Endocrinol Metab. 25(2):142-146, June 2010 CASE REPORT 전두엽위축과정신지체를동반한칼만증후군 (Kallmann s Syndrome) 1 예 현소영 박승국 1 강동구 정승욱 이대호 고관표 제주대학교의과대학내과학교실, 가정의학과교실 1 A Case of Kallmann s Syndrome with Frontal Lobe Atrophy and Mental Retardation Soyoung Hyun, Seungguk Park 1, Dong Gu Kang, Seung Uk Jeong, Dea Ho Lee, Gwanpyo Koh Departments of Internal Medicine and Family Medicine 1, Jeju National University School of Medicine, Jeju, Korea Kallmann s syndrome is a rare condition, and this is defined as hypogonadotropic hypogonadism and anosmia or hyposmia. The syndrome may be associated with cleft lip, cleft palate, color blindness, skeletal abnormalities, renal agenesis, sensory neural hearing loss, obesity, etc. About 10 cases of Kallmann s syndrome have been reported in Korea, but there are no reports on cases of Kallmann s syndrome with atrophy of the frontal lobe, severe mental retardation and unilateral renal agenesis. We experienced a case of 17-year-old boy with abnormalities of the olfactory system, as was noted on magnetic resonance imaging (MRI). He had an atrophy of the frontal lobe, mental retardation, a micropenis and unilateral renal agenesis. Hormonal assay documented low levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and thyroid-stimulating hormone (TSH). So, we report here on an unusual case of Kallmann s syndrome along with briefly reviewing the relevant medical literature. (Endocrinol Metab 25:142-146, 2010) Key Words: Frontal lobe atrophy, Kallmann s syndrome, Mental retardation 서론 증례 칼만증후군 (Kallmann s syndrome) 은성선기능저하증과함께후각신경계의발달이상이동반되어나타나는드문유전질환으로성선자극호르몬 (gonadotropin) 단독결핍의흔한원인중의하나이다. 임상적으로는성선기능저하증이나무후각증외에구순열, 구개열, 잠복고환, 색맹, 청각장애, 신장기형및골격계이상등의여러가지신체적이상이동반될수있다 [1]. 지금까지칼만증후군증례는국내에서 10여차례보고되었으나전두엽위축과중증정신지체가동반된경우는없었다. 이에저자들은전두엽위축및중증정신지체와일측성콩팥무형성이동반되었던증례를경험하였기에문헌고찰과함께보고하는바이다. Received: 23 June 2009, Accepted: 27 January 2010 Corresponding author: Gwanpyo Koh Department of Internal Medicine, Jeju National University Hopital, 1753-3 Ara 1-dong, Jeju 690-716, Korea Tel: +82.64-717-1520, Fax: +82.64-717-1131, E-mail : okdom@medmail.co.kr 17세남자가성적유치증을주소로본원내분비내과에내원하였다. 과거력에서정상분만으로태어났고출생당시구순열, 구개열등의기형은없었다. 초기아동기에발달상태가전반적으로느려서 20 개월후에서고걷기가가능하였으며, 4-5세경이되어서야말하기시작했다고하였다. 8세때정신지체장애 3등급으로진단받았고현재장애학교고등 1학년으로재학중이었으며또래에비해사춘기가늦은상태였다. 환자는냄새를못맡는다고느낀적은없었으며, 화장실악취와커피냄새는맡을수있다고하였다. 1남 1녀중큰아들이었고부모와형제들의특이질환과기형의병력은없었으나환자이모의큰아들과외삼촌의큰아들이정신지체진단을받은병력이있었다. 진찰소견에서신장 183 cm, 체중 95 kg, 체질량지수 28.35 kg/ m 2 이며허리둘레 114 cm, 엉덩이둘레 106 cm, 완폭 (arm span) 193.5 cm였다. 양쪽유방비대가있었고 (Fig. 1) 음경의길이는약 5 cm이었으며고환의부피는오른쪽이약 5 ml, 왼쪽은정상으로측정되었다. 음경은 tanner stage II였고, 턱수염및액와모, 음모가없어서
A Case of Kallmann s Syndrome with Frontal Lobe Atrophy and Mental Retardation 143 Fig. 2. The patient revealed to be delayed sexual development with small testis and penis volume of right testis is 5 ml and left testis is normal volume. Length of penis is 3.5 cm (Tanner stage II). There are no pubic hairs and axillary hairs (Tanner stage I ). Fig. 1. General appearance of the patient. tanner stage I으로관찰되었다 (Fig. 2). 입원당시생체징후는혈압 130/80 mmhg, 맥박수 100회 / 분, 호흡수 18회 / 분, 체온 36.6 였다. 흉부신체검사에서호흡음은정상이었고, 심박동은규칙적이었으며심잡음은들리지않았다. 복부신체검사에서간과비장의종대는관찰되지않았고복부종괴도촉지되지않았다. 말초혈액검사에서혈색소 13 g/dl, 백혈구 8,700/µL, 혈소판 242,000/µL 이었고, 혈청생화학검사에서공복혈당 100 mg/dl, 총단백 7.6 g/dl, 알부민 3.4 g/dl, 총빌리루빈 0.3 mg/dl, AST 20 IU/L, ALT 23 IU/L, BUN 29.9 mg/ dl, 혈청크레아티닌 1.7 mg/dl, 총칼슘 8.7 mg/dl, 나트륨 141 meq/l, 칼륨 3.8 meq/l, 요검사에서단백뇨 3+, 적혈구 1+ 이었다. 크레아티닌상승과단백뇨소견이관찰되었으므로 24시간단백뇨정량검사를시행하였고그결과, 1,853 mg/day 로측정되었으나혈청핵항체와보체및한랭글로불린은정상범위였고, 면역글로불린 A 가 713.9 mg/dl이었으며나머지면역글로불린은정상이었다. 기저호르몬검사에서에스트로젠 7 pg/ml 이하 (11.6-41.2 pg/ml), 테스 Fig. 3. Abdominal CT scan shows non-visualization of left kidney. 토스테론 0.63 pg/ml (8.8-27.0 pg/ml), 총테스토스테론 36.5 ng/dl (241-827 ng/dl), 난포자극호르몬 (FSH) 0.35 miu/ml (1.4-18.1 miu/ ml), 황체형성호르몬 (LH) 0.32 miu/ml (1.5-9.3 miu/ml), 프로락틴 9.02 ng/ml (2.1-17.7 ng/ml), 인슐린양성장인자 -I (IGF-1) 322.19 ng/ ml (250-499 ng/ml), T3 1.28 ng/ml (0.80-2.00 ng/ml), 유리 T4 1.35 ng/dl (0.93-1.70 ng/dl), 갑상선자극호르몬 (TSH) 2.96 μiu/ml (0.27-4.20 μiu/ml) 이었다. 염색체검사에서는 46, XY의정상핵형을보였고, 방사선학적검사에서흉부 X-선촬영은정상이었으며, 복부컴퓨터단층촬영에서왼쪽콩팥이없음이발견되었다 (Fig. 3). 성선자극호르몬부족의감별검사중뇌하수체자기공명영상에서전두엽위축과소뇌증이관찰되었고뇌하수체의이상은발견되지
144 Hyun S, et al. Fig. 4. Coronal section of brain MRI of the patient shows bilateral absence of both olfactory bulb. But, olfactory sulcus is intact (arrow). Sagittal section of brain MRI of the patient shows an atrophy of frontal lobe and relatively small size brain volume, small size pituitary gland. Table 1. Results of the combined pituitary stimulation test 0 min 30 min 60 min 90 min 120 min Glucose (mg/dl) 98 45 56 79 94 ACTH (pg/ml) 28.27 95.22 181.60 122.90 46.90 Cortisol (µg/dl) 19.49 15.74 23.2 24.35 24.77 GH (ng/ml) 5.63 1.31 3.41 9.60 5.40 FSH (IU/mL) 0.35 2.18 2.37 2.4 2.97 LH (IU/mL) 0.32 3.42 3.78 3.99 4.00 PRL (ng/ml) 9.02 29.98 44.36 38.52 30.75 TSH (µiu/ml) 2.96 4.64 3.84 3.10 2.51 ACTH, adrenocorticotropic hormone; FSH, follicle stimulating hormone; GH, growth hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid-stimulating hormone. Table 2. After result of the post-gnrh priming GnRH and TRH stimulation tests Hormone 0 min 30 min 60 min 90 min 120 min FSH (IU/mL) 2.97 5.32 5.81 5.83 5.65 LH (IU/mL) 2.43 29.03 25.62 23.37 21.08 TSH (µiu/ml) 0.15 3.28 2.69 2.24 1.97 FSH, follicle stimulating hormone; GnRH, gonadotropin releasing hormone; LH, luteinizing hormone; TRH, thyrotropin releasing hormone; TSH, thyroid-stimulating hormone. 않았다. 성선자극호르몬의감소원인중후각계의이상유무를알기위해후각자기공명촬영을시행하였는데 T1, T2 강조영상에서양측의후각망울 (olfactory bulb) 이관찰되지않아서칼만증후군으로진단할수있었다. 하지만후각이랑 (olfactory sulcus) 에는이상이없었다 (Fig. 4). 뇌하수체호르몬이상여부를판별하기위하여 TRH (Protirelin) 200 μg 정주, GnRH (Gonadorelin) 100 μg 정주와인슐린 10 U 정주후시행한복합뇌하수체자극검사결과에서난포자극호르몬, 황체형성호르몬, 갑상선자극호르몬의반응이저하되어있었고, 이를 제외한다른뇌하수체전엽호르몬들은정상반응을보였다 (Table 1). 이후시상하부와뇌하수체성기능저하에대해정확히감별하기위해성선자극호르몬감작 (priming) 후성선자극호르몬자극검사를재시행하기로하였다 [2]. 일주일동안 GnRH 400 µg을매일정주하였고일주일후다시자극검사를하였는데이전검사와비교하였을때난포자극호르몬과황체형성호르몬의뚜렷한상승이있었다. 또한동시에시행한 TRH 자극검사에서갑상선자극호르몬은이전검사와동일하게여전히낮은수치를보였다 (Table 2). 이어시행한
A Case of Kallmann s Syndrome with Frontal Lobe Atrophy and Mental Retardation 145 신체검사에서신경학적장애는발견할수없었고, 정신지체에대한정확한평가를위한 K-WISC III, BGT (Bender Visual-Motor Gestalt Test), ADS ( 시각, 청각 ) 검사에서지능지수 32로중증정신지체로진단되었다. 후각장애에대한객관적판정을위해후각검사 (olfactory identification test) 를시행하였고우측에서 16개항목중 7개, 좌측에서 16개항목중 5개만을감지하여중증정신지체를감안하더라도뚜렷한후각감소를나타냈다. 그외동반될수있는청각이상에대해이비인후과에서구강검사, 유발전위검사 (evoked potential test) 및청력계 (audiometer) 검사를시행하였는데정상이었다. 환자의단백뇨및크레아티닌상승은신장내과협진을통해서신장이한쪽이므로조직검사의금기에해당하여임상적으로왼쪽콩팥무형성에의한이차성국소분절사구체경화증으로추정하였고이에단백뇨치료를위해안지오텐신전환효소억제제복용을시작하였다. 또한환자의성선호르몬감소에대한치료로보호자와유전상담후이차성징발달을유도하기위해 2주간격으로테스토스테론 (Jenasteron) 100 mg을근육내주사하면서현재외래경과관찰중이다. 고찰칼만증후군은성선자극호르몬단독결핍에의한성선기능저하증 (hypogonadotropic hypogonadism) 의가장흔한원인으로, 후각신경계의발육부전이나형성부전과관련하여사춘기발달지연의임상양상과무후각증또는중증의저후각증을특징으로하는유전질환이다 [3]. 상염색체우성및열성등다양한유전방식이알려져있지만환자의대부분은산재성으로나타난다 [4]. 발병률은남자의경우 10,000명당 1명, 여자의경우 50,000명당 1명으로알려져있으며 [5], 이는성염색체관련유전형식의상대적으로높은비율에기인하는것으로보인다 [6]. 1856년 Maestre에의해처음으로기술된후 [4] 1944년 Kallmann이처음성선자극호르몬분비호르몬의결핍에의한성선기능저하증환자를보고하였으며, 1954년 de Morsier 는부검을통해뇌하수체와후각망울의위축을관찰, 이를보고한바있다. 임상적소견으로남자의경우에는성적유치증 (sexual infantilism), 유환관체형 (eunuchoid habitus) 을가지며, 높은목소리와여성형유방이나타나고, 여자의경우에는일차성무월경, 작은크기의난소, 자궁과유방의발달저하, 액와, 음부의음모발달저하, 낮은목소리등이나타나며이외에도신경학적이상으로는경상운동 (mirror movement), 청력소실, 소뇌성운동실조등이있을수있고, 동반기형으로콩팥과골의이상, 색맹, 구순열, 구개열, 비만, 당뇨병등이존재할수있다 [7]. 본증례의환자는전두엽의위축과중증정신지체및일측성콩팥무형성의기형, 비만을동반하였다. 뇌의이상에대한보고는두개내낭종 [8], 해마형성이상을동반하였던경우가있었다 [9]. 칼만증후군은다양한비뇨기계이상을동반할수있고특히 X 연관유전형일경우에일측성혹은양측성콩팥무형성, 저형성, 말굽콩팥, 물콩팥 [10], 양측성방광-요관 -콩팥역류 [11] 와왼쪽요관중복이상이동반된다 [12]. 칼만증후군의진단은동반되는여러가지기형을바탕으로성선호르몬검사와염색체검사, 방사선학적검사등을종합하여판단할수있는데, 성선자극호르몬자극검사에대한황체형성호르몬, 난포자극호르몬의반응을보면무반응과난포자극호르몬단독반응, 황체형성호르몬단독반응, 난포자극호르몬및황체형성호르몬정상반응등매우다양하게나타날수있다. 또한 Yoshimoto 등 [2] 은성선자극호르몬 (LHRH) 을매일 400 μg씩 2-23일정맥주사후황체형성호르몬의급격한상승을보고하여 7일이상투여후뇌하수체반응이정상으로회복됨을주장하였다. 성선자극호르몬을여러번투여할때는대부분황체형성호르몬과난포자극호르몬이증가하게되며특히, 생리적용량을박동성방법으로투여하면정상분비능이회복되는것으로알려져있다 [13]. 뇌하수체-갑상선호르몬분비능을살펴보면 T3, T4, 유리 T4는정상이나, 일부에서갑상선자극호르몬분비호르몬 (TRH) 에대한갑상선자극호르몬반응저하가있는경우가있다 [4]. 그러나본증례에서갑상선자극호르몬분비호르몬에대한갑상선자극호르몬의반응만으로는시상하부와뇌하수체의결함을감별할수없었다. 칼만증후군의치료로는정상적인이차성징발현과월경을위해서테스토스테론혹은에스트로젠투여를할수있고, 임신을위해서는황체형성호르몬유사물질인 hcg (human chorionic gonadotropin) 와 hmg (human menopausal gonadotropin) 를함께사용하거나혹은성선자극호르몬박동성펌프 (pulsatile pump) 투여가가능하다. 매회당 25 ng/kg씩 60분, 90분또는 120분간격으로정맥주사나피하주사를해야한다 [14]. 정상적인성기능을원하는경우 2주마다 50-100 mg의테스토스테론투여로시작하여 200-300 mg으로증량하여사용할수있는데, 이경우정자형성을유도할수는없으며장기간사용하면전립선암, 간기능장애, 혈구생성촉진, 유방비대의합병증이발생할수있기때문에일시적인방법으로이용된다 [15]. 본환자의경우유전상담후이차성징발현을위해테스토스테론 (Jenasteron) 을투여하면서추적관찰중이다. 국내에서는 1980년이후칼만증후군에대한보고가 10 예정도있었으나 [16-20] 전두엽위축과정신지체가동반된예는없었다. 본환자의경우유전자검사를시행하지않았으나칼만증후군의가족력이없는것으로보아산재성인경우로추정되며 KAL gene 이나기타알려진유전자에대한검사가추가적으로이루어져야할것으로여겨진다. 요약저자들은성적유치증으로내원한 17세남자의검사결과에서성선자극호르몬및남성호르몬의부족과함께후각계의이상이관찰되어칼만증후군으로진단할수있었다. 본환자의경우칼만증후군
146 Hyun S, et al. 에서는지금껏보고되지않았던전두엽위축, 왼쪽콩팥무형성및 중증정신지체를함께동반하였고, 또한갑상선자극호르몬분비호 르몬에대한갑상선자극호르몬의반응저하가관찰되어이에문헌 고찰과함께보고한다. 참고문헌 1. Merriam GR, Beitins IZ, Bode HH: Father-to-son transmission of hypogonadism with anosmia: Kallmann s syndrome. Am J Dis Child 131: 1216-1219, 1977 2. Yoshimoto Y, Moridera K, Imura H: Restoration of normal pituitary gonadotropin reserve by administration of luteinizing-hormone-releasing hormone in patients with hypogonadotropic hypogonadism. N Engl J Med 292:242-245, 1975 3. Naftolin F, Harris GW, Bobrow M: Effect of purified luteinizing hormone releasing factor on normal and hypogonadotrophic anosmic men. Nature 232:496-497, 1971 4. Lieblich JM, Rogol AD, White BJ, Rosen SW: Syndrome of anosmia with hypogonadotropic hypogonadism (Kallmann syndrome): clinical and laboratory studies in 23 cases. Am J Med 73:506-519, 1982 5. Jones JR, Kemmann E: Olfacto-genital dysplasia in the female. Obstet Gynecol Annu 5:443-466, 1976 6. Santen RJ, Paulsen CA: Hypogonadotropic eunuchoidism. I. Clinical study of the mode of inheritance. J Clin Endocrinol Metab 36:47-54, 1973 7. Valk TW, Corley KP, Kelch RP, Marshall JC: Hypogonadotropic hypogonadism: hormonal responses to low dose pulsatile administration of gonadotropin-releasing hormone. J Clin Endocrinol Metab 51:730-738, 1980 8. Moorman JR, Crain B, Osborne D: Kallmann s syndrome with associated cardiovascular and intracranial anomalies. Am J Med 77:369-372, 1984 9. Itoh M, Houdou S, Mizushima M, Tokita Y, Kawahara H, Ishii S, Ohama E: Two autopsied cases of Kallmann s syndrome with dysplasia of the hippocampus. J Child Neurol 12:510-513, 1997 10. Martul P, Pineda J, Levilliers J, Vazquez JA, Rodriguez-Soriano J, Loridan L, Diaz-Perez JL: Hypogonadotrophic hypogonadism with hyposmia, X- linked ichthyosis, and renal malformation syndrome. Clin Endocrinol (Oxf) 42:121-128, 1995 11. O Neill MJ, Tridjaja B, Smith MJ, Bell KM, Warne GL, Sinclair AH: Familial Kallmann syndrome: a novel splice acceptor mutation in the KAL gene. Hum Mutat 11:340-342, 1998 12. Levy CM, Knudtzon J: Kallmann syndrome in two sisters with other developmental anomalies also affecting their father. Clin Genet 43:51-53, 1993 13. Colle ML, Asch RH, Greenblatt RB: Kallmann s syndrome: effect of repeated stimulation of pituitary-gonadal axis with LH-RH. J Reprod Med 18:31-34, 1977 14. Crowley WF Jr, McArthur JW: Simulation of the normal menstrual cycle in Kallmann s syndrome by pulsatile administration of luteinizing hormone-releasing hormone (LHRH). J Clin Endocrinol Metab 51:173-175, 1980 15. Whitcomb RW, Crowley WF Jr: Clinical review 4: Diagnosis and treatment of isolated gonadotropin-releasing hormone deficiency in men. J Clin Endocrinol Metab 70:3-7, 1990 16. Choi YK, Kim YS, Yoo JH, Jung NJ, Lee JI, Kim SW: Hypogonadotropic hypogonadism with anosmia (Kallmann s syndrome) and response to luteinizing hormone-releasing hormone (LH-RH). Korean J Intern Med 23:253-258, 1980 17. Hong SC, Yoo YS, Kim ES, Kim SC, Park SH, Kim JK, Kang SH: Development of KVSS test (Korean version of Sniffin sticks test). Korean J Otolaryngol - Head Neck Surg 42:855-860, 1999 18. Lee EJ, Hong SW, Hong YK, Yoon JS, Mok JO, Kim YJ, Park HK, Kim CH, Kim SJ, Byun DW, Bae WK, Sub KI, Yoo MH: A case of Kallmann s syndrome with unilateral renal aplasia and diabetes mellitus. J Korean Soc Endocrinol 20:96-102, 2005 19. Cho YW, Han SW, Oh DY, Whang SG, Kim SJ, Lee HC, Huh KB: Two cases of hypogonadotropic hypogonadism with anosmia (Kallmann s syndrome). J Korean Soc Endocrinol 5:308-313, 1990 20. Nam YS, Kim NK, Jeong CJ, Cha SH, Cha KY: A case of Kallmann syndrome conceived by administration of gonadotropin. Korean J Obstet Gynecol 45:714-717, 2002