대한내분비학회지 : 제 24권제 1 호 2009 증 례 10.3803/jkes.2009.24.1.33 뇌하수체전엽호르몬이상을동반한중격 - 시신경형성장애 1 예 아주대학교의과대학내분비대사내과학교실, 신경과학교실 1, 안과학교실 2, 영상의학교실 3 이진우 황의경 김태호 윤형영 정재호 최용원 용석우 1 안재홍 2 김선용 3 김호성 3 정윤석 A Case of Septo-optic Dysplasia Associated with Anterior Pituitary Hormone Abnormalities Jin-Woo Lee, Eui-Kyung Hwang, Tae-Ho Kim, Hyung-Young Yoon, Jae Ho Jung, Yong Won Choi, Suk-Woo Yong 1, Jae-Hong Ahn 2, Sun-Yong Kim 3, Ho Sung Kim 3, Yoon-Sok Chung Departments of Endocrinology and Metabolism, Neurology 1, Ophthalmology 2, and Radiology 3, Ajou University School of Medicine ABSTRACT Septo-optic dysplasia (SOD) is a rare congenital malformation syndrome that is manifested by a triad of optic nerve hypoplasia, midline brain abnormalities and hypopituitarism. It is known to be associated with homeobox gene HESX1 mutation in some familial cases. We experienced a case of SOD in a 23 year-old male who presented with short stature and delayed puberty. The basal serum levels of testosterone and IGF-1 were low and the prolactin level was high. The combined pituitary stimulation study revealed decreased growth hormone responses. Brain MRI revealed complete agenesis of the corpus callosum, hypoplasia of the anterior pituitary gland and herniation of the third ventricle into the pituitary fossa. On the neurologic and ophthalmologic examinations, there was no definite abnormality except mild optic atrophy on the optical coherence tomography. Genetic analysis using polymerase chain reaction with direct sequencing revealed no HESX1 mutation. (J Korean Endocr Soc 24:33~37, 2009) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key Words: Septo-optic dysplasia, hypopituitarism, HESX1 mutation 서론 1) 중격- 시신경형성장애 (septo-optic dysplasia, SOD) 는 10 만명당 2명정도의낮은유병률을갖는드문선천성질환으로시신경형성부전, 뇌량이나투명중격등의중간선뇌이상및뇌하수체형성부전에의한뇌하수체기능저하증을특징으로한다 [1]. 1956년 de Morsier에의해명명된이후 de Morsier's syndrome으로도불려진다 [2]. 이질환의원인으로 HESX1 돌연변이가알려져있으나 [5], 가족형중에서도일부에서만발견되며, 대부분의가족형및빈도가많은산발형에서는아직원인이정확히밝혀져있지않다. 대부분의환자들은영유아기에안구진탕, 시력저하, 경 련등의증상으로나타나추가적인방사선검사등을통해진단되나 [3], 드물게는영유아기이후에성장지연이나성발달지연, 요붕증등의증상으로나타나는경우도있다 [4]. 국내에서는주로안과학회에보고되다가 [5], 최근요붕증을동반한증례가내분비학회에보고된바있었다 [6]. 저자들은저신장증, 성발달지연으로내원한 23세남자에서중격-시신경형성장애를진단하고, 원인감별을위해유전자검사를시행하였으며, 뇌하수체호르몬이상을진단하였고, 호르몬치료를시행하며경과관찰중인환자를경험하였기에문헌고찰과함께보고하는바이다. 증례 접수일자 : 2008년 8월 15일통과일자 : 2008년 10월 24일책임저자 : 정윤석, 아주대학교의과대학내분비대사내과학교실 * 본연구는경기도의경기도지역협력연구센터사업의일환으로수행하였음. 환자 : 23세남자주소 : 저신장및성발달지연현병력 : 초등학교 3학년때저신장으로인근병원에서검사결과성장호르몬결핍증을진단받았고고등학교 1학년 - 33 -
대한내분비학회지 : 제 24 권제 1 호 2009 때까지성장호르몬을투여받았으며, 당시 2차성징이나타나지않아시행한검사에서남성호르몬감소소견보여남성호르몬을투여받았으며 1년전고프로락틴혈증이발견되어 bromocriptine을복용하며지내던중최근원인감별위해시행한뇌자기공명영상촬영에서뇌량형성부전및뇌하수체위축소견이보여내분비대사내과에의뢰되었다. 과거력 : 주산기시절의특별한병력은없었고, 원시및난시, 사시, 치아결손으로치료받은과거력이있었다. 가족력 : 뇌질환, 안질환및호르몬이상질환을의심할만한가족력은없었다. 진찰소견 : 내원당시생체활력징후는체온 36.6, 맥박 65회 / 분, 호흡 20회 / 분, 혈압 126/76 mmhg이었고, 의식은명료하였다. 키 167 cm이고체중 67.3 kg이었다. 호흡음, 심음, 장음은정상적으로청진되었고복부의팽만, 간및비 장비대등은관찰되지않았다. 사춘기발달은 Tanner stage 4기에해당하였다. 혈액검사소견 : 말초혈액검사에서백혈구 8,300/mm³, 혈색소 14.1 g/dl, 혈소판 280,000/mm³ 이었다. 생화학검사에서혈액요소질소 11.6 mg/dl, 크레아티닌 1.0 mg/dl, 나트륨 143 mmol/l, 칼륨 4.8 mmol/l, 염소 105 mmol/l였으며, 혈액삼투압농도 299 mosm/l, 소변삼투압농도 659 mosm/l로정상이었다. 호르몬검사소견 : 갑상선자극호르몬 1.97 uiu/ml, 유리 T4 1.16 ng/dl, 부신피질자극호르몬 84 pg/ml로정상소견을보였고프로락틴 23.1 ng/ml로증가된소견을보였으며, 테스토스테론 0.30 ng/ml, IGF-1 127 ng/ml ( 정상치 179~777 ng/ml) 로감소된소견을보였고황체형성호르몬 2.3 miu/ml, 난포자극호르몬 1.8 miu/ml로테스토스테론 Table 1. Combined pituitary stimulation test Glucose (mg/dl) TSH (μiu/ml) Prolactin (ng/ml) GH (ng/ml) Cortisol (μg/dl ) ACTH (pg/ml) LH (miu/ml) FSH (miu/ml) 0 min 89 1.97 23.1 0.73 14.2 84 2.3 1.8 30 min 23 12.79 40.8 0.57 12.5 65 5.2 2.8 60 min 96 13.38 43.4 0.98 20.2 85 4.3 2.4 90 min 72 10.80 35.8 0.94 15.3 54 4.6 3.1 120 min 92 9.00 31.8 0.67 13.0 51 3.9 2.7 Interpretation appropriate normal Basal hyperprolactinemia and decreased response to stimulation deficiency normal normal deficiency deficiency A B C D Fig 1. Brain MRI. A, B. T1-weighted sagittal view showed complete agenesis of corpus callosum and septum pellucidum. Hypoplasia of anterior pituitary gland and ectopic location of posterior pituitary gland were observed. Herniation of infundibular recess of the third ventricle into pituitary fossa was noted. C. There was no corpus callosum or anterior commisure in T2-weighted axial view. D. Ectopic posterior pituitary gland was well visualized in T1-weighted coronal view. - 34 -
- 이진우외 10 인 : 뇌하수체전엽호르몬이상을동반한중격 - 시신경형성장애 1 예 - 농도에비해상대적인감소소견을보였다. 복합뇌하수체자극검사에서는자극에대한성장호르몬, 황체형성호르몬및난포자극호르몬의반응이저하된소견을보였다 (Table 1). 방사선소견 : 뇌자기공명영상촬영에서는뇌량의형성부전및투명중격결손과뇌하수체전엽의형성저하증과뇌하수체후엽의이소성위치가관찰되었다. 뇌하수체오목으로의제3뇌실의이탈과뇌하수체오목앞쪽으로뇌실질의전반적인하향이탈소견이관찰되었다 (Fig. 1). 안과소견 : 나안시력은우안 0.8 좌안 1.0이었으며교정시력은양안 1.0이었다. 구면렌즈대응치는우안 -0.75D, 좌안 +0.125D이었다. 동공의대광반사는정상이었고안압은우안 13 mmhg 좌안 12 mmhg으로정상이었다. 세극등검사에서각막, 전방, 홍채및수정체는정상이었다. 안저검사에서시신경은유두함몰부위의경계가불분명하였으며유두주위맥락막위축 (peripapillary chorioretinal atrophy) 소견이 전방향에걸쳐관찰되었다. 황반부를포함한중심망막이나주변부망막은정상적인소견을보였다. 광간섭단층촬영검사 (optical coherence tomography) 에서두눈의시신경상측에서망막신경섬유층의국소적결손소견이관찰되었다. 시야검사에서는양안의전반적인감도저하소견과하측시야에국소적인감도저하소견이산발적으로발견되었으나임상적으로의미있는변화는아니었다 (Fig. 2). 유전자검사방법및결과 : 중합효소연쇄반응을통하여유전자증폭을하였다. 시발체는 Dattani 등 [13] 의논문에근거하여바이오니어회사에의뢰하여제작하였다. 주형 DNA 증폭은 Maxime PCR Premix kit (intron, Korea) 를이용하였다. 중합효소연쇄반응은 PTC-200 (MJ Reaserch) 을사용하였고, 방법은 94 에서 5분간변성시킨후, 94 에서 30초간변성한후, 각엑손에적합한온도에서 30초간결합, 72 에서 30초간합성과정을 30회시행하였고최종적으로합성과정을 72 에서 10분간시행하였다 (Table 2). 중 A B Fig. 2. Ophthalmologic examination. A. Visual field analysis showed generalized reduction of sensitivity without significant visual field defect in both eyes. B. Optical coherence tomography showed focal retinal nerve fiber layer defect in superior segments of optic nerve head in both eyes (red arrow) suggesting mild optic nerve hypoplasia. - 35 -
대한내분비학회지 : 제 24 권제 1 호 2009 Table 2. Primer sequences and polymerase chain reaction conditions for the HESX1 gene Primer Sequence (5' 3') Annealing T ( ) Exon 1F AGCTGTTGCTCTGTGCAGACCACGAGA 65 Exon 1R ACAAAGAATTGAAACAATTAAGCTGTGGCA Exon 2F TGGAACATAAGATTGACCATCTAAGACA 55 Exon 2R AGCCTTTATATTATCATTATTGGGTGAA Exon 3F AGCTCATTTTTGGAGACATACTTGAATA 60 Exon 3R TAACATTTCAACATCATGAATAACAACT Exon 4F GAATAATAAAATAATGTTTCTGAGACCTAT 60 Exon 4R TCATGCTCTGCAATTAGAAGATAATTTCAC 합효소연쇄반응이종료된시료에서 10 μl를취하여 0.5 μ g/ml의 ethidium bromide가첨가된 1.8% 아가로즈겔에전기영동하여확인하였다. 4개의엑손에대하여직접염기서열분석을마크로젠회사에분석의뢰하여결과를얻었다. 중격- 시신경형성장애와관련하여기존에보고된돌연변이부위인 Q6H, R160C, S170L, T181A를포함한전체 HESX1 유전자부위에서해당돌연변이는관찰되지않았다. 임상경과및치료 : 환자는뇌량의형성장애및뇌하수체기능저하증이동반된중격- 시신경형성장애로진단되었다. 남성호르몬결핍에대하여 testosterone undecanoate (Andriol Testocap) 80 mg bid, 고프로락틴혈증에대하여 bromocriptine mesylate (Parlodel) 1.25 mg (1일 1회 ) 경구투여하면서현재양호한상태로외래추적관찰중이다. 고찰 1941년 Reeves이선천성실명을보인생후 7개월된영아에서시신경형성부전과투명중격의결손이동반되어있던예를보고하였고, 1956년 de Morsier[2] 이선천성시신경형성부전환자의부검후처음으로중격- 시신경형성장애로명명하였으며, 이후투명중격의결손을보인 36명의환자중 9명에서시신경형성부전이동반되어있었음을보고하였다 [7]. 1970년에는 Hoyt 등이중격 -시신경형성장애가뇌하수체성저신장증과연관되었음을처음으로기술하였고, 같은해에 Kaplan 등이중격 -시신경형성장애가요붕증및뇌하수체기능저하증과관련되며, 이는간뇌의병변에의한시상하부호르몬및항이뇨호르몬의감소에기인할것이라고기술하였다 [8]. 1972년에는 Billson과 Hopkins[9] 가뇌하수체기능저하및요붕증, 선천성시신경형성부전을보인환자에서투명중격은정상적이었음을기술하면서선천성시신경형성부전에동반되는구조적이상및뇌하수체의기능이상이다양한범주로나타날수있음을보고하였다. 중격- 시신경형성장애는대부분의경우산발형으로나타나나 [10] 소수에서는상염색체열성유전의형태를보이기도하며 [11], 일부에서는상염색체우성으로나타난다 [12]. 가족성으로나타나는경우중일부에서는 3번염색체에있 는호메오박스유전자인 HESX1 돌연변이가보고되고있으나 [13], 본증례의경우해당돌연변이는관찰되지않았다. 그외에도 SOX2, SOX3 유전자의변이와관련되었다는보고가있다 [14]. 이질환의다른원인으로임신당시모체의낮은연령, 당뇨병의병력, 임신중음주, 코카인, 항전간제복용등이보고되어왔으나 [15~19], 본증례에서는해당사항이없었다. 임상양상은유아기에시력저하, 안구진탕, 사시등의안과적증상으로가장먼저나타나는경우가흔하고시력장애의정도는거의정상적인시력에서부터실명에이르기까지다양하게나타날수있다 [3]. 중격- 시신경형성장애에있어서시신경형성부전이동반되는빈도는 75% 에서 80% 로보고되었으며두눈이동시에이환되는경우가더흔하다 [2]. 본증례의경우영유아기에원시, 난시및사시등의병력이있었으나, 안과검사에서사시는발견되지않았고경도의굴절이상만발견되었다. 안저검사에서시신경형성부전소견은확실하지않았으나, 광간섭단층촬영검사에서시신경주위망막신경섬유층의경한위축소견이관찰되어시신경의국소적형성부전이동반되었음을시사하였다. 그러나시력저하나의미있는시야결손은관찰되지않았다. 뇌하수체기능저하는신생아기에저혈당이나경련, 2주이상지속되는신생아황달과같은양상으로나타날수있으며, 이후에는성장호르몬의결핍이가장많이동반되기때문에저신장으로나타나는경우가가장많고, 그외에사춘기지연, 요붕증등으로나타나는경우도보고되었다 [20]. 본증례에서도저신장증및성발달지연등의증상이나타났으나, 치료에반응을보였고, 경련이나요붕증등환자상태의급격한변화를유발할수있는증상들이없었기때문에충분한평가가미루어졌던것으로생각된다. 본증례에서관찰되는고프로락틴혈증의원인은제3뇌실이뇌하수체오목으로이탈되면서뇌하수체줄기를압박하여발생된것으로보이며이는공터키안증후군과유사한기전으로생각된다. 결론적으로뇌하수체기능저하증을보이는환자에서영유아기의안과적혹은신경과적증상동반의과거력이있을때적절한영상검사및안과검사를통해중격 -시신경형성장애등의선천성질환을고려해보아야할것이다. - 36 -
- 이진우외 10 인 : 뇌하수체전엽호르몬이상을동반한중격 - 시신경형성장애 1 예 - 요약저자들은저신장증및성발달지연을보였던환자에서중격-시신경형성장애를진단하고, 원인감별을위한유전자검사에서 HESX1 돌연변이는관찰되지않은상태로, 호르몬치료를시행하며경과관찰중인증례를경험하였기에문헌고찰과함께보고하는바이다. 참고문헌 1. Dattani MT, Robinson IC: The molecular basis for developmental disorders of the pituitary gland in man. Clin Genet 57:337-346, 2000 2. De Morsier G: Studies on malformation of cranio -encephalic sutures. III. Agenesis of the septum pellucidum with malformation of the optic tract. Schweiz Arch Neurol Psychiatr 77:267-292, 1956 3. Haddad NG, Eugster EA: Hypopituitarism and neurodevelopmental abnormalities in relation to central nervous system structural defects in children with optic nerve hypoplasia. J Pediatr Endocrinol Metab 18:853-858, 2005 4. Traggiai C, Stanhope R: Endocrinopathies associated with midline cerebral and cranial malformations. J Pediatr 140:252-255, 2002 5. Won Hae Lee, Song Hee Park, Hanho Shin: A case of septo-optic dysplasia. J Kor Ophth Soc 32:110-116, 1991 6. Soo Kyoung Kim, Tae Sik Jung, Jong Ryeal Hahm, Sang Min Lee, Sung Won Moon, Kyeong Ju Lee, Soon Il Chung: A case of central diabetes insipidus combined with septo-optic dysplasia and schizencephaly in 31-year-old woman. J Kor Endocrine Soc 22:339-343, 2007 7. De Morsier G: Median cranioencephalic dysraphias and olfactogenital dysplasia. World Neurol 3:485-506, 1962 8. Hoyt WF, Kaplan SL, Grumbach MM, Glaser JS: Septo-optic dysplasia and pituitary dwarfism. Lancet 1:893-894, 1970 9. Billson FA, Hopkins IJ: Optic hypoplasia and hypopituitarism. Lancet 1:905, 1972 10. Dattani MT, Preece M: Growth hormone deficiency and related disorders: insights into causation, diagnosis, and treatment. Lancet 363:1977-1987, 2004 11. Wales JK, Quarrell OW: Evidence for possible Mendelian inheritance of septo-optic dysplasia. Acta Paediatr 85:391-392, 1996 12. Thomas PQ, Dattani MT, Brickman JM, McNay D, Warne G, Zacharin M, Cameron F, Hurst J, Woods K, Dunger D, Stanhope R, Forrest S, Robinson IC, Beddington RS: Heterozygous HESX1 mutations associated with isolated congenital pituitary hypolasia and septo-optic dysplasia. Hum Mol Genet 10:39-45, 2001 13. Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Martensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC: Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19:125-133, 1998 14. Kelberman D, Dattani MT: Septo-Optic Dysplasia - Novel insights into the aetiology. Horm Res 69:257-265, 2008 15. Donat JF: Septo-optic dysplasia in an infant of a diabetic mother. Arch Neurol 38:590-591, 1981 16. Parson SH, Dhillon B, Findlater GS, Kaufman MH: Optic nerve hypoplasia in the fetal alcohol syndrome: a mouse model. J Anat 186(Pt 2):313-320, 1995 17. Hoyt CS, Billson FA: Maternal anticonvulsants and optic nerve hypoplasia. Br J Ophthalmol 62:3-6, 1978 18. Dominguez R, Aguirre Vila-Coro A, Slopis JM, Bohan TP: Brain and ocular abnormalities in infants with in utero exposure to cocaine and other street drugs. Am J Dis Child 145:688-695, 1991 19. Woods K, Dattani MT: Transcription factors involved in disorders of forebrain and pituitary development. In Epstein J, Wynshaw-Boris. AJ(eds) Inborn Errors of Development: The Molecular Basis of Clinical Disorders on Morphogenesis, New York, Oxford University Press 540-551, 2004 20. Birkebaek NH, Patel L, Wright NB, Grigg JR, Sinha S, Hall CM, Price DA, Lloyd IC, Clayton PE: Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab 88:5281-5286, 2003-37 -