Case Report pISSN 1738-2637 J Korean Soc Radiol 2012;67(5):367-370

An Isolated Pulmonary Mimicking a Tumor as the Initial Finding of Vascular Ehlers-Danlos Syndrome1 폐종양으로 오인된 폐혈종이 초기소견으로 발현된 혈관성 엘러스-단로스 증후군1

Eun-Ju Kang, MD1, Ki-Nam Lee, MD1, Pil Jo Choi, MD2, Chang-Seok Ki, MD3 Departments of 1Radiology, 2Thoracic Surgery, Dong-A University Medicine Center, Dong-A University College of Medicine, Busan, Korea 3Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

The vascular type of Ehlers-Danlos syndrome (vEDS) is an uncommon inherited dis- order characterized by abnormalities in type III collagen, presenting itself as arterial Received July 30, 2012; Accepted September 5, 2012 dissection or rupture. We report a case of an isolated mim- Corresponding author: Ki-Nam Lee, MD Department of Radiology, Dong-A University Medicine icking a lung tumor in an 18-year-old man which turned out to be the initial find- Center, Dong-A University College of Medicine, ing of vEDS. and occurred repeatedly for 15 months 26 Daesingongwon-ro, Seo-gu, Busan 602-715, Korea. following the surgical removal of the mass, and were treated by repeated left upper Tel. 82-51-240-5367 Fax. 82-51-253-4931 E-mail: [email protected] and lower lobectomy and thoracotomy. The diagnosis of vEDS was confirmed by pathologic and genetic studies. Copyrights © 2012 The Korean Society of Radiology

Index terms Ehlers-Danlos Syndrome Lung CT

INTRODUCTION ferred to our hospital from another hospital due to recurrent scanty . Physical examination revealed a normal ap- The vascular type of Ehlers-Danlos syndrome (vEDS) is the pearance of the face and skin. His parents were healthy without most severe form of Ehlers-Danlos syndrome. Patients with relevant past medical history. The results of laboratory exami- vEDS show deficiency or abnormality in type III collagen re- nations including study were normal. Chest radio- sponsible for production of vascular structures. The disease graph showed a well-defined mass in the medial aspect of the causes organs to become fragile and vulnerable to rupture, left upper lung zone (Fig. 1A). Chest computed tomography which may lead to sudden death. The diagnosis of vEDS is of- (CT) demonstrated a well-defined, non-enhancing mass of rel- ten delayed until a catastrophic complication occurs or is dis- atively high attenuation (about 75 Hounsfield units) in the left covered in postmortem examination. Here we report an un- upper lobe (Fig. 1B). The initial impression was a benign tumor usual case of an isolated pulmonary hematoma mimicking a that had originated from lung parenchyma. On the lung CT lung tumor in an 18-year-old man which turned out to be the scan, the adjacent lung parenchyma was clear and there was no initial finding of vEDS. evidence of aspiration or bronchiectasis. For pathological confirmation of the diagnosis, surgical removal of the mass was CASE REPORT performed using video-assisted thoracoscopic surgery which revealed an old hemorrhage and benign fibrosis. There were no An 18-year-old man, who had been in good health, was re- complications during or immediately after surgery. Six months submit.radiology.or.kr J Korean Soc Radiol 2012;67(5):367-370 367 Vascular Ehlers-Danlos Syndrome after discharge, the patient revisited the hospital due to dys- III collagen gene (COL3A1) was performed after obtaining in- pnea, and his chest radiograph revealed a left-sided pneumo- formed consent from the patient. A heterozygous mutation in thorax (Fig. 1C). A chest tube was inserted, and chest CT exon 13 at c.889 of the COL3A1 gene from guanine to adenine showed a huge cavity with internal air-hemorrhage level in the (c.899G > A) was detected (Fig. 1F). This mutation converted left lower lobe, and a smaller cavity surrounded by patchy glycine to aspartate at amino acid position 300 (Gly300Asp). ground-glass opacity in the left upper lobe (Fig. 1D, E). A large Based on these findings, a diagnosis of vEDS was made. amount of blood was continuously drained (> 150 mL/min) Eleven months after the initial presentation, the patient de- through the inserted chest tube, and the huge hemorrhagic veloped dyspnea and the chest radiograph at this time showed cavity was shown to almost completely occupy the left lower a right-sided pneumothorax. He was treated via chest tube in- lobe, for which the patient underwent a left lower lobectomy. sertion without any complications. He again developed dys- Immediately after this surgical procedure, hemothorax and pnea with hemoptysis after 2 months, and a large hematoma massive hemoptysis developed, which were treated with an ad- with surrounding hemorrhage was detected on chest radiogra- ditional operation of a left upper lobectomy and thoracic drain- phy (Fig. 1G). A chest CT scan detected small air cavities in the age. The lung specimen revealed an organized hematoma with large hematoma accompanied with pneumothorax (Fig. 1H). cavity formation, and an old and fresh intraparenchymal hem- Because the patient’s vital signs were unstable, he was managed orrhage. There was no evidence of vasculitis or bronchiectasis. only by conservative therapies, such as controlling blood pres- A genetic study was performed in order to determine the fra- sure by keeping him in an absolute bed rest state in the inten- gility of the underlying lung tissue that may have caused the re- sive care unit. Operation or endovascular treatment was not current hematoma and pneumothorax. An analysis of the type considered at this point. After receiving conservative manage-

A B C D

E F G H Fig. 1. Sequential chest radiograph and CT images of an 18-year-old man with vascular Ehlers-Danlos syndrome. A. Chest radiograph shows a well-defined mass in the medial aspect of the left upper lung zone. B. Chest computed tomography (CT) demonstrates a well-defined, non-enhancing mass of relatively high attenuation (about 75 Hounsfield units) in the left upper lobe. C-E. Chest radiograph and CT obtained six months later. The chest radiograph reveals a left-sided pneumothorax (C). A chest tube was inserted, and chest CT shows a huge cavity with internal air-hemorrhage level in the left lower lobe and a small cavity surrounded by patchy ground glass opacity in the left upper lobe (D, E). F. Direct sequencing analysis in the patient demonstrates a heterozygous variation (c.899G > A) resulting in a p.Gly300Asp mutation in the COL3A1 gene. G, H. Chest radiograph and CT obtained thirteen months after the initial presentation. A large hematoma with surrounding hemorrhage is de- tected on chest radiography (G). The chest CT scan shows small air cavities in the large hematoma and a small amount of pneumothorax (H).

368 J Korean Soc Radiol 2012;67(5):367-370 submit.radiology.or.kr Eun-Ju Kang, et al ment for about 1 month, the patient was discharged from the ma appearing as a solitary lung mass without any other accom- hospital. On serial follow-up chest radiography, the size of the panying radiologic findings (e.g. pneumothorax, hemothorax hematoma was decreased but not completely resolved. Also, re- or cavity formation) or clinical manifestations has not been re- petitive pneumothorax and other small developed. ported previously as an initial manifestation of vEDS. It may Currently, the patient is under close observation with his blood have been caused by silent laceration of the lung parenchyma pressure under control at the cardiovascular department of our which formed a chronic organized hematoma that mimicked a hospital. solitary pulmonary mass. Because vEDS has the worst prognosis of all types of EDS, bio- DISCUSSION chemical confirmation is necessary to establish the diagnosis. Di- agnosis is made by demonstration of structurally abnormal colla- EDS is an uncommon inherited disorder characterized by gen III or direct mutation analysis (1-6). Patients with this type of abnormalities in the components of the extracellular matrix EDS should avoid heavy physical exercise and playing musical such as collagen, which cause hyperextensibility of the skin, hy- instruments, all of which could increase intrathoracic pressure permobility of large joints and easy bruising (1). The frequency (9). Coughing and constipation should be prevented since the of this syndrome is reported to be 1 in 10000 (2). EDS was clas- fragile intestinal walls can cause a high recurrence rate of colon sified into the following six types in a conference at Ville- perforation (10). Pregnancy should be closely monitored due to franche in 1997, drawing upon the accumulated clinical experi- an increased risk of death from uterine rupture (5). ence and advances in molecular genetics: the classic type, the There are some controversies regarding the therapeutic op- hypermobility type, the vascular type, the kyphoscoliosis type, tions for vEDS, due to a broad spectrum of disease manifesta- the arthrochalasia type and the dermatosparaxis type (3). tions. Conservative management with regulation of blood pres- The vEDS is an autosomal dominant inherited disease sure is the treatment traditionally recommended for vEDS caused by a single allele mutation in the COL3A1 gene coding patients with asymptomatic complications. Patients with frank for type III collagen, which results in qualitative or quantitative require emergent operative repair or catheter-directed abnormalities of mature type III collagen protein (1). The vEDS embolization (11). Currently, there is no effective method to accounts for less than 4% of all EDS patients and has the worst prevent the complications associated with vEDS. Further stud- prognosis (4). The most common initial complications in vEDS ies are required to determine how to prevent these complica- patients are arterial dissection or rupture and gastrointestinal tions using gene therapy (1). rupture; these initial complications rarely develop in other organs We had made two mistakes during the process of diagnosis (5). In vEDS patients, skin hyperextensibility and joint hypermo- and treatment of the present case. First, we should have consid- bility are uncommon findings, which make vEDS different from ered a follow up image study with conservative treatment or the other types of EDS (1). The vEDS patients demonstrate ec- CT guided transthoracic needle biopsy instead of surgical re- chymosis, translucent skin and a distinctive facial appearance moval since the first impression of the solitary mass was of a with prominent eyes, a thin pinched nose, small lips, hollow benign nature and the first excisional operation may have influ- cheeks, and lobeless ears (2). enced all the sequential hemorrhagic events or accelerated the The most common respiratory complication of vEDS is complications. Second, after excision of the mass, the specimen spontaneous pneumothorax. Since type III collagen is synthe- showed only an old hemorrhage with fibrotic tissue. At that time, sized not only in the vessel walls but also by fibroblasts within we should have evaluated the cause of hemorrhage through a ge- the lung parenchyma, tears in the lung parenchyma are not un- netic study, and determine the treatment plan with consider- common in these patients (6). Additionally reported findings ation of the background connective tissue disorder. include hemothorax due to ruptured thoracic arteries, thick- In summary, we report here a rare case of vEDS with a unique walled cavities, bullous lung disease and bronchiectasis (7, 8). initial presentation of an isolated pulmonary hematoma. Al- To the best of our knowledge, an isolated pulmonary hemato- though the diagnosis of vEDS depends on pathologic and ge- submit.radiology.or.kr J Korean Soc Radiol 2012;67(5):367-370 369 Vascular Ehlers-Danlos Syndrome netic studies, vEDS should be suspected in cases of pulmonary the vascular type. N Engl J Med 2000;342:673-680 hematoma or repetitive pneumothorax and hemorrhage of un- 6. Selim B, Lane CR, Rubinowitz AN, Siner JM. Spontaneous known origin. hemothorax and recurrent hemoptysis in a 26-year-old man with skin lesions. Chest 2010;137:480-483 REFERENCES 7. Herman TE, McAlister WH. Cavitary pulmonary lesions in type IV Ehlers-Danlos syndrome. Pediatr Radiol 1994;24: 1. Watanabe A, Shimada T. Vascular type of Ehlers-Danlos 263-265 syndrome. J Nippon Med Sch 2008;75:254-261 8. Ishiguro T, Takayanagi N, Kawabata Y, Matsushima H, Yo- 2. Abel MD, Carrasco LR. Ehlers-Danlos syndrome: classifica- shii Y, Harasawa K, et al. Ehlers-Danlos syndrome with re- tions, oral manifestations, and dental considerations. Oral current spontaneous pneumothoraces and cavitary lesion Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102: on chest X-ray as the initial complications. Intern Med 582-590 2009;48:717-722 3. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wen- 9. Dimsdale JE, Nelesen RA. French-horn hypertension. N strup RJ. Ehlers-Danlos syndromes: revised nosology, Ville- Engl J Med 1995;333:326-327 franche, 1997. Ehlers-Danlos National Foundation (USA) 10. Sykes EM Jr. Colon perforation in Ehlers-Danlos syndrome. and Ehlers-Danlos Support Group (UK). Am J Med Genet Report of two cases and review of the literature. Am J 1998;77:31-37 Surg 1984;147:410-413 4. Germain DP. Clinical and genetic features of vascular 11. Oderich GS, Panneton JM, Bower TC, Lindor NM, Cherry Ehlers-Danlos syndrome. Ann Vasc Surg 2002;16:391-397 KJ, Noel AA, et al. The spectrum, management and clinical 5. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year and genetic features of Ehlers-Danlos syndrome type IV, experience. J Vasc Surg 2005;42:98-106

폐종양으로 오인된 폐혈종이 초기소견으로 발현된 혈관성 엘러스-단로스 증후군1

강은주1 · 이기남1 · 최필조2 · 기창석3

혈관성 엘러스-단로스 증후군은 드문 유전질환으로 3형 교원질의 이상이 특징이며 주로 동맥박리와 파열로 나타난다. 저 자들은 18세 남자에서 폐종양으로 오인된 고립된 폐혈종이 초기소견인 혈관성 엘러스-단로스 증후군을 보고한다. 종양 의 수술적 제거 이후에 15개월 동안 기흉과 혈흉이 반복적으로 나타났고 좌상엽 및 좌하엽절제술과 흉강절개술을 다수 시행하여 치료하였다. 병리학적 유전학적 검사를 통해 혈관성 엘러스-단로스 증후군으로 진단되었다.

동아대학교 의과대학 동아대학교의료원 1영상의학과, 2흉부외과, 3성균관대학교 의과대학 삼성의료원 진단검사의학과

370 J Korean Soc Radiol 2012;67(5):367-370 submit.radiology.or.kr