1) 대한소아내분비학회지 : 제 16 권제 1 호 2011 증례 특발성중추성요붕증이동반된터너증후군 1 례 인하대학교의학전문대학원소아과학교실 1, 영상의학교실 2 강빈 1 ㆍ성현우 1 ㆍ김복기 1 ㆍ박신영 1 ㆍ김순기 1 ㆍ권영세 1 ㆍ임명관 2 ㆍ이지은 1 A Case of Turner Syndrome Associated with Idiopathic Central Diabetes Insipidus Ben Kang, M.D. 1, Hyeoun U Sung, M.D. 1, Bok Ki Kim, M.D. 1, Sin Young Park, M.D. 1 Soon Ki Kim, M.D. 1, Young Se Kwon, M.D. 1, Myung Kwan Lim, M.D. 2, and Ji Eun Lee, M.D. 1 Departments of Pediatrics 1, and Radiology 2, Inha University School of Medicine, Incheon, Korea We report a case of Turner syndrome associated with idiopathic central diabetes insipidus in a 12-year-old girl, who presented with polyuria and polydipsia after a year. The patient was very short and and centrally obese, and was initially diagnosed with Turner syndrome, hyperlipidema, and diabetes mellitus. A water deprivation test revealed central diabetes insipidus, and sellar magnetic resonance imaging (MRI) showed a thickening of the pituitary stalk, with normal high signal intensity in the posterior pituitary gland. Replacement therapy with desmopressin was initiated, and follow-up sellar MRI findings after two years showed spontaneous regression of the thickened pituitary stalk. There are only few reports of concomitant Turner syndrome with central diabetes insipidus worldwide. Further observation is needed in order to disclose the cause of central diabetes insipidus in patients having Turner syndrome. (J Korean Soc Pediatr Endocrinol 2011;16:56-60) Key Words: Turner syndrome; Diabetes insipidus, neurogenic 서 중추성요붕증은다양한원인에의해시상하부-뇌하수체후엽체계의손상이발생하면서항이뇨호르몬의합성이나분비저하가초래되는매우드문질환이다. 그원인으로는두부외상, 두개내종양이나수술, 침윤성병변, 자가면역질환, 유전자돌연변이등이있으며, 30-50% 는원인을밝힐수없는경우로특발성으로여긴다 1). 터너증후군은 1938년처음으로기술되었으며 2), 출생여아 2,000-5,000명중 1명의빈도로발생하는가장흔한성염색체이상질환중하나이다 3). 특징적인임상양상은저신장증과성선발육이상, 전형적인표현형이상이며, 그외에도다양한장기들에서정도의차이를두고이상소견을동반할 Received: 25 March, 2011, Revised: 15 April, 2011 Accepted: 25 April, 2011 Address for correspondence: Ji Eun Lee, M.D. Department of Pediatrics, Inha University School of Medicine, Sinheung-dong 3-ga, Jung-gu, Incheon 400-711, Korea Tel: +82.32-890-3617, Fax: +82.32-890-2844 E-mail: anicca@inha.ac.kr 론 수있다. 대부분심혈관계질환, 신기형, 안과적이상및내분비질환등을동반한다고알려져있다. 그러나동반된이상으로중추성요붕증이보고된적은드물다 4). 저자들은터너증후군여아에서특발성중추성요붕증이동반된 1례를경험하여보고하고자한다. 증례환아 : 김, 여자, 12세 8개월주소 : 1년전부터시작된구갈 (thirst) 및수분과다섭취, 다뇨현병력 : 재태연령 40주, 2.5 kg, 자연분만으로출생했으며성장하면서언어발달지연및경증의지능저하가있었다. 또래에비해항상키가작았다고했으나, 검사를받은적은없었다. 1년전부터소변횟수및소변량증가를동반한갈증호소와다량의물섭취가시작되었으며야간수면중에도깨서소변누고물마시는등야뇨및다뇨가진행하여병원을방문하게되었다. 하루수분섭취량은 4-5 L이었고, 하루소변량은 4 56 대한소아내분비학회지 : 제 16 권제 1 호 2011 년
L 정도였으며최근체중감소는없었다. 과거력 : 머리부상이나신경관련질환병력은없었다. 가족력 : 특이한사항이없었다. 진찰소견 : 신체계측에서는신장이 127 cm (height SDS, -3.5) 체중이 41 kg (weight SDS, +0.1), body mass index (BMI) 는 27.3 kg/m 2 이었고, 복부 / 엉덩이둘레비는 1.2로복부비만을보였다. 얼굴에서는소하악증, 내안각췌피, 낮은후두모발선이있었고신체검사에서방패가슴, 외반주, 손발의부종및성적유치증 ( 성성숙도유방발달 1단계, 음모발달 1단계 ) 이있었다. 피부발진등은없었다. 전체적인검사 : 염색체검사에서환아의핵형은 45,X/ 46,XX 이었다. 기본혈액검사에서나트륨 144 meq/l, 칼륨 4.0 meq/l, 염소 106 meq/l였고, 혈청삼투압은 309 mosm/ kg로높은반면, 요비중 1.005, 요삼투압은 73 mosm/kg로저하가관찰되었다. 총콜레스테롤 241 mg/dl, 중성지방 209 mg/dl, 고밀도지질단백질콜레스테롤 34 mg/dl, 저밀도지질단백질콜레스테롤은 176 mg/dl이었다. 간기능검사에서 aspartate aminotransferase (AST) 101 IU/L, alanine aminotransferase (ALT) 186 IU/L로증가되어있었고혈청 β- human chorionic gonadotropin (HCG) 1.0 mu/ml, 뇌척수액 β -HCG 1.04 mu/ml, alpha-fetoprotein (AFP) 1.7 ng/ml로정상범위내있었으며 insulin-like growth factor (IGF)-1 347.5 ng/ml 였다. 1. 수분제한검사 8시간수분제한후오전 8시에검사를시작하였으며첫검사에서요비중 1.010, 요삼투압 154 mosm/kg, 혈청삼투압 309 mosm/kg, 혈청나트륨 144 meq/l 로환아는이미심한갈증을호소하고있었다. 2시간수분제한을하는동안에도환아는 40분간격으로소변량 200 ml 정도누었고 38 C의발열이발생하며급격한탈수증상을보여즉시항이뇨호르몬을투여하였다. 투여직전혈청삼투압은 321 mosm/kg, 혈청나트륨 152 meq/l까지증가한반면, 요비중 1.010, 요삼투압 247 mosm/kg로경미하게증가하였다. 항이뇨호르몬투여후소변량이감소하면서, 요비중 1.020, 요삼투압이 680 mosm/kg로급격히증가하여중추성요붕증에합당하였다. 기본 ADH 수치는 0.56 pg/ml였고, 항이뇨호르몬투여전수치는 0.66 pg/ml였다. 2. 경구당부하검사내원시시행한혈당수치는 270 mg/dl였고 HbA1c 5.7% 였다. 수분제한검사시행후탈수를충분히교정한상태에서 3 일후경구당부하검사를시행하였다. 공복혈당은 116 mg/dl, 120분혈당이 256 mg/dl로서내당능장애에서당뇨병으로진행되는상태로판단되었다. 3. 뇌하수체호르몬검사 (Table 1) 갑상샘기능검사는 free thyroxine (T4) 1.19 ng/dl, triiodo thyronine (T3) 131 ng/dl, thyroid stimulating hormone (TSH) 5.62 miu/l으로정상이었고초기검사에서 luteinizing hormone (LH) 2.49 miu/ml, follicle stimulating hormone (FSH) 18.5 miu/ml, estradiol 42.6 pg/ml였다. 복합뇌하수체전엽호르몬유발검사에서성장호르몬최고치는 10 ng/ml 이상으로결핍은없었으며, LH 최고치 16.4 miu/ml, FSH 최고치 58.2 miu/ml로성선자극호르몬증가성성선저하증에합당한소견을보였다. Cortisol 최고치는 26.7 µg/dl로결핍은없었으며 prolactin 수치는기저치 8.96 ng/ml, 최고치 31.2 ng/ml 로정상이었다. TSH 최고치 35.9 mu/l로약간증가되어있었다. 4. 영상검사 골연령은 12세였다. 뇌하수체자기공명영상에서는뇌하수체줄기비후가있고, T1 조영강조영상에서뇌하수체후엽에고신호강도를보였으며, 뇌하수체전엽과후엽의모양은정상이었다 (Fig. 1A). 복부및골반초음파에서는간에중등도의지방침윤이있었고, 자궁의크기는 2.5 cm으로역연령에비해자궁발육이미숙하였으며양측난소는찾을수없었다. 골스캔에서는특이소견이발견되지않았다. 치료및경과 (Table 2): 환아는하루 2회 1-deamino-8-Darginine vasopressin (DDAVP) 을경구복용하면서다음, 다뇨가점차소실되었다. 터너증후군의치료로성장호르몬및여성호르몬제투여를시작하였고, 당뇨병치료제로메트포민 (metformin) 투여를병행하였다. 치료 6개월째항티로글로불린항체 (anti thyroglobulin antibody) 487.6 U/mL( 정상범위 1-100), 항미소항체 (antimicrosomal antibody) 500 U/mL ( 정상범위 1-70) 으로양성인일차성갑상샘기능저하증이발생 Table 1. Combined anterior pituitary test results TSH (miu/l) Prolactin (ng/ml) Cortisol (μg/dl) LH (miu/l) FSH (miu/l) GH (ng/ml) 0 min 30 min 60 min 90 min 120 min 5.62 8.96 26.70 4.67 33.10 1.01 35.90 31.2 8.96 14.80 42.60 8.29 30.40 18.7 8.39 16.40 50.70 18.00 22.50 14.8 18.50 15.70 58.30 15.46 10.60 14.3 17.60 13.30 58.20 9.74 Abbreviations: TSH, thyroid-stimulating hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; GH, growth hormone. 특발성중추성요붕증이동반된터너증후군 1 례 57
Fig. 1. T1-weighted contrast enhanced sagittal images of sella magnetic resonance images taken initially, a year later, and two years later. (A) Initial images reveal a thickened pituitary stalk (3.8 mm) with a strong enhancement in the anterior and posterior pituitary glands, with no definitive abnormal pituitary mass. (B) Follow-up imaging taken a year later shows a slightly decreased pituitary stalk thickness (3.3 mm). (C) Follow-up imaging taken two years later demonstrates a nearly normal pituitary stalk thickness (2.7 mm). Table 2. Clinical findings and laboratory results before and after treatment with DDAVP and metformin Clinical findings Height (cm) Weight (kg) Urination volume (L/day) Presence of polydipsia Presence of thirst, nocturia Laboratory results Urine specific gravity Urine osmolarity (mosm/kg) Serum sodium (meq/l) Serum osmolarity (mosm/kg) HbA1c (%) Fasting blood glucose (mg/dl) Abbreviation: DDAVP, 1-deamino-8-D-arginine vasopressin. Before treatment 1 yr after treatment 2 yr after treatment 127 41 4 Yes Yes 1.005 75 144 309 5.7 116 132 41.6 1.8-2.3 1.015 351 145 294 7.2 145 136.8 42.4 1.8-2.3 1.015 408 140 291 7.4 130 하여갑상샘호르몬제투약을시작하였다. 이후정기적인호르몬검사및뇌하수체자기공명영상검사를시행하던중 1 년후추적관찰한뇌하수체자기공명영상에서뇌하수체줄기비후는일부호전되었고 (Fig. 1B), 2년후추적관찰에서는뇌하수체줄기비후가거의정상화되었다 (Fig. 1C). 현재경구 DDAVP 용량은 0.2 mg bid 로유지하고있으며하루소변량은큰변화없이약 2 L로유지되고있다. 고찰중추성요붕증은 25,000 명중 1명의발병률을보일정도로드문질환으로항이뇨호르몬을분비하는시상하부신경이 80% 이상손상되어야다뇨와다음증상이나타난다. 그원인으로는특발성이 30-50% 를차지하는것으로알려져있다. 특발성중추성요붕증의가장흔한뇌자기공명영상소견은뇌하수체후엽신호소실로진단시 94% 의환자에서나타 난다. 본증례에서나타난뇌하수체줄기비후는중추성요붕증소아의약 1/3에서나타난다. 소아에서뇌하수체줄기비후에대한통일된정의및측정방법은없으나, 통상적으로뇌자기공명영상촬영에서뇌하수체줄기의일부분에서측정한직경이 3 mm이상일경우로정의할수있다 5, 6). 뇌하수체줄기비후는특히중추성요붕증의원인질환중생식세포종, 랑게르한스조직구증, 림프구성누두부-뇌하수체염 (lymphocytic infundibulo-hypophysitis) 또는신경뇌하수체염 (infundibulo-neurohypophysitis), 자가면역질환과특발성에서흔하게나타난다. 진단시뇌하수체줄기두께는다양한크기를나타날수있으며, 시간에따라변화가능하다 7). 특발성중추성요붕증소아의 50-60% 에서진단시뇌하수체줄기비후가발견되고, 이중 30-50% 는자연적으로소실되는데, 대부분림프구성누두부-신경뇌하수체염이나림프구성뇌하수체염의가능성이높다 8). 특발성중추성요붕증에 58 대한소아내분비학회지 : 제 16 권제 1 호 2011 년
서뇌하수체줄기비후의발생기전은정확하게알려지지않았으나림프구성뇌하수체염또는누두부-신경뇌하수체염이라불리는자가면역또는염증성질환과관련있는것으로보인다. 본증례의경우진단시중추성요붕증의기저원인으로랑게르한스조직구증이나뇌종양등의가능성을생각하여골스캔이나피부증상을면밀히관찰하였고, 초기에특발성으로진단하였다. 그러나특발성중추성요붕증은두개강내의진행성질환의초기증상으로인할수있어 9) 장기간의정기적인뇌자기공명영상검사를시행하였으며, 추적관찰중랑게르한스조직구증과뇌종양을배제할수있었다. 본증례의경우초기진단시뇌하수체줄기비후가있었으나, 2년관찰과정중에저절로소실된것으로보아그원인으로림프구성누두부-신경뇌하수체염의가능성을고려할수있었다. 림프구성뇌하수체염 (lymphocytic hypophysitis) 은 1962년첫보고된질환으로뇌하수체에염증이생기는매우드문질환이다 10). 이는신경내분비질환의일종으로뇌하수체에자가면역염증이발생하여다양한정도의뇌하수체기능저하증으로발현된다. 림프구성뇌하수체염은발생부위에따라림프구성누두부-전뇌하수체염 (lymphocytic infundibulopanhypophysitis) 과림프구성누두부-신경뇌하수체염이있는데 11), 그중림프구성누두부-신경뇌하수체염은 1970년대소개된특발성중추성요붕증의원인중하나다 12, 13). 평균 30 대여성에게호발하며, 질환의 20-25% 에서시신경염등의자가면역상태가동시에발병한다. 소아나사춘기환아에서의명확한진단기준은없으나 2002년발표된진단기준 (Table 3) 에맞추어본다면본증례의경우림프구성누두부-신경뇌하수체염의증으로진단가능하다 14). 증례에서자가면역질환의일종인하시모토갑상샘염발병과림프구성누두부-신경뇌하수체염으로추정되는특발성중추성요붕증과의관련성을기전으로추측해보았으나알수는없다. 터너증후군에서의임상양상에대한연구는국내에서도밝혀져있다 15-17). 임상양상은특징적인외모외에도동반질환으로신장, 심혈관기형, 갑상샘질환및청력장애등이대표적이며, 뇌하수체나시상하부의병변과의관련성은보고된바없다. 본증례는모자이시즘 (mosaicism) 핵형을가진터너증후군으로내원당시비만, 2형당뇨병전단계, 고지혈증, 비알콜성지방간이있는대사증후군을동반하고있었다. 첫진단시탈수를동일하게유발하는중추성요붕증과내당능장애가합병되어나타난점은흥미로운데검사를위한 8 시간수분제한만으로도환아는소변량감소없는심한구갈을보이면서기초혈액, 소변검사결과는이미요붕증진단기준에합당하였다. 또한초기당화혈색소 5.7% 에비해무작위혈당검사 270 mg/dl 치는탈수로인해과장반응일수있으나탈수교정후시행한경구당부하검사 2시간수치가 256 mg/dl 이었고추적관찰시혈당수치가점차증가하는양상 Table 3. A guide for the diagnosis of lymphocytic infundibulo-neurohypophysitis I. Major symptoms Typical symptoms of diabetes insipidus: polyuria, polydipsia, thirst II. Examination findings 1. Typical examination findings of central diabetes insipidus 2. Radiologic findings of thickening of the pituitary stalk or neurohypophysis, and homogeneous enhancement of the pituitary stalk or neurohypophysis after the administration of contrast material 3. Pituitary biopsy: infiltration of mature lymphocytes or plasma cells, and chronic inflammation III. Reference 1. rmal function of anterior pituitary lobe in many cases 2. Hyposecretion of growth hormone and/or gonadotropins, and hyperprolactinemia in some cases (A) 3. Spontaneous disappearance of thickening of the pituitary stalk or neurohypophysis Criteria of diagnosis: Definite diagnosis: a case including both I and II Suspicious diagnosis: a case including I, II 1, and II 2 (B) (A) There are cases of otherwise typical lymphocytic infundibulo-neurohypophysitis but presenting with extensive and severe adenohypophysial involvement as well (B) Differential diagnosis 1. Germ cell tumors 2. Rathke s cleft cyst 3. Granulomatous hypophysitis (sarcoidosis, Wegener granulomatosis, Langerhans histiocytosis, etc.) 4. Inflammatory pseudotumors: Tolosa Hunt syndrome, etc. Source: Reference 14. 특발성중추성요붕증이동반된터너증후군 1 례 59
으로볼때내당능장애에서당뇨병으로진행되는과정으로평가하였다. 반면추적관찰중항갑상샘항체가양성인하시모토갑상샘염이발생하여갑상샘호르몬제투여를시작하였으나첫검사시 TSH 수치는정상치의상한선이었고 TSH 자극검사에서도경한과장반응을나타내서입원당시무증상성일차성갑상샘저하증이이미시작되었을것으로추측된다. 현재까지터너증후군에서특발성중추성요붕증이발생한경우는국외에서 2례보고되어있다. 1례는 45,X 핵형을가진 17세의터너증후군여아로특발성중추성요붕증이동반되었고, 기타호르몬이상은없었다 18). 다른 1례는 32세여성으로다음, 다뇨증으로검사한결과특발성중추성요붕증이있었고, 터너증후군의전형적인임상양상이있었으며, 45,X 핵형의터너증후군이동반되어있음을확인한경우이다 4). 아쉽게도두증례모두뇌검사로컴퓨터단층촬영만을시행하여뇌하수체줄기비후나뇌하수체후엽신호의이상을알수없었다. 저자들은터너증후군여아에서특발성중추성요붕증이동반된환자의증례를경험하여문헌고찰과함께보고하는바이다. 터너증후군에서중추성요붕증의원인을밝혀내기위해서는추후보다많은보고와연구가필요하다. 요 본증례의환아는염색체검사에서 45,X/46,XX의핵형을가진터너증후군으로진단되었고, 수분제한검사및항이뇨호르몬투여후요삼투압이증가하여중추성요붕증에합당하였다. 또한, 뇌하수체자기공명영상에서뇌하수체줄기의비후를보였으나, 2년관찰과정중에뇌하수체줄기의비후는저절로소실되었다. 터너증후군에서심혈관계질환, 신기형, 안과적이상및내분비질환등이동반되는것으로잘알려져있다. 반면, 터너증후군에서중추성요붕증이보고된적은드물며, 뇌하수체자기공명영상을처음으로시행하였기에보고하는바이다. 약 References 1) Greger NG, Kirkland RT, Clayton GW, Kirkland JL. Central diabetes insipidus. 22 years' experience. Am J Dis Child 1986;140:551-4. 2) Turner HH. A syndrome of infantilism, congenital webbed neck, and cubitus valgus. Endocrinology 1938;23:566-74. 3) Sybert VP, McCauley E. Turner's syndrome. N Engl J Med 2004;351:1227-38. 4) Balkin MS, Hoffman R, Willner J. Idiopathic diabetes insipidus occurring in a patient with Turner's syndrome. Mt Sinai J Med 1978;45:742-7. 5) Schmitt S, Wichmann W, Martin E, Zachmann M, Schoenle EJ. Pituitary stalk thickening with diabetes insipidus preceding typical manifestations of Langerhans cell histiocytosis in children. Eur J Pediatr 1993;152:399-401. 6) Leger J, Velasquez A, Garel C, Hassan M, Czernichow P. Thickened pituitary stalk on magnetic resonance imaging in children with central diabetes insipidus. J Clin Endocrinol Metab 1999;84:1954-60. 7) Ghirardello S, Garrè ML, Rossi A, Maghnie M. The diagnosis of children with central diabetes insipidus. J Pediatr Endocrinol Metab 2007;20:359-75. 8) Maghnie M, Cosi G, Genovese E, Manca-Bitti ML, Cohen A, Zecca S, et al. Central diabetes insipidus in children and young adults. N Engl J Med 2000;343:998-1007. 9) Chung SJ, Lee SY, Shin CH, Yang SW. Clinical, endocrinological and radiological courses in patients who was initially diagnosed as idiopathic central diabetes insipidus. Korean J Pediatr 2007;50:1110-5. 10) Goudie RB, Pinkerton PH. Anterior hypophysitis and Hashimoto's disease in a young woman. J Pathol Bacteriol 1962; 83:584-5. 11) Abe T. Lymphocytic infundibulo-neurohypophysitis and infundibulo-panhypophysitis regarded as lymphocytic hypophysitis variant. Brain Tumor Pathol 2008;25:59-66. 12) Saito T, Yoshida S, Nakao K, Takanashi R. Chronic hypernatremia associated with inflammation of the neurohypophysis. J Clin Endocrinol Metab 1970;31:391-6. 13) Imura H, Nakao K, Shimatsu A, Ogawa Y, Sando T, Fujisawa I, et al. Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus. N Engl J Med 1993;329: 683-9. 14) A Ministry of Health, Labour and Welfare grants-in-aid-forscientific-research intractable disease conquest research enterprise. The surveillance-study group about a hypophysis functional disorder: a guide of a diagnosis and the treatment of the self-immune hypothalamus pituitary gland inflammation (2002 generalization/assignment research report). Tokyo: Ministry of Health, Labour and Welfare, Japan; 2003. p141-3. 15) Yeo CY, Kim CJ, Woo YJ, Lee DY, Kim MS, Kim EY, et al. Clinical disease characteristics according to karyotype in Turner syndrome. Korean J Pediatr 2010;53:158-62. 16) Jang GC, Shin HJ, Kim DH. Clinical manifestations according to karyotype in Turner syndrome. J Korean Soc Pediatr Endocrinol 2000;5:163-70. 17) Choi YM, Jee BC, Choe J, Oh SK, Hwang DY, Suh CS, et al. Clinical and cytogenetic features in Turner syndrome. Korean J Obstet Gynecol 2000;43:295-301. 18) Vulkov I, Spasov S. Association of gonadal dysgenesis and diabetes insipidus. Akush Ginekol (Sofiia) 1973;12:497-500. 60 대한소아내분비학회지 : 제 16 권제 1 호 2011 년