, Niermeijer MF. Prenatal diagnosis by ultrasound in pregnancies at risk for autosomal recessive polycystic kidney disease. Ultrasound Med Biol 1990;16:355-9. 10) Jeong MS, Shin YJ, Park HJ. Specific prenatal histories and associated congenital anomalies related to hydronephrosis in newborn infants. J Korean Soc Neonatol 2006;13:105-10. 11) Zerres K, Mucher G, Bachner L, Deschennes G, Eggermann T, Kaariainen H, et al. Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21- cen. Nat Genet 1994;7:429-32. 12) Ward CJ, Hogan MC, Rossetti S, Walker D, Sneddon T, Wang X, et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 2002;30:259-69. 13) Rossetti S, Torra R, Coto E, Consugar M, Kubly V, Malaga S, et al. A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees. Kidney Int 2003;64:391-403. 14) Kim JT, Hur YJ, Park JM, Kim MJ, Park YN, Lee JS. Caroli s syndrome with autosomal recessive polycystic kidney disease in a two month old infant. Yonsei Med J 2006;47:131-4. 15) Seo JW. A case of bilateral polycystic kidney: prenatal ultrasonographic diagnosis. Korean J Obstet Gynecol 1991;34: 1625-9. 16) Lim G, Lee JH, Park YS, Kim KS, Won HS. Incidence and outcome of congenital anomalies of the kidney and urinary tract detected by prenatal ultrasonography: a single center study. Korean J Pediatr 2009;52:464-70. 17) Bergmann C, Senderek J, Windelen E, Kupper F, Middeldorf I, Schneider F, et al. Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Kidney Int 2005;67:829-48.
68 Jae Eun Baek, et al. A Case of PKHD1 Gene Mutation 유전자돌연변이로확진된상염색체열성다낭신질환신생아 1 례 연세대학교의과대학소아과학교실백재은 이순민 은호선 박민수 박국인 남궁란 이철 상염색체열성다낭신질환은양측신장을광범위하게침범하는유전질환으로서, 태아기에신세뇨관의발육이상으로발생하며, 대부분의경우에서임신후반기나신생아기에발견되고, 산전초음파에서신장크기의증가를동반한음영증가나, 양수과소증을확인한다하더라도 ARPKD 를진단하기는어렵다. 저자들은출생직후부터임상증상을보이고, 영상의학적으로팽창된신장과담관의확장을보여 ARPKD 에합당하며, 유전자검사로 PKHD1 유전자의돌연변이를확인하였기에보고하는바이다.