Korean J Lab Med 2010;30:249-54 DOI 10.3343/kjlm.2010.30.3.249 ase Report Diagnostic Hematology Diamond-Blackfan Anemia onfirmed by RPS19 Gene Mutation Analysis: A ase Study and Literature Review of Korean Patients Hyojin hae, M.D. 1, Joonhong Park, M.D. 1, Myungshin Kim, M.D. 1, Jihyang Lim, M.D. 1, Yonggoo Kim, M.D. 1, Kyungja Han, M.D. 1, Jaewook Lee, M.D. 2, Nak Gyun hung, M.D. 2, Bin ho, M.D. 2, and Hack Ki Kim, M.D. 2 Department of Laboratory Medicine 1 and Division of Pediatric Hematology/Oncology 2, Department of Pediatrics, ollege of Medicine, The atholic University of Korea, Seoul, Korea Diamond-Blackfan anemia (DBA) is a rare congenital erythroid hypoplastic anemia that usually presents early in infancy and is inherited in up to 45% of cases. It is characterized by red cell aplasia, congenital anomalies, and a predisposition to cancer. orticosteroids and red blood cell transfusions are the mainstays of therapy. We describe a case of 3-month-old infant who presented with severe anemia, elevated levels of HbF and adenosine deaminase and bilateral hydronephrosis, who was later confirmed as DBA by mutation analysis using the direct sequencing method. Direct sequencing analysis of RPS19 gene was performed with both cdna and genomic DNA extracted from peripheral blood and a c.3g>a point mutation of exon 2 resulting in p.met1ile was identified in this patient. The patient showed an inadequate response to steroid therapy and a partial response to RB transfusion with a follow-up Hb level of 8.3 g/dl on her last visit to the outpatient clinic. DBA is a genetically and phenotypically heterogeneous disease, and we have reviewed the clinical characteristics of 25 Korean patients thus far reported in the literature. To our knowledge, this is the first case of DBA confirmed by mutation analysis in Korea, and mutation identification using molecular method is recommended for confirmation of this genetically and phenotypically heterogeneous disease. (Korean J Lab Med 2010;30:249-54) Key Words : Diamond-Blackfan anemia, Sequencing analysis, RPS19 서 Diamond-Blackfan 빈혈 (Diamond-Blackfan anemia, DBA) 은주로영아기때발병하는드문선천성적혈구계저형성빈혈 (congenital erythroid hypoplastic anemia) 이다 [1]. DBA 의발생빈도는백만명당약 6명이고남녀간혹은인종간차이는없다 [2]. 적혈구의생산장애로인한대적혈구정색소성빈혈과출생시선천성기형을동반하는것이이질환의특징적인 Received : December 30, 2009 Manuscript No : KJLM10-004 Revision received : March 10, 2010 Accepted : April 30, 2010 orresponding author : Myungshin Kim, M.D. Department of Laboratory Medicine, Seoul St. Mary s Hospital, 505 Banpo-dong, Seocho-gu, Seoul 137-701, Korea Tel : +82-2-2258-1645, Fax : +82-2-2258-1719 E-mail : microkim@catholic.ac.kr *The first authorship was distributed equally between Hyojin hae and Joonhong Park. ISSN 1598-6535 론 The Korean Society for Laboratory Medicine 임상증상이고다른악성질환으로이행할수있다. Diamond 와 Blackfan [1] 이 1938년에처음보고한이래, Diamond 등 [3] 에의해 1976년에처음진단기준이정의되었으며, 질환에대한연구가진행됨에따라명확한진단기준이제시되었다 [4]. DBA 환자의약 45% 에서가족력이있으며이들대부분은상염색체우성유전양상을보인다 [5]. 현재까지질환과관련된염색체이상과다양한유전자가보고되었으며 DBA 환자의약 45% 는질환과연관된유전자들에대한돌연변이검사를통하여분자유전학적인확진이가능하다 [6]. 국내에서는총 25 명의 DBA 환자에대한증례보고가있었으나 [7-24] 아직까지 DBA 관련유전자의돌연변이를보고한증례는없었다. 이에저자들은반복적인수혈치료에도교정되지않는빈혈을보인 1명의환아에서 DBA 유전자중하나인 RPS19 유전자의돌연변이검사로 DBA를확진하였기에이를국내 25예의 DBA 증례들에관한문헌고찰과함께보고하는바이다. 249
250 Korean J Lab Med 2010;30:249-54 증례 3개월된여아가출생시부터지속된빈혈을주소로본원으로전원되었다. 환아는출생시, 생후 1, 2개월에총 3차례의적혈구수혈을받았으나빈혈이지속되었다. 환아는제왕절개술로출생하였고재태기간은 36주로미숙아였고출생체중은 1.81 kg 로저체중아였으며자궁내성장지연 (intrauterine growth retardation) 이있었다. 환아의형제는없었다. 내원시활력징후는정상범위였고이학적소견상기타특이소견은없었다. 내원시시행한일반혈액검사에서백혈구수 8.79 10 9 /L, 혈소판수 539 10 9 /L이었으며백혈구감별계산은정상범위였다. 혈색소는 5.0 g/dl, 적혈구용적률은 14.8%, 평균적혈구용적 (mean corpuscular volume, MV) 78.3 fl, 평균적혈구혈색소 (mean corpuscular hemoglobin, MH) 26.5 pg, 평균적혈구혈색소농도 (mean corpuscular hemoglobin concentration, MH) 33.8%, 망상적혈구 0.25% 이었다. 신장초음파소견상양쪽신장에 1등급 (grade) 의수신증 (hydronephrosis) 이있었다. 말초혈액도말에서정적혈구성정색소성빈혈이관찰되었다 (Fig. 1). 헤모글로빈 F (HbF) 는증가하였으며, 직접 (direct) 과간접 (indirect) oombs test는모두음성이었다. 골수천자도말검사에서세포충실도는 50% 이었으며적혈구계전구세포가현저히감소하였으나과립구계전구세포와거대핵세포의수와형태는정상이었다 (Fig. 1). 골수검체로시행된염색체검사에서는분석된 20개의분열중기세포에서모두정상핵형을보였다. DBA 연관유전자인 RPS19 유전자에대한분자유전학적검사를 genomic DNA (gdna) 와 complementary DNA (cdna) 를대상으로시행하였으며, cdna를이용한염기서열분석에사 용한시발체는 forward: 5 -AGGTTATGTT-3 와 reverse: 5 -GAGGAATTTATTAAAGA-3 이었으며, gdna를이용하여 RPS19의 2번째엑손에대한염기서열분석에사용한시발체는 forward: 5 -GGGGTAAGGTTTAG- GAT-3 와 reverse: 5 -AGTTTTGAATAGT-3 이었다. PR 반응은 95 1분, 62 1분, 72 30초의조건으로 35회반복하였으며동일한시발체와 BigDye Terminator v3.1 cycle sequencing kit (Applied Biosystems, Foster ity, A, USA) 를직접염기서열분석에사용하였다. 참조서열과비교한결과 gdna와 cdna를이용한염기서열분석모두에서 RPS19 Gene RPS19 RPS24 RPS17 RPL35A RPL11 RPL5 % of DBA attributes to mutations 6 genes associated with DBA The RPS19 gene structure 25% 3% 1 family 2% 6.5% 10% 5 UTR Exon 2 Exon 3 Exon 4 Exon 5 Exon 6 ATG RPS19 sequencing chromatogram. The G to A substitution is expected to produce a methionine to isoleucine substitution of the initiation codon T A G A T R T G G A G A G T T A Y G G A T T A G A T R T G G A G T A A T R T G G A G Fig. 2. (A) Genes associated with DBA. (B) The gene structure of RPS19. () Direct sequencing analysis of RPS19. The G to A substitution is expected to produce a methionine to isoleucine substitution of the initiation codon. Abbreviation: DBA, Diamond-Blackfan anemia. G G G G A B A B Fig. 1. Bone marrow aspirate (A, Wright-Giemsa stain, 400) and bone marrow biopsy (B, hematoxylin and eosin stain, 200) showing normal cellularity and characteristic paucity of erythroid precursors. The other lineages show no evident abnormalities.
hae H, et al., DBA onfirmed by RPS19 Gene Mutation 251 유전자의두번째엑손에서 c.3g>a 점돌연변이가발견되었고이는첫번째아미노산인메티오닌이이소류신으로변하는과오돌연변이였다 (Fig. 2). 환아는입원하여수혈을받고임상증상이호전되어 3일후퇴원하였으며퇴원시혈색소는 8.2 g/dl, 적혈구용적률은 24.6%, MV 81.5 fl, MH 27.2 pg, MH 33.3% 이었다. 외래추적관찰중환아는스테로이드치료에반응하지않아정기적인적혈구수혈로치료중이고향후조혈모세포이식을위한준비를진행하고있다. 고찰 Diamond와 Blackfan [1] 에의해선천성적혈구계저형성빈혈로처음보고된 DBA는주로신생아기나이른영아기때심한 빈혈이관찰되는데환자의 90% 이상이생후 1세이전에진단되며진단시의평균연령은생후 8주이다 [25]. 환자들은주로빈혈에따른동반증상이나타나게되며약 50% 의환자에서출생시선천성기형을동반하는데, 머리, 얼굴, 신장, 심장, 그리고엄지손가락의기형이흔하며성장지연이관찰되기도한다 [25]. 본증례의환아에서도 DBA에흔히동반되는신체적기형중신기형을확인할수있었으며, 또한본증례의환아와같은자궁내성장지연은 20% 에서발견된다 [26]. DBA의혈액학적이상은빈혈, 대적혈구증가증 (macrocytosis), 망상적혈구감소증 (reticulocytopenia), 골수내의적혈구계전구세포의현저한감소가특징적이며이는 DBA의주요진단기준들이다 [4]. 본증례의환아는출생시부터지속된빈혈이있었으며생후 3개월경내원하여시행한혈액학적검사소견상정적혈구성정색소성빈혈, 망상적혈구감소증, 그리고골수내 Table 1. linical characteristics of 26 Diamond-Blackfan anemia cases in Korea ase No. Age at Age at diagnosis presentation (month) (month) Sex Hb (g/dl) Reticulocyte (%) Inheritance ongenital anomalies Steroid responsive Growth retardation Reference 1 28 At birth M 2.5 0 Sporadic N N Y [7] 2 6 3 M 5.1 0.3 Sporadic N N Y [8] 3 13 10 M 3.5 0.1 Sporadic N N Y [9] 4 14 12 F 3.5 0.4 Sporadic N N Y [10] 5 8 20 days M 1.3 0.1 Sporadic Hypertelorism N N [11] 6 21 16 M 4.0 0.3 Sporadic N N Y [12] 7 6 2 M 2.4 ND Sporadic N N Y [13] 8 18 11 M 2.3 0.2 Sporadic N N N [14] 9 22 At birth M 1.4 0 Sporadic Bifid thumb N Y [15] 10 11 8 M 4.0 0.1 Sporadic N N N [16] 11 10 10 M 3.0 0.05 Sporadic N N N [17] 12 3 1 M 7.4 0.1 Sporadic Hypertelorism, Y Y [18] flat nasal bridge, webbed neck 13 4 1 F 5.5 0.1 Sporadic Hypoplastic thumb N N [18] 14 6 2 M 2.4 0.3 Sporadic N N Y [18] 15 4 10 days F 3.2 1.1 Sporadic Umbilical hernia N Y [19] 16 6 3 F 3.0 0.3 Sporadic N N Y [20] 17 11 1 F 5.3 1.0 Sporadic N N Y [21] 18 2 1 F 3.1 0.8 Sporadic N Y Y [22] 19 1 At birth M 3.6 0.1 Sporadic Delayed growth of N Y [23] carpal bone 20 11 At birth M 4.3 0.09 Sporadic N Y Y [24] 21 8 4 M 6.4 0.16 Sporadic N N Y [24] 22 2 1 F 1.9 0.17 Sporadic Ventricular septal defect, N Y [24] polydactyly 23 3 2 F 4.6 0.3 Familial Mitral valve prolapse N Y [24] 24 3 2 F 5.3 0.1 Familial Atrial septal defect, polydactyly Y Y [24] 25 18 At birth M 8.0 0.19 Sporadic Tetralogy of Fallot, strabismus N Y [24] 26 3 At birth F 5.0 0.25 Sporadic Bilateral Hydronephrosis Y N Present study Abbreviations: M, male; F, female; Y, yes; N, no; ND, not determined.
252 Korean J Lab Med 2010;30:249-54 적혈구계전구세포의현저한감소소견이관찰되었다. 적혈구생성의장애는혈청내엽산, 비타민 B12, 적혈구생성인자 (erythropoietin) 그리고적혈구내 adenosine deaminase (ADA) 수치의증가를동반하며특히적혈구 ADA의증가소견은 DBA 환자의약 80-89% 에서관찰된다 [27]. 또한스트레스조혈 (stress hematopoiesis) 의추가적인특징인 HbF 수치의증가와 i 항원의지속도자주관찰되는 DBA의특징이다. DBA의치료는스테로이드와적혈구수혈이주된치료형태이다. 스테로이드의치료의경우첫치료에 70-80% 의환자가반응을보이나 [25] 장기적인치료반응은환자에따라매우다양하다. 조혈모세포이식은스테로이드치료에반응하지않거나지속적인수혈이필요한경우에고려되며현재로써는유일한완치요법이다. 국내에서는 1962년첫증례가보고된이후총 25 명의 DBA 환자에대한증례보고가있으며이들의임상적특징을요약해보면 (Table 1)[7-24] 진단시평균연령은생후 10개월이며약 70% 가생후 1세이전에진단되었다. 첫증상발현시기는평균 4개월이며 90% 이상에서생후 1세이전에첫증상발현이있었다. 선천성기형의빈도는외국의보고와유사하여약 50% 에서동반되었으며엄지손가락, 심장, 얼굴의순으로빈도가높았고그중성장지연은 20% 에서발견되었다. 스테로이드치료에대한반응도외국의보고와유사하여 80% 의환자에서반응을보였다. 가족력이있는증례는 2예로두환아는일란성쌍생아였고그외의경우는산발적으로발병한경우였다. 성별에따른발생빈도 (16:9) 가남아에서더높았으나이는적은증례수로인한편향으로사료되며그밖의특성들은외국의증례보고와매우유사하였다. 다만체계화되어있는국내 DBA 등록체계가없고증례환자들에대한분자유전학적검사는시행된예가없어한국인 DBA 증례에서의분자유전학적돌연변이의특성은살펴볼수없었다. DBA에관련된유전자는현재까지모두 6개의유전자가발견되었고 (Fig. 2) 이들유전자의분자유전학적검사를통해 DBA 환자의 45% 는확진이가능하다. 가장돌연변이발견율이높은관련유전자인 RPS19는 small ribosomal protein 19를부호화하는유전자로전체 DBA 환자의 25% 에서돌연변이가발견된다 [6]. 이외에도 small ribosomal subunit을부호화하는 2 개의유전자인 RPS24, RPS17, large ribosomal subunit을부호화하는 3개의유전자인 RPL35A, RPL11 그리고 RPL5가알려져있다. 리보솜의구조단백을부호화하는상기유전자들의돌연변이는이형접합 (heterozygote) 이일반적이므로질환은해당단백의반수체기능부전 (haploinsufficiency) 에의한 것으로생각되고있으며, 리보솜단백과빈혈간의상관성은아직불명확하나돌연변이에의한리보솜생합성의결함이질환과돌연변이의관계를설명하는가장일반적으로받아들여지고있는가설이다 [21]. 또한 DBA뿐아니라 dyskeratosis congenita, cartilage-hair hypoplasia, Shwachman-Diamond syndrome 등이질적인여러유전적골수기능부전증후군들 (inherited bone marrow failure syndromes) 에서돌연변이를보이는유전자들이리보솜합성에관여하는인자를부호화한다는점도리보솜단백과조혈간의상관성을강하게시사하는흥미로운사실들이다 [28]. 본증례환아에서돌연변이가발견된 RPS19 유전자는길이는 11 kb로 6개의엑손으로구성되어있으며 (Fig. 2) 돌연변이는유전자전체에걸쳐보고되어있다. RPS19 유전자의전체돌연변이중무의미 (nonsense) 돌연변이, 과오돌연변이, 결손과삽입, splice-site 돌연변이, 그리고거대결실과염색체재배열은 RPS19 유전자의돌연변이중각각 19%, 38%, 26%, 11%, 7% 를차지하며이중가장흔한돌연변이의종류는과오돌연변이이다 [6]. 본증례의환아에서는 RPS19 유전자의 2번째엑손에서 3번째염기가 G에서 A로변하여첫번째아미노산인메티오닌이이소류신으로변하는과오변이를유발하는점돌연변이가관찰되었고이돌연변이는기존에 Proust 등 [29] 이보고한돌연변이와동일하며 Proust 등은이를 50명의대조군을대상으로검사하여돌연변이임을확인하였다. 또한본증례환자와염기변이는다르나아미노산의변이는동일한돌연변이가 3명의환자에서보고된바있으며 [30, 31] 이들개시코돈과연관된과오돌연변이는정상부위에서유전암호해독 (translation) 의개시를차단하는것으로생각된다 [30]. RPS19 유전자에대한유전형-표현형간의명확한상관성은아직까지뚜렷이밝혀진바는없으며그주된이유로는 RPS19 유전자의돌연변이가매우다양한표현형을나타내며심지어는동일한돌연변이도빈혈, 치료반응, 그리고선천성기형이다양하게나타나는등질환자체의표현형적이형성 (heterogeneity) 도큰원인중하나로지목되고있다 [6]. 그러나유럽과북미 DBA 등록체계 (registry) 의최근 10 년간의임상자료를분석한 ampagnoli 등 [6] 의보고에의하면 RPS19 유전자돌연변이를보이는 DBA 환자군은스테로이드첫치료에반응하는비율이 47% 로전체 DBA 환자군의반응비율인 70% 에비해통계적으로유의하게낮으며 (P<0.0001) 수혈치료에의존하거나조혈모세포이식이필요할확률이통계적으로유의하게높다고 (P< 0.0001) 보고하였다. 실제로본증례환아와동일한아미노산의변화가보고된 3예의증례환자모두선천성기형은동반되지
hae H, et al., DBA onfirmed by RPS19 Gene Mutation 253 않았으며스테로이드치료에대한반응은서로상이하였는데한명은스테로이드치료에반응하였으나나머지두명은반응하지않았다 [30]. 따라서 DBA 관련유전자들의유전형-표현형간상관성은아직불명확하나, 향후낭포성섬유종 (cystic fibrosis) 의경우에서처럼 [32] DBA 관련유전자돌연변이의분자생물학적인효과에따라환자별맞춤치료및유전자치료가적용가능한분야중하나로생각되며따라서국내의 DBA 환자들에대한분자유전학적검사가더욱활발히진행될필요가있을것으로여겨진다. 요약 Diamond-Blackfan 빈혈 (Diamond-Blackfan anemia, DBA) 은주로영아기때발병하는드문선천성적혈구계저형성빈혈 (congenital erythroid hypoplastic anemia) 이며 DBA 환자의약 45% 에서가족력이있다. DBA는적혈구의생산장애로인한빈혈과출생시선천성기형을동반하는것이이질환의특징적인임상증상이고다른악성질환으로이행할수있다. DBA의주된치료는스테로이드와적혈구수혈이다. 저자들은심한빈혈, HbF와 adenosine deaminase의증가, 그리고양측성수신증으로내원한 3개월된영아에서직접염기서열분석법을통한돌연변이검사를통해 DBA를확진한증례를보고하는바이다. RPS19 유전자의직접염기서열분석은말초혈액에서추출한 cdna와 genomic DNA에대해시행하였으며 2번째엑손의 c.3g>a 점돌연변이에의한 p.met1ile 과오돌연변이를검출하였다. 환아는스테로이드치료에반응하지않았고적혈구수혈에도일시적인반응을보였으며마지막외래방문시혈색소는 8.3 g/dl이었다. DBA는유전학적으로나표현형적으로이형성을보이는질환으로여기에서는현재까지국내에서보고된한국인환자 25예에대한임상적특성을분석하였다. 본증례는돌연변이검사로확진된 DBA의첫국내증례보고로생각되며유전학적, 표현형적이형성을보이는 DBA를확진하기위해서분자유전학적검사법을사용한돌연변이의검출이필수적이라고여겨진다. 참고문헌 1. Diamond LK and Blackfan KD. Hypoplastic anemia. Am J Dis hild 1938; 56:464-7. 2. ampagnoli MF, Garelli E, Quarello P, arando A, Varotto S, Nobili B, et al. Molecular basis of Diamond-Blackfan anemia: new findings from the Italian registry and a review of the literature. Haematologica 2004;89:480-9. 3. Diamond LK, Wang W, Alter BP. ongenital hypoplastic anemia. Adv Pediatr 1976;22:349-78. 4. Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, et al. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol 2008;142:859-76. 5. Orfali KA, Ohene-Abuakwa Y, Ball SE. Diamond Blackfan anaemia in the UK: clinical and genetic heterogeneity. Br J Haematol 2004;125: 243-52. 6. ampagnoli MF, Ramenghi U, Armiraglio M, Quarello P, Garelli E, arando A, et al. RPS19 mutations in patients with Diamond-Blackfan anemia. Hum Mutat 2008;29:911-20. 7. Lee HY, Sydow Gv, Savosnick R. A case of congenital hypoplastic anemia. J Korean Pediatr Soc 1962;3:66-70. (, Sydow Gv, Savosnick R. ongenital hypoplastic anemia의 1. 소아과 1962;3:66-70.) 8. Shin B and Whang KS. A case of congenital hypoplastic anemia. J Korean Med Assoc 1966;9:531-5. ( 및 基. 의 1. 대한의학협회지 1966;9:531-5.) 9. Park SW, Shin SM, Shin AR, Ko KW, Hong Y. ongenital hypoplastic anemia (Blackfan-Diamond syndrome). Korean J Hematol 1974; 9:19-25. ( 박성원, 신상만, 신애라, 고광욱, 홍창의.. 대한혈액학회잡지 1974;9:19-25.) 10. Lee GR, Kim HS, Park MJ, Ahn DH. A case of congenital hypoplastic anemia. J Korean Pediatr Soc 1975;16:73-7. ( 貴, 金,,. ongenital hypoplastic anemia의1. 소아과 1975;16:73-7.) 11. Kim GP, Lee KS, ha SD, Lee DB, Kim SM, Lee M. A case report of congenital pure red cell anemia. Korean J Hematol 1976;11:39-45. ( 김광평, 이경수, 차상덕, 이두봉, 김선무, 이종무. ongenital pure red cell anemia 1예. 대한혈액학회잡지 1976;11:39-45.) 12. Kim DS, Lee, Lee HK, Kim KY, Yun DJ. A case of congenital hypoplastic anemia. J Korean Pediatr Soc 1980;23:771-5. ( 김동수, 이철, 이홍규, 김길영, 윤덕진. ongenital hypoplastic anemia의 1예. 소아과 1980;23:771-5.) 13. Lee MH and Ahn HS. A case report of congenital hypoplastic anemia. New Med J 1982;25:31-5. ( 이명현및안효섭. ongenital hypoplastic anemia의1예. 최신의학 1982;25:31-5.) 14. Woo YJ, Ma JS, Hwang TJ. A case of congenital hypoplastic anemia. J Korean Pediatr Soc 1983;26:188-92. ( 우영종, 마재숙, 황태주. ongenital hypoplastic anemia의1례. 소아과 1983;26:188-92.) 15. Jung HG, Whang TG, Park IS, Kim H, Lee SY. A case of congenital
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