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1 대한안과학회지 2015 년제 56 권제 8 호 J Korean Ophthalmol Soc 2015;56(8): ISSN (Print) ISSN (Online) Case Report 망막이상을보이는주버트증후군 1 예 A Case of Joubert Syndrome Accompanied with Retinal Abnormality 박정열 김성일 전혜신 최희영 Jung Yul Park, MD, Sung Il Kim, MD, Hye Shin Jeon, MD, Hee Young Choi, MD, PhD 부산대학교의학전문대학원안과학교실 Department of Ophthalmology, Pusan National University School of Medicine, Busan, Korea Purpose: Joubert syndrome is a rare disorder which affects the cerebellum and the brain stem. Herein, we report a case of Joubert syndrome accompanied with retinal abnormality. Case summary: A 9-year-old female visited our hospital with chief complaints of low vision in both eyes, nystagmus, and lack of gaze movement. The best-corrected visual acuity in her right eye was 20/80 and in the left 20/80 and heterotropia was not observed. She appeared to have incomplete total color blindness on the color vision test. The anterior segment test showed no abnormal findings other than diffuse pigmentation and degeneration of the peripheral retina, vascular attenuation, and pale optic disc in both eyes on fundus examination. The patient showed overall developmental delay and decreased muscle tension, but genetic and congenital metabolic disease tests were normal. The molar tooth sign of the midbrain, defect in the lower part of the cerebellum and dilatation of the fourth ventricle were observed on magnetic resonance imaging. Conclusions: Appropriate evaluation of retinitis pigmentosa and visual function should be performed in Joubert syndrome patients. J Korean Ophthalmol Soc 2015;56(8): Key Words: Joubert syndrome, Molar tooth sign, Retinal abnormality, Retinitis pigmentosa, Staphyloma 주버트증후군은드문상염색체열성질환으로임상적으로진단되고방사선학적으로확진한다. 1,2 1969년 Marie Joubert에의해처음기술되었으며, 소뇌와뇌간을주로침범하는매우드문질환이다. 1 그이후전세계적으로약 200 증례정도의주버트증후군이보고되었다. 3 주버트증후군은뇌자기공명영상 (magnetic resonance imaging, MRI) 에서특징적인대구치징후 (Molar tooth sign) 와함께일과성과호흡, 이상안운동, 운동실조, 발달지연등을 Received: Revised: Accepted: Address reprint requests to Hee Young Choi, MD, PhD Department of Ophthalmology, Pusan National University Hospital, #179 Gudeok-ro, Seo-gu, Busan , Korea Tel: , Fax: hychoi@pusan.ac.kr 특징으로한다. 1,2,4 대구치징후란소뇌충부의형성부전과깊이가깊어진각간와, 수평방향으로길게늘어지고두꺼워진상소뇌각에의해자기공명영상의횡단면에서보여지는형태를일컫는말이다. 주버트증후군의안구운동이상은안진, 사시, 안운동실조증등다양한형태로나타나며 2,4 망막색소변성증, 맥락막망막결손, 황반주변부시야결손, 황색반안저, 레베르선천흑암시등의망막이상역시드물게동반될수있다고보고되었다 주버트증후군은전세계적으로소수의증례들만이보고되었으며더욱이망막이상을동반한주버트증후군환자의증례는국내에아직보고된바없다. 또한주버트증후군환자의안저소견과안구광학단층촬영소견은국내에알려진바없다. 이에저자들은망막색소변성증의망막이상을보이는주버트증후군으로진단된한여아에대해증례보고를하고자한다. c2015 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 1304

- 박정열외 : 망막이상을보이는주버트증후군 - 증례보고 9세여아가양안저시력과안진, 주시장애를주소로내원하였다. 2004년타병원에서시행한유전자검사및선천대사질환검사에서특이소견이없었던환아로 2005년본원소아과에서시행한발달검사상전반적발달지연과근긴장도저하를보이며운동, 언어및인지부분의심한장애를보인병력이있었다.

2 - 박정열외 : 망막이상을보이는주버트증후군 - 증례보고 9세여아가양안저시력과안진, 주시장애를주소로내원하였다. 2004년타병원에서시행한유전자검사및선천대사질환검사에서특이소견이없었던환아로 2005년본원소아과에서시행한발달검사상전반적발달지연과근긴장도저하를보이며운동, 언어및인지부분의심한장애를보인병력이있었다. 내원시최대교정시력우안 20/80, 좌안 20/80이었으며조절마비굴절검사에서경도의근시및도난시가관찰되었다. 양안모두주시는불완전했고눈떨림이동반되어있었다. 사시는관찰되지않았으나근거리에서시행한티트무스검사상 200초의불량한입체시를보였으며워트-4-등검사상근거리와원거리에서양안모두 융합을시키지못하며불량한융합력을보였다. 색각검사상양안전색약을보였다. 전안부검사는이상소견을보이지않았으나안저검사상양안주변부망막의미만성색소침착및맥락망막색소변성, 망막세동맥의세약, 시신경유두의상대적창백이관찰되었으며유전성망막변성질환의감별을위해시행한어머니의안저검사는정상소견을보였다 (Fig. 1). 빛간섭단층촬영 (Spectral domain optical coherence tomography [SD-OCT], Heidelberg engineering, Heidelberg, Germany) 에서양안후극부의포도종, 광수용체의내절과외절을포함한전반적인소실을확인할수있었고 Swedish Interactive Threshold algorithm-fast (SITA-Fast, Humphrey Field Analyzer, Zeiss/ Humphrey Systems, Dublin, CA, USA) 를이용한시야검사 A B Figure 1. (A) Fundus photographs of patient eye. Both eyes show mottling appearance of the retinal pigment epithelium with bony-spicule pigmentation. Waxy pallor optic nerve head and mild attenuation of the retinal arterioles are observed. (B) Fundus photographs of the patients mother's eye. No abnormal findings are observed. 1305

3 - 대한안과학회지 2015 년제 56 권제 8 호 - A B Figure 2. Optical coherence tomography findings (horizontal scans) of case (A, B). Both images show loss of photoreceptor (defect in inner and outer segment junction layer) layer on the fovea. Posterior staphyloma is also observed on the fovea. 에서전시야결손에가까운모습을보였다 (Fig. 2, 3). 뇌자기공명영상촬영에서중뇌의대구치징후 (molar tooth sign) 및소뇌하충부의결손, 제4 뇌실의확장소견, 상소뇌각이두꺼워지고평행하게배열된모습을보였다. 뇌랑이나대뇌에는이상소견이관찰되지않았다 (Fig. 4). 환자는임상소견, 안구광학단층촬영, 안저검사및뇌자기공명영상소견등을바탕으로망막색소변성증과후극부의포도종을동반한주버트증후군으로진단되었다. 고찰 주버트증후군은발생률이 1/80,000-1/100,000인매우드문상염색체열성유전질환이다. 14 소아신경과의사인 Joubert et al 1 에의해 1969년캐나다의몬트리올에서처음보고되었으며, 프랑스계캐나다인가족의세남자아이와한여자아이 4남매에대한보고였다. 이들모두는소뇌충부의무형성을특징으로하고있었다. 15, 년 Saraiva and Baraitser 7 는 1992년에여러가지보고들을바탕으로주버트증후군은소뇌충부의저형성, 근 1306

4 - 박정열외 : 망막이상을보이는주버트증후군 - A B Figure 3. (A, B) Humphrey visual field test (SITA-Fast) showing nearly total visual field defect on both eyes. The visual field test result of the left eye shows some fixation losses and low test reliability due to the patient poor cooperation. SITA-Fast = Swedish Interactive Threshold algorithm-fast; POS = positive; NEG = negative; N/A = not available; ASB = apostilb; RX = prescription; DS = Dioptres sphere; DC = Dioptres cylinder; GHT = glaucoma hemifield test; VFI = visual field index; MD = mean deviation; PSD = pattern standard deviation. A B C Figure 4. Cranial magnetic resonance imaging shows (A) molar tooth sign and elongated superior cerebellar peduncles (yellow arrows) which are classic finding of Joubert syndrome. (B) bat-wing morphology of 4th ventricle (yellow arrow) and (C) thickened superior cerebellar peducle (upper yellow arrow) and cerebellar vermis hypoplasia (lower yellow arrow) are also observed. 긴장도의저하, 전반적인발달지연, 그리고특징정인호흡패턴이나이상안구운동중한개를포함하도록하는진단기준을제시하였다. 이상호흡패턴은일과성의무호흡과과 호흡이반복적으로신생아시기에나타나는것이며나이가들어감에따라호전되고소뇌충부의형성부전과연관된전형적인증상일것이라고생각했다 일차눈위치에서 1307

5 - 대한안과학회지 2015 년제 56 권제 8 호 - 안구진탕또한종종관찰되며수평사시또한드물지않으나 8,9 본증례의경우사시는관찰되지않았다. 주버트증후군은표현형에따라 6개의아형으로분류되는데순수한주버트증후군, 안구의결함이있는주버트증후군, 신장의결함이있는주버트증후군, 안구와신장의결함이동반된주버트증후군, 간의손상이있는주버트증후군, 입과얼굴, 사지의손상이있는주버트증후군이다. 18 본증례의경우안구의결함이동반된주버트증후군으로분류할수있다. 또한주버트증후군은망막변성의유무에따라다시두가지로분류될수있는데망막변성은대부분광수용체세포의진행성퇴행으로인한형태가대부분이다. 7 종류로는막망색소변성, 황반분리증, 시신경유두드루젠, 황색반안저, 맥락막망막결손등이있다. 망막의변성을가진환자에서는다발성신낭종질환을보이는경우가많으며생존율또한낮아진다. 이중망막색소변성은광수용체의진행성기능장애로양안을모두침범하며주변시야손상이진행하고, 환자는야맹을호소하는것을특징으로하는질환이다. 안저검사에서보이는검은뼛조각모양의검은색소성변화는이질환의특징적소견이며전기생리검사와시야검사상광수용체의진행성소실이보일때진단을한다. 대부분망막의변성에의한안과적증상을보이나간혹전신적인질환을동반하기도한다 최근주버트증후군의원인이될것이라생각되는유전자들이세포이하기관인일차섬모의위치단백을인코딩하고있다는사실이밝혀졌다. 14 일차섬모는유동성이없는몸의모든세포근처에서발견되며특히광수용체의내절 / 외절을연결하는얇은구조로되어있는연결섬모도포함된다저자들이보고하는환자의경우안저검사상양안의주변부망막에검은뼛조각모양의미만성색소변성및침착, 주시장애를보여임상적으로망막색소변성이라고진단하였다. 전시야결손에가까운결과를보인시야검사의경우협조가어려운소아환자에서 SITA-FAST 를통해측정한시야검사라는데한계가있으며수회의측정에도낮은신뢰도와높은주시상실률을보였다. 하지만빛간섭단층촬영에서보인후극부포도종과황반부광수용체내절과외절의전반적인상실은시야검사에서나타난전시야결손소견과밀접한연관성을보여준다. 이번증례의경우망막색소변성과후극부의포도종그리고황반부광수용체의소실이동반된주버트증후군으로국내에서발견된첫보고이다. 아쉽게도추가적인추적관찰이이루어지지못해전기생리검사를통한망막세포의손상정도및시력예후에대한정보는얻을수가없었으며신 뢰도가낮은시야검사의재평가가이루어지지못한한계가있다. 추후전기생리검사를통해현재의광수용체의손상정도와시력의예후를평가하고신낭종등동반질환에대한추가적인평가가필요하며정기적인안구광학단층촬영으로망막의변화및후극부의변화를지켜볼필요가있다. 또한망막색소변성을가진환아에서전반적인발달지연및안구운동이상을보인다면주버트증후군을의심해보아야하며뇌자기공명영상촬영을고려함과동시에동반된전신이상을확인하는것이필요하겠다. REFERENCES 1) Joubert M, Eisenring JJ, Robb JP, Andermann F. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 1969;19: ) Maria BL, Boltshauser E, Palmer SC, Tran TX. Clinical features and revised diagnostic criteria in Joubert syndrome. J Child Neurol 1999;14:583-90; discussion ) Merritt L. Recognition of the clinical signs and symptoms of Joubert syndrome. Adv Neonatal Care 2003;3:178-86; quiz ) Boltshauser E, Isler W. Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis. Neuropadiatrie 1977;8: ) Yang HK, Yu YS, Hwang JM. Joubert syndrome associated with Leber's congenital amaurosis. J Korean Ophthalmol Soc 2008;49: ) Lambert SR, Kriss A, Gresty M, et al. Joubert syndrome. Arch Ophthalmol 1989;107: ) Saraiva JM, Baraitser M. Joubert syndrome: a review. Am J Med Genet 1992;43: ) Maria BL, Hoang KB, Tusa RJ, et al. "Joubert syndrome" revisited: key ocular motor signs with magnetic resonance imaging correlation. J Child Neurol 1997;12: ) Maria BL, Quisling RG, Rosainz LC, et al. Molar tooth sign in Joubert syndrome: clinical, radiologic, and pathologic significance. J Child Neurol 1999;14: ) Hodgkins PR, Harris CM, Shawkat FS, et al. Joubert syndrome: long-term follow-up. Dev Med Child Neurol 2004;46: ) Keskinbora KH. Ocular and oculomotor findings of Joubert syndrome. J Pediatr Ophthalmol Strabismus 2008;45: ) Khan AO, Oystreck DT, Seidahmed MZ, et al. Ophthalmic features of Joubert syndrome. Ophthalmology 2008;115: ) Sturm V, Leiba H, Menke MN, et al. Ophthalmological findings in Joubert syndrome. Eye (Lond) 2010;24: ) Romani M, Micalizzi A, Valente EM. Joubert syndrome: congenital cerebellar ataxia with the molar tooth. Lancet Neurol 2013;12: ) Pellegrino JE, Lensch MW, Muenke M, Chance PF. Clinical and molecular analysis in Joubert syndrome. Am J Med Genet 1997; 72: ) Satran D, Pierpont ME, Dobyns WB. Cerebello-oculo-renal syndromes including Arima, Senior-Löken and COACH syndromes: more than just variants of Joubert syndrome. Am J Med Genet 1308

6 - 박정열외 : 망막이상을보이는주버트증후군 ;86: ) al-talabani JA, Shubbar AI, Sobkey E. Cranial sonographic findings in Joubert's syndrome. J Clin Ultrasound 1999;27: ) Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. J Am Soc Nephrol 2007;18: ) Berson EL, Rosner B, Sandberg MA, Dryja TP. Ocular findings in patients with autosomal dominant retinitis pigmentosa and a rhodopsin gene defect (Pro-23-His). Arch Ophthalmol 1991;109: ) Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet 2006;368: ) Bujakowska K, Maubaret C, Chakarova CF, et al. Study of genetargeted mouse models of splicing factor gene Prpf31 implicated in human autosomal dominant retinitis pigmentosa (RP). Invest Ophthalmol Vis Sci 2009;50: = 국문초록 = 망막이상을보이는주버트증후군 1 예 목적 : 주버트증후군은소뇌와뇌간을주로침범하는드문질환으로, 주버트증후군에동반된망막이상 1 예를경험하였기에보고하고자한다. 증례요약 : 9 세여아가양안저시력과안진, 주시장애를주소로내원하였다. 내원시최대교정시력우안 20/80, 좌안 20/80 이었으며사시는관찰되지않았다. 색각검사상양안전색약소견을보였다. 전안부검사상이상소견을보이지않았으나안저검사상양안주변부망막의미만성색소침착및변성, 혈관세약, 시신경유두의창백이관찰되었다. 환아는전반적인발달지연, 근긴장도저하가있었으나유전자검사및선천대사질환검사는정상이었다. 뇌자기공명영상에서중뇌의대구치징후 (molar tooth sign) 및소뇌하충부결손, 제 4 뇌실확장이관찰되었다. 결론 : 주버트증후군에서망막색소변성및시기능이상이발생할수있으므로이에대한적절한평가가필요하다. < 대한안과학회지 2015;56(8): > 1309

<283732372D3733312920B4D9C3CAC1A120BCD2C7C1C6AEC4DCC5C3C6AEB7BBC1EEC0C720B3EBBEC8C0C720BDC3B7C2BAB8C1A4BFA120B4EBC7D120C0AFBFEBBCBA20C6F2B0A1283035292E687770>

<283732372D3733312920B4D9C3CAC1A120BCD2C7C1C6AEC4DCC5C3C6AEB7BBC1EEC0C720B3EBBEC8C0C720BDC3B7C2BAB8C1A4BFA120B4EBC7D120C0AFBFEBBCBA20C6F2B0A1283035292E687770> 대한안과학회지 제 49 권 제 5 호 2008 J Korean Ophthalmol Soc 49(5):727-731, 2008 DOI : 10.3341/jkos.2008.49.5.727 다초점 소프트콘택트렌즈의 노안의 시력보정에 대한 유용성 평가 김현경 1 김효명 2 정성근 1 가톨릭대학교 의과대학 성모병원 안과학교실 1, 고려대학교 의과대학 안암병원 안과학교실