대한안과학회지 2015 년제 56 권제 2 호 J Korean Ophthalmol Soc 2015;56(2):270-274 ISSN 0378-6471 (Print) ISSN 2092-9374 (Online) http://dx.doi.org/10.3341/jkos.2015.56.2.270 Case Report 결막신경종에의해조기진단된다발성내분비종양 1 예 Multiple Endocrine Neoplasia Type 2: Early Diagnosis ased on Conjunctival Neuroma 한규진 하명숙 Kyu Jin Han, MD, Myung Sook Ha, MD, PhD 건양대학교의과대학안과학교실 Department of Ophthalmology, Konyang University College of Medicine, Daejeon, Korea Purpose: To report a case of multiple endocrine neoplasia type 2 (MEN 2) diagnosed early based on conjunctival neuroma. Case summary: 15-year-old female presented with red eye and conjunctival mass in both eyes. 5 x 5 mm-sized yellowish conjunctival mass adjacent to the limbus was observed in her right eye and a 3 x 3 mm-sized mass in her left eye. Excisional biopsy was performed and the patient was diagnosed with conjunctival neuroma. Other abnormalities were not found on the ophthalmic examination, but she had characteristic appearances such as thickened upper eyelid, mild telecanthus and nodular edematous upper lip. She was transferred to the Endocrinology Department for systemic evaluation in consideration of multiple endocrine neoplasia. bdominal pelvic computed tomography and a 24-hr urine collection analysis showed asymptomatic pheochromocytoma. Thyroid ultrasonography and fine-needle biopsy revealed medullary thyroid carcinoma. Finally, MEN type 2 was confirmed by using a RET mutation gene test. Conclusions: Thyroid carcinoma can occur in MEN 2 in combination with pheochromocytoma and mucosal neuroma. Thickened corneal nerve fiber and perilimbal conjunctival mass have been regarded as ophthalmologic characteristics of MEN 2 and may be accompanied by telecanthus, thickened upper eyelid and marfanoid habitus. biopsy of the mass is required for pathological diagnosis. Medullary thyroid carcinoma is the most significant clinical component of MEN 2 syndrome and thyroidectomy is indicated. MEN 2 may be a rare syndrome, but its consequences are serious and the ophthalmologist may play a lifesaving role in its diagnosis. J Korean Ophthalmol Soc 2015;56(2):270-274 Key Words: Conjunctival neuroma, Multiple endocrine neoplasia 다발성내분비종양 (Multiple endocrine neoplasia, MEN) 2형은서로다른 3개의유전성내분비종양을표현형으로 Received: 2014. 5. 10. Revised: 2014. 10. 12. ccepted: 2015. 1. 27. ddress reprint requests to Myung Sook Ha, MD, PhD Department of Ophthalmology, Konyang University Hospital, #158 Gwanjeodong-ro, Seo-gu, Daejeon 302-812, Korea Tel: 82-42-600-9258, Fax: 82-42-600-9251 E-mail: hmseye@kyuh.ac.kr * This study was presented as a poster at the 111th nnual Meeting of the Korean Ophthalmological Society 2014. 하는증후군이다. 다발성내분비종양 2형은갑상선수질암과동반하여부신갈색세포종양, 부갑상선기능항진증이발생하며 2형은다발성내분비종양 2형에점막신경종이동반된다. 이외에마르팡형체형, 위장관계신경절신경종증이동반되기도한다. 1 이중갑상선수질암은초기에진단, 치료가이루어지지않을경우, 사망률이높으므로예방적갑상선절제술이필요하다. 2 다발성내분비종양 2형은다발성내분비종양의아형중에서도가장유병률이낮아, 1,000,000명당 1명정도로낮지만진단이늦어질경우사망률이높아조기진단이중요하며, 이때안면및전안부 c2015 The Korean Ophthalmological Society This is an Open ccess article distributed under the terms of the Creative Commons ttribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 270
- 한규진 하명숙 : 다발성내분비종양환자에서의결막신경종 - 의특징적소견들이도움이될수있다. 3,4 저자들은결막종양을통해조기에다발성내분비종양 2형이진단된환자를경험하였기에이를보고하고자한다. 증례보고 Figure 1. Slit-lamp photographs at the first visit. () Yellowish nodular mass was adjacent to the limbus in the right eye. () The mass presents characteristic plexiform vessels in the left eye. 15세여자환자가양안의안구결막종괴로내원하였다. 환자는 6개월전부터크기가증가하는안구결막종괴와충혈을호소하였으며, 안검염및결막염치료외특이안과적과거력은없었다. 초진시나안시력은양안 0.9였고, 안압은우안 18 mmhg, 좌안 16 mmhg 였다. 세극등현미경검사상우안 5 mm x 5 mm, 좌안 3 mm x 2 mm 크기의연황색결절이각각 7시방향과 2시방향의각막윤부에인접해관찰되었다 (Fig. 1). 결절과인접한각막윤부는불규칙하게두꺼워져있었으나염증소견은없었고, 각막, 망막및시신경의특이이상소견은관찰되지않았다. 특징적으로환자의안면부는경도의눈구석벌어짐증, 두꺼워진상안검, 윗입술의결절형부종이동반되어있었다 (Fig. 2). 이에양안결막조직절제생검술시행하였으며, 병리조직검사상결막기질의신경섬유및신경종이확진되었다 (Fig. 3). 이에저자들은병리조직검사결과와안면부의특징적소견으로다발성내분비종양의심하전신적인검사를위해내분비내과에협진의뢰하였다. 내과검사상부신컴퓨터단층촬영 (drenal dynamic CT) 에서 1.4 cm 크기의우측부신결절이관찰되었고 (Fig. 4), 24 시간소변검사에서메타네프린 (Metanephrine) 133.43 ug/day ( 참조치 : 52-341 ug/day), 노르에피네프린 (Norepinephrine) 83.34 ug/day ( 참조치 : 80 ug/day 이하 ) 측정되어임상적으로부신종양에대해무증상의부신갈색세포종양으로진단되었다. 갑상선초음파검사에서갑상선우측중간엽과좌측중간엽에각각 10 mm, 5 mm 크기의불규칙한저음영결절이관찰되었고 (Fig. 5), 혈청칼시토닌 (Calcitonin) 69.9 Pg/mL ( 참조치 : 4.8 Pg/mL) 로증가되어있어세침생검술을시행한결과, 병리조직학적으로갑상선수질암이확진되었다. 임상적으로결막신경종과부신갈색세포종양, 갑상선수질암을표현형으로하는다발성내분비종양 2형을확인하였고, 이를 RET 유전자검사를통해확진하였다. 갑상선수질암에대한갑상선절제술및가족력에대한유전상담을권유하였으나, 환자개인적인사정으로타병원으로전원되었다. Figure 2. Clinical photographs. () Photograph reveals mild telecanthus, thickened upper lids. () Photograph reveals nodular mass on the upper lip. 고 찰 다발성내분비종양은서로다른두가지이상의내분비 271
- 대한안과학회지 2015년 제 56 권 제 2 호 - Figure 3. Histologic feature and immunohistochemical staining of the conjunctival neuroma. () Hematoxylin and eosin (H&E) staining shows enlarged nerve fibers (arrow) in the substantia propria ( 100). () Immunohistochemical staining reveals diffuse expression of S100 ( 100). Figure 4. bdomino-pelvic CT shows 1.4 cm-sized nodule (arrow) at the right adrenal gland. () xial plane, () coronal plane. Figure 5. Thyroid ultrsonography shows 0.5 cm-sized irregular marked hypoechogenic nodule (arrow) at the left mid-pole () and 1.0 cm-sized irregular marked hypoechogenic nodule at the right mid-pole (). 로 명명하였다. 다발성 내분비 종양 2형은 2형과 2형의 아 형으로 나뉘며, 다발성 내분비 종양 2형은 갑상선 수질암, 종양을 갖는 증후군으로 Sipple5이 1961년 가족성 갑상선 부신 갈색세포종양, 부갑상선 질환의 표현형을 보이고, 다발 수질암과 부신 갈색세포종양 간의 연관성을 제기한 후, 갑 성 내분비 종양 2형은 갑상선 수질암, 부신 갈색세포종양, 상선 수질암, 부신 갈색세포종양과 부갑상선 종양 또는 비 다발성 점막 신경종의 표현형을 보인다.1 다발성 내분비 종양 대증을 특징으로 하는 질환군을 다발성 내분비 종양 2형으 은 10번 염색체에 위치하는 RET 원발암유전자(Proto-onco- 272
- 한규진 하명숙 : 다발성내분비종양환자에서의결막신경종 - gene) 의돌연변이로인해발생하며유전된다. 다발성내분비종양 2형의 95% 이상은 RET 원발암유전자의 918 코돈 (M918T) 돌연변이로인해발생하며일부 883코돈 (883F) 의돌연변이로인해발생하기도한다. 6 다발성내분비종양 2형의진단시기는생후 2일에서 52 세 ( 평균 18.9세 ) 까지다양하며, 전형적인내분비증상외에전신및다른기관의병변이동반되기도한다. 7 다발성내분비종양 2형환자는진단이전에장기간의설사및변비등의소화기계병력이있거나마르팡형체형, 입술, 혀, 구강점막의결절등을동반한다. 8 마르팡형체형은다발성내분비종양 2형환자의 75% 에서관찰되며, 9 본환자의경우에서도이와같은특징을관찰할수있었다. 환자는양안안구결막종양외에경도의눈구석벌어짐증, 두꺼워진상안검, 윗입술의결절형부종이동반되어있어다발성내분비종양환자에서보이는특징적병변들을관찰할수있었다. 일부에서경도의눈꺼풀처짐, 하안검외반등이보고된바가있었으나, 10 본환자에서는이와같은특징은두드러지지않았다. 그밖에환자가족력상특이점이확인되지않았으나, 환자는소아기의반복적인장염으로잦은입원치료의경력이있었다. 다발성내분비종양 2형환자에서관찰되는구강과입술의병변은비교적어린연령에서첫증상으로나타나지만, 특징적인안검및전안부병변들의발생시기에대해서는알려진바가없다. 11 다발성내분비종양 2형의중요예후인자는갑상선수질암이다. 갑상선수질암의평균 5년생존율은산발형과가족형을포함하여약 80% 로보고된다. 하지만, 다발성내분비종양의갑상선수질암은단독갑상선수질암보다침습적으로진단시 5년생존율이 35% 에불과하며, 진단시림프절전이가존재하는경우가 81% 에달한다. 1 다발성내분비종양 2형은전형적인가족형의형태로무증상시기에유전학적진단이가능하나, 다발성내분비종양 2형은갑상선수질암의치명률이다발성내분비종양 2형보다높을뿐만아니라, 환자의 50% 가산발형의형태로나타난다. 10 Parker et al 10 은다발성내분비종양 2형환자 3명을대상으로관찰되는안과적소견들로두꺼워진각막신경, 눈꺼풀의외반, 눈꺼풀처짐을보고하였고, Eter et al 12 은다발성내분비종양 2형 2명에서두꺼워진각막신경, 결막부종을동반한결막하종양을보고하였다. Jacobs and Hawes 13 는다발성내분비종양 2형 3명에서두꺼워진각막신경을비롯한특징적안과소견이질환의조기진단에중요한단서임을기술한바있다. 국내에서는구강점막, 혀, 입술에서발생한점막신경종을통해다발성내분비종양 2형을조기진단한사례들이보고되었으나, 14 이들보고에서는안과 적평가가이루어지지않았거나, 특이소견이관찰되지않았다. 본증례는결막신경종을통해다발성내분비종양 2 형이조기진단된국내의최초보고로갑상선수질암및갈색세포종양으로인한증상이없는상태에서양안의결막종양및동반된안면부특징을통해비교적이른시기에다발성내분비종양 2형을진단할수있었다. 이전증례들에서두꺼워진각막신경이질환의특징적소견으로발표된바있으나, 본증례의환자에서는각막의특이소견이발견되지않았다. 결론적으로다발성내분비종양 2형이드문질환이기는하나, 그치명률이높고다양한전신질환을동반하므로이에해당하는특징적안면부소견을보이는환자에서는외안부병변에대한진단적조직검사가반드시필요하며, 질환의초기진단에안과적검사가중요한역할을할수있을것으로생각한다. REFERENCES 1) Marsh DJ, Learoyd DL, Robinson G. Medullary thyroid carcinoma: recent advances and management update. Thyroid 1995;5: 407-24. 2) Marsh DJ, Mulligan LM, Eng C. RET proto-oncogene mutations in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. Horm Res 1997;47:168-78. 3) rauckhoff M, Machens, Hess S, et al. Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2: n exploratory analysis. Surgery 2008;144:1044-50; discussion 1050-3. 4) rauckhoff M, Gimm O, Weiss CL, et al. Multiple endocrine neoplasia 2 syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg 2004;28:1305-11. 5) Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. m J Med 1961;31:163-6. 6) Gimm O, Marsh DJ, ndrew SD, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2 without codon 918 mutation. J Clin Endocrinol Metab 1997;82:3902-4. 7) Carney J, Sizemore GW, Hayles V. C-cell disease of the thyroid gland in multiple endocrine neoplasia, type 2b. Cancer 1979;44: 2173-83. 8) Carney J, ianco J Jr, Sizemore GW, Hayles. Multiple endocrine neoplasia with skeletal manifestations. J one Joint Surg m 1981;63:405-10. 9) Morrison PJ, Nevin NC. Multiple endocrine neoplasia type 2 (mucosal neuroma syndrome, Wagenmann-Froboese syndrome). J Med Genet 1996;33:779-82. 10) Parker DG, Robinson G, O'Donnell. External ophthalmic findings in multiple endocrine neoplasia type 2. Clin Experiment Ophthalmol 2004;32:420-3. 11) ine E, ine L, Huupponen T, et al. Visible corneal nerve fibers and neuromas of the conjunctiva--a syndrome of type-3 multiple endocrine adenomatosis in two generations. Graefes rch Clin 273
- 대한안과학회지 2015 년제 56 권제 2 호 - Exp Ophthalmol 1987;225:213-6. 12) Eter N, Klingmüller D, Höppner W, Spitznas M. Typical ocular findings in a patient with multiple endocrine neoplasia type 2b syndrome. Graefes rch Clin Exp Ophthalmol 2001;239:391-4. 13) Jacobs JM, Hawes MJ. From eyelid bumps to thyroid lumps: report of a MEN type IIb family and review of the literature. Ophthal Plast Reconstr Surg 2001;17:195-201. 14) Lee MJ, Chung KH, Park JS, et al. Multiple Endocrine Neoplasia Type 2: Early Diagnosis by Multiple Mucosal Neuroma and Its DN nalysis. nn Dermatol 2010;22:452-5. = 국문초록 = 결막신경종에의해조기진단된다발성내분비종양 1 예 목적 : 결막신경종에의해진단된다발성내분비종양 1 예를보고하고자한다. 증례요약 : 6 개월전부터크기가증가하는양안의안구결막종괴를호소하는 15 세여자환자가내원하였다. 세극등현미경검사상우안 5 mm x 5 mm, 좌안 3 mm x 2 mm 크기의각막윤부와접하는연황색의결절이관찰되었다. 결절과인접한각막윤부는두꺼워져있었으나, 기타안저및시신경의특이소견은관찰되지않았다. 환자는경도의눈구석벌어짐증, 두꺼워진상안검, 윗입술의결절형부종이동반되어있었다. 병리조직검사상결막종괴는결막기질신경섬유및신경종으로진단되었고, 안면부특징상다발성내분비종양이의심되어전신적인검사를시행하였다. 전신검사에서갑상선수질암, 부신갈색세포종양이발견되었고, 유전자검사에서 RET 돌연변이가확인되어다발성내분비종양 2 형으로진단되었다. 결론 : 다발성내분비종양 2 형은유병률은낮지만, 진단이늦어질경우사망률이높아조기진단이중요하며이때안면및전안부의특징적소견들이진단에중요한단서가될수있다. 저자들은결막종양으로조기에다발성내분비종양 2 형이진단된환자를경험하였기에이를보고하고자한다. < 대한안과학회지 2015;56(2):270-274> 274