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대한진단검사의학회지제 29 권제 1 호 2009 Korean J Lab Med 2009;29:77-81 DOI 10.3343/kjlm.2009.29.1.77 Case Report Diagnostic Genetics 4p 아종말체의결실을동반한모자익형 4 번환염색체 1 예 김정현 1 오필수 2 나혜연 2 김선희 1 조현찬 3 성균관의대삼성서울병원진단검사의학과 1, 한림의대소아청소년과학교실 2, 한림의대진단검사의학교실 3 Case of Mosaic Ring Chromosome 4 with Subtelomeric 4p Deletion Jeong Hyun Kim, M.D. 1, Phil Soo Oh, M.D. 2, Hye Yeon Na, M.D. 2, Sun-Hee Kim, M.D. 1, and Hyoun Chan Cho, M.D. 3 Department of Laboratory Medicine 1, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Departments of Pediatrics 2 and Laboratory Medicine 3, Hallym University School of Medicine, Seoul, Korea Ring chromosome is a structural abnormality that is thought to be the result of fusion and breakage in the short and long arms of chromosome. Wolf-Hirschhorn syndrome (WHS) is a well-known congenital anomaly in the ring chromosome 4 with a partial deletion of the distal short arm. Here we report a 10-month-old male of mosaic ring chromosome 4 with the chief complaint of severe short stature. He showed the height of -4 standard deviation, subtle hypothyroidism and mild atrial septal defect/ventricular septal defect, and also a mild language developmental delay was suspected. rain magnetic resonance imaging showed multifocal leukomalacia. Chromosomal analysis of the peripheral blood showed the mosaic karyotype with [46,XY,r(4)(p16q35)[84]/45,XY,-4[9]/91,XXYY, dic r(4;4)(p16q35;p16q35)[5]/46,xy,dic r(4;4)(p16q35;p16q35)[2]]. FISH study showed the deletion of the 4p subtelomeric region with the intact 4q subtelomeric and WHS region. oth paternal and maternal karyotypes were normal. We compared the phenotypic variation with the previously reported cases of ring chromosome 4. The ring chromosome 4 with the subtelomeric deletion of short arm seems to be related with the phenotype of short stature. (Korean J Lab Med 2009; 29:77-81) Key Words : r(4) chromosome, Mosaic ring chromosome, Short stature 서 환염색체 (ring chromosome) 는염색체의구조적이상중에서염색체의장완과단완의말단이일부소실되어양쪽끝끼리붙어서환상형을형성하는것을지칭한다 [1]. 환자들은임상적으로발달지체를흔히나타내며, 소실된유전자부위정도에따라비교적경한임상양상부터심한이상까지다양하게나타난 Received : September 25, 2008 Manuscript No : KJLM2175 Revision received : December 24, 2008 ccepted : December 30, 2008 Corresponding author : Phil Soo Oh, M.D. Department of Pediatrics, Hallym University Medical Center, 94-200 Yeongdeungpo-dong 2-ga, Yeongdeungpo-gu, Seoul 150-719, Korea Tel : +82-2-2639-5200, Fax : +82-2-2636-1008 E-mail : ohphilia@unitel.co.kr 론 다 [2]. 4번환염색체의경우염색체말단부위의소실부위와범위에따라다양한임상양상을나타낼수있으며, 비교적임상양상이잘알려진 Wolf-Hirschhorn 증후군 (WHS) 을보일수있다 [3, 4]. 저자들은심한저신장을주소로내원하여염색체검사를시행한환아에서 WHS 부위의소실없이 4번염색체단완의말단소실을동반한환염색체를관찰하여문헌고찰과함께보고하는바이다. 증례생후 10개월남아가심한저신장을주소로내원하여염색체검사를시행하였다. 환아는 41주만삭아로제왕절개로출생시키는 46 cm로 3 백분위수, 체중은 2.8 kg로 10-25 백분위수에 77

78 김정현 오필수 나혜연외 2 인 해당하였다. 생후 2주째시행한심장초음파에서 7 mm 2차공심방중격결손및 2-3 mm 심실중격결손을보였다. 8개월에시행한추적검사에서는심실중격결손은막혔으며심방중격결손은 4 mm로줄었다. 아버지의키는 170 cm, 어머니의키는 156 cm 였고형제는없었으며가족력상별다른특이사항은없었다. 환아는평상시식욕이부진하였고내원당시키는 64 cm로 -4 표준편차 (SD) 의저신장을보였으며체중은 6.1 kg, 두위는 41 cm 정도였다. 환아의외래추적관찰에서경한언어발달지체를확인할수있었다. 검사소견으로골연령은약 6개월, 성장호르몬자극검사는정상이었으며, magnetic resonance imaging (MRI) 검사상뇌하수체는정상이었으나양측두정후두부위, 오른쪽측두엽및양측전두엽에서다병소성백색연화증소견과좌측전두엽에정맥혈관종소견을볼수있었다 (Fig. 1). 또한출생당시시행한선천성대사이상검사상특이소견이없었으나, 생후 10 개월내원당시시행한갑상샘호르몬검사에서 T3 126.74 ng/dl, T4 4.5 μg/dl, thyroid-stimulating hormone (TSH) 10.96 μiu/ml, thyroxine-binding globulin (TG) 16.2 μg/ ml로경미한갑상샘기능저하의소견을보였다. 1. 세포유전학적검사환아의말초혈액을이용하여세포유전학적검사를시행하였다. 말초혈액의림프구를 phytohaemagglutinin (PH) 를첨가한 RPMI 배지에서 3일간배양하였고, 제작된슬라이드를 G-분염법을통해염색하였다. 총 100개의분열세포를분석한결과다음과같은모자익형의핵형을보였다 : [46,XY,r(4)(p16- q35)[84]/45,xy,-4[9]/91,xxyy,dic r(4;4)(p16q35;p16q35)[5]/ 46,XY,dic r(4;4)(p16q35;p16q35)[2]] (Fig. 2). 추가적으로 r(4) 와연관한염색체말단의소실여부와 4p 결실증후군 (deletion syndrome) 과연관된 WHS의소실여부를알아보기위해 FISH 분석을실시하였다. FISH probe는 4p subtelomeric probe (Cytocell, Oxfordshire, UK), 4q subtelomeric probe 및 WHS probe (bbott Molecular/Vysis, Des Plaines, IL, US) 로검사하였다. 그결과 4q 아종말체 (subtelomere) 및 WHS 부위 Right Left Right Left Fig. 1. rain MRI showing multifocal leukomalacia in the bilateral occipito-parietal, right temporal and bilateral frontal lobes () and venous angioma in the left frontal lobe (). r(4)(p16q35) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Y X Fig. 2. () Giemsa-banding karyogram of peripheral blood cells: 46,XY,r(4)(p16q35). () Partial karyogram showing normal chromosome 4 (left side) and dic r(4;4)(p16q35;p16q35) (right side).

Case of Mosaic Ring Chromosome 4 79 4q Sub-Telomere C Fig. 3. Metaphase FISH of peripheral blood cells using a 4p subtelomeric probe (Cytocell, UK), 4q subtelomeric and WHS probes (bbott Molecular/Vysis, US). () The single green color indicates deletion of a 4p subtelomere. (, C) Intact 4q and WHS probes were detected. 는보존되어있었으며 4p subtelomeric 부위에서만소실을보이는소견을나타내었다 (Fig. 3). 환아부모의염색체검사는정상소견을나타내었다. 고찰환염색체를보이는환자에서흔히나타나는임상양상인저신장과발달지체는환염색체에서설명되는두가지기전인동적모자익형 (dynamic mosaicism) 에의한현상과흔히동반되어나타나는유전자의소실에의해설명되고있다 [5]. 동적모자익형으로설명되는현상은환형의염색체가분열시자매염색분체교환 (sister chromatid exchange) 현상에의해세포분열시이차적인염색체의소실이나획득이일어나게되고이상이있는세포가사멸하는현상을말한다. 이는환염색체가형성된염색체의종류에상관없이지속적인세포의분열시전반적인환자의성장을감소시키는요인이되게된다. 이러한환염색체의특징으로환자에서보이는임상적특징과외형이염색체의소실에의해일어나는것인지, 또는모자익형에수반되어나타나는염색체의부분적이수성 (aneuploidy) 에의해나타나는것인지는명확히알려지지않고있다. 현재까지국내에서보고된환염색체증례는약십여편이존재하며주로 13번, 18 번, 21 번등의 acrocentric 염색체에서많이보고되었다. Kim 등 [6] 의보고에따르면국내에서염색체검사가의뢰되었던 4,117명의환자들을분석한결과전체염색체이상중환염색체이상은 1.5% 를차지하는것으로나타났다. 환염색체이상을보고한증례들에서이상을보인환염색체의말단결실여부는 FISH 검사에서만결실부위가판별되고핵형 분석에의해파악되지않는증례들이있었으며, 핵형분석만실시하여정확한염색체핵형이기재되지않는증례들도존재하였다 [7-9]. 4p 말단부위의소실을보고한문헌으로부터미국생명공학정보센터 (National Center for iotechnology Information, NCI) 의염색체지도를이용하여염색체소실부위와증상발현을비교해보면염색체소실의정도와표현형이밀접한연관성을보이며, 특히염색체의말단부위소실은저신장및발달지체의표현형을공통적으로포함하는것으로나타났다. Lee 등 [10] 의보고에의하면저신장과불임을주소로내원한환자의염색체검사상 46,XX,r(4)/45,XX,-4/46,XX,dic r(4)/ 47,XX,r(4),+r(4)/46,XX의핵형을나타내었고, bacterial artificial chromosome (C) clone을이용한 FISH 검사를통해 4번염색체가단완의말단으로부터약 800 Kb 정도소실되었음을알수있었다. 후에이환자는특별한조치없이임신하여정상핵형의태아를임신한것으로보고되었다. 또한 Piers 등 [11] 은경련과발달지체로내원하여염색체검사상 46,XX,r(4)(p16q35) 의핵형을보였던 2세여아를보고하였다. 환아는추가적인검사를통해난청과 2형당뇨의증상을수반함을확인할수있었다. DN 다형성표지자를이용한분자유전학적검사상 4번염색체말단으로부터약 1.7 Mb 부위에위치하는 Fibroblast Growth Factor Receptor 3 (FGFR3) 와 WHS 부위는보존되었고 0.4 Mb 부위의 D4S3359 부위는소실되었음이확인되어, 환아의염색체소실부위는 4번염색체단완의약 0.4 Mb 부터 1.7 Mb 사이로예상되었다. WHS 부위가보존된 4p 결실증례와는달리 WHS 부위의소실을포함한 r(4) 의경우발달지체와저체중외에소두증과구순

80 김정현 오필수 나혜연외 2 인 구개열을공통적으로포함하고있었다 [12-14]. 이부위는 4번염색체의말단으로부터약 1.9 Mb 위치에존재한다 [15]. 최근 4번염색체단완의원위부소실없이근위부소실 (proximal interstitial deletion) 만보인 WHS의경우특징적인저신장또는성장지연및심장기형의표현형을나타내지않았다는증례들이보고되었다 [16-18]. 이러한보고들을바탕으로유전형-표현형간의유전자지도작성 (mapping) 이시도되면서 4p 말단으로부터 400-760 bp 부위, 즉원위부말단이저신장을초래하는부위임이제시되고있다 [19]. FISH 미세결실 (microdeletion) probe가임상적으로도입되면서염색체검사상유사한핵형을나타내는환자들에서좀더세분화된보고가이루어지고있고, 4p 미세결실을나타내는경우 WHS와유사한양상을나타내나경한타입의표현형을보이는 Pitt-Rogers-Danks 증후군 (PRDS) 을구분하여기술하고있다 [20, 21]. 본증례에서와같이 4p 아종말체부위의소실이확인되었으며 WHS에서나타나는특징적인안면의기형없이저신장을보이는경우 WHS나 PRDS의부위보다말단부위의유전자소실로유추해볼수있다. 한편, 뇌 MRI 검사상다병소성백색연화증소견을볼수있었는데, 이는수초형성 (myelination) 이잘안되어나타나는현상으로생각되었다. 발달지체와소두증, 구순열등다발성기형을보이는 16개월된환아에서 4번환염색체가발견되었고뇌 MRI상수초형성이잘안된소견이관찰된바있으며 [11], 18번환염색체를가진환아의뇌 MRI에서도비정상적인수초형성을보인경우가있었다 [22]. 본증례의환아에서나타나는여러가지임상양상이아종말체부위의결실을동반한 r(4) 에서특이한양상인지에대하여는좀더많은보고가필요할것으로생각되며, 여러문헌에서공통적으로나타나는임상양상인저신장은 4번염색체단완말단의소실에의한것으로생각된다. 요약환염색체는염색체의장완과단완의말단이일부소실되어양쪽끝끼리붙어서고리형태를형성하는염색체의구조적이상으로, 4번염색체에서발생하는경우 Wolf-Hirschhorn 증후군 (WHS) 을보일수있다. 본증례는심한저신장을주소로내원한생후 10 개월남아에서 4번염색체의모자익형을보인환아에대한보고이다. 환아는 -4 표준편차 (SD) 의저신장, 경미한갑상샘기능저하, 경한심방중격결손및심실중격결손그리고경한언어발달지체소견을보였다. 뇌자기공명영상검사상다병소 성백색연화증소견이관찰되었다. 환아의말초혈액을이용한염색체검사상 [46,XY,r(4)(p16q35)[84]/45,XY,-4[9]/91,XXYY, dic r(4;4) (p16q35;p16q35)[5]/46,xy,dic r(4;4)(p16q35;p16- q35)[2]] 의모자익형을보였고, 환염색체를보인 4번염색체의말단부위의소실을보기위해시행한 FISH 검사상 4q 아종말체및 WHS 부위는보존되었으나 4p 아종말체부위가소실된소견을보였다. 환아의부모핵형은정상소견이었다. 본환아의증례와더불어 4번환염색체를나타내어단완의소실부위를보인증례를문헌고찰을통해비교해보았다. 본증례는 4번염색체의환염색체형성시아종말체의일부가소실된경우로 4번염색체단완말단의소실은저신장의표현형과연관성이있을것으로생각된다. 참고문헌 1. Gardner RJ and Sutherland GR, eds. Chromosome abnormalities and genetic counseling. 3rd ed. Oxford: Oxford University Press, 2004:178-81. 2. Shashi V, White JR, Pettenati MJ, Root SK, ell WL. Ring chromosome 17: phenotype variation by deletion size. Clin Genet 2003;64: 361-5. 3. ergemann D, Cole F, Hirschhorn K. The etiology of Wolf-Hirschhorn syndrome. Trends Genet 2005;21:188-95. 4. Rauch, Schellmoser S, Kraus C, Dorr HG, Trautmann U, ltherr MR, et al. First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation. m J Med Genet 2001;99:338-42. 5. Kosztolanyi G. Does ring syndrome exist? n analysis of 207 case reports on patients with a ring autosome. Hum Genet 1987;75:174-9. 6. Kim SS, Jung SC, Kim HJ, Moon HR, Lee JS. Chromosome abnormalities in a referred population for suspected chromosomal aberrations: a report of 4117 cases. J Korean Med Sci 1999;14:373-6. 7. Hwang SJ, Lee JH, Park IY, Moon H, Oh JH, Lee GS, et al. case of de novo ring (13) chromosome with deletion 13q32.2 qter. Korean J Obstet Gynecol 2002;45:323-6. ( 황성진, 이지현, 박인양, 문희봉, 오준환, 이귀세라등. 새로발생한 13q32.2 qter 결손과동반된 13번환상염색체환아 1예. 대한산부인과학회지 2002;45:323-6.) 8. Park YM, Nho HN, Kim SZ, hn YM. Cytogenetic evaluation of a patient with ring chromosome 9 presenting failure to thrive and developmental delay. Korean J Pediatr 2008;51:426-30. ( 박윤미, 노한내, 김숙자, 안영민. 성장부진과발달지연을보인환아에서확인된환

Case of Mosaic Ring Chromosome 4 81 상 9번염색체 1예의세포유전학적인연구. Korean J Pediatr 2008;51: 426-30.) 9. Jung YK and Lee GH. case of ring chromosome 20 with mental retardation and epilepsy. Korean J Pediatr 2005;48:108-11. ( 정연경및이경훈. 정신지체와간질을동반한 20 환 (Ring) 염색체증후군 1예. Korean J Pediatr 2005;48:108-11.) 10. Lee MH, Park SY, Kim YM, Kim JM, Yoo KJ, Lee HH, et al. Molecular cytogenetic characterization of ring chromosome 4 in a female having a chromosomally normal child. Cytogenet Genome Res 2005;111:175-8. 11. lackett PR, Li S, Mulvihill JJ. Ring chromosome 4 in a patient with early onset type 2 diabetes, deafness, and developmental delay. m J Med Genet 2005;137:213-6. 12. alci S, Engiz O, ktas D, Vargel I, eksac MS, Mrasek K, et al. Ring chromosome 4 and Wolf-Hirschhorn syndrome (WHS) in a child with multiple anomalies. m J Med Genet 2006;140:628-32. 13. Laleye, lao MJ, djagba M, Hans C, Delneste D, Gnamey DK, et al. Wolf Hirshhorn syndrome in a case of ring chromosome 4: phenotype and molecular cytogenetic findings. Genet Couns 2006; 17:35-40. 14. Wieczorek D, Krause M, Majewski F, lbrecht, Horn D, Riess O, et al. Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: analysis of 13 patients with a de novo deletion. Eur J Hum Genet 2000;8:519-26. 15. Dietze I, Fritz, Huhle D, Simoens W, Piecha E, Rehder H. Clinical, cytogenetic and molecular investigation in a fetus with Wolf-Hirschhorn syndrome with paternally derived 4p deletion. Case report and review of the literature. Fetal Diagn Ther 2004;19:251-60. 16. Chitayat D, Ruvalcaba RH, abul R, Teshima IE, Posnick JC, Vekemans MJ, et al. Syndrome of proximal interstitial deletion 4p15: report of three cases and review of the literature. m J Med Genet 1995;55:147-54. 17. Van uggenhout G, Melotte C, Dutta, Froyen G, Van Hummelen P, Marynen P, et al. Mild Wolf-Hirschhorn syndrome: micro-array CGH analysis of atypical 4p16.3 deletions enables refinement of the genotype-phenotype map. J Med Genet 2004;41:691-8. 18. White DM, Pillers D, Reiss J, rown MG, Magenis RE. Interstitial deletions of the short arm of chromosome 4 in patients with a similar combination of multiple minor anomalies and mental retardation. m J Med Genet 1995;57:588-97. 19. Concolino D, Rossi E, Strisciuglio P, Iembo M, Giorda R, Ciccone R, et al. Deletion of a 760 kb region at 4p16 determines the prenatal and postnatal growth retardation characteristic of Wolf-Hirschhorn syndrome. J Med Genet 2007;44:647-50. 20. Moretti P, Ferrari M, Di attista S, Di attista C. The 4P-syndrome. Case description and literature review. Minerva Pediatr 2001;53:23-8. 21. Dufke, Seidel J, Schoning M, Dobler-Neumann M, Kelbova C, Liehr T, et al. Microdeletion 4p16.3 in three unrelated patients with Wolf-Hirschhorn syndrome. Cytogenet Cell Genet 2000;91:81-4. 22. Nakayama J, Hamano K, Shimakura Y, Iwasaki N, Nakahara C, Imoto N, et al. bnormal myelination in a patient with ring chromosome 18. Neuropediatrics 1997;28:335-7.