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704
●症 例
要旨:症例は 20歳男性.2003 年に喀血を主訴に初診した.胸部CTにて血液の吸入によると思われるすりガラス影を認めたが診断に至らなかった.経過観察の 2カ月後の胸部CTですりガラス影は改善していたが,空洞を伴う結節影が出現した.4カ月後には新しい結節も出現した.診断確定のため胸腔鏡下肺生検を施行した.その結果,胸膜の剝離と肺組織・肺血管の断裂ならびに肺血腫を認めた.胸膜と肺結合組織の脆弱性が存在すると考え,Ehlers-Danlos 症候群を疑った.培養皮膚線維芽細胞の生化学的解析と遺伝子解析を行い,線維芽細胞 III 型コラーゲン産生の著しい低下と,III 型コラーゲン遺伝子(COL3A1)の変異を認めたため,血管型Ehlers-Danlos 症候群と診断した.喀血,肺裂傷に伴う肺血腫を認めた場合,Ehlers-Danlos症候群も鑑別の一つとして考慮する必要がある.キーワード:Ehlers-Danlos 症候群,肺裂傷,肺血腫,喀血
Ehlers-Danlos syndrome,Laceration of the lung,Hematoma of the lung,Hemoptysis
Fig. 2 Chest CT over time. Chest CT in 2003 showed ground glass opacities indicating pulmonary hemorrhage. Two months later, a nodule emerged in the right lung. Four months later, the shape of the nodule transformed and new lesions emerged.
Fig. 3 a: Macroscopic feature of the pleura. Laceration of the pleura exposing the lung (arrow). b: Cut sur-face of the lung showing hematoma formation (arrow). c: Disrupted tip of the pleura (arrow). Hematoxylin-eosin staining (magnification,×40). d: Disrupted tip of the pleura (arrow). Elastica van-Gieson staining (magnification,×40).
Ehlers-Danlos 症候群による肺裂傷と肺血腫 707
Fig. 4 a: Panoramic view of the lung showing acute and organizing hematomas (boxes). Hematoxylin-eo-sin staining. b: Acute hematoma compressing the surrounding lung tissue. Hematoxylin-eosin staining (magnification,×20). c: Organizing hematoma compressing the surrounding lung tissue and a tiny acute hematoma (arrow). Hematoxylin-eosin staining (magnification,×40). d: Organizing hematoma surrounded by fibrous capsule with no lung tissue in the hematoma. Elastica van-Gieson staining (magnification,×40).
Fig. 5 Analysis of collagen production by cultured fibroblasts. Fluorograms of sodium dodecyl sulphate-polyacrylamide gel electrophoresis of procollagen ob-tained from dermal fibroblasts of the patient and from those of an age and sex-matched normal volunteer. Both fibroblasts were cultured in appropri-ate medium with 5 μCi/mL of 2,3-[3H] proline. After collagen samples were treated with 0.1% pepsin, they were separated by SDS/5% polyacrylamide gel elec-trophoresis in the presence (reduction+) or absence (reduction- ) of 2-mercaptoethanol. Then, the gels were exposed to X-rays. Type I I I collagen secreted by the cells from the patient (P) was much less than that secreted by the control cells (C).
Fig. 6 Genetic analysis examining the mRNA coding sequence of cultured dermal fibroblasts from the patient (COL3A1). A point mutation from guanine (G) to adenine (A) was detected in exon 26 at c. 1808 of COL3A1. ※ indicates positions of glycine.
では IV型 EDSに分類される.本症は臨床的には動脈の断裂による臓器の出血,腸穿孔,子宮破裂などが主要な合併症であり,臨床的には薄く透ける皮膚,甚だしい打ち身(顕著に見られる出血斑),特徴的鳥様顔貌なども重要な臨床所見である.初発症状は易出血性のエピソードが多く,本症例でも 16 歳時のサッカーでの筋肉挫傷手術時に,凝固系に異常がないにも関わらず止血困難で,大量輸血をうけている.また,特徴的な顔貌(半透明な皮膚,大きな眼,細い鼻,小さな口唇,陥没した頬,耳たぶのない耳)を本症の 29%に認めるとされており4),本症例でも細い顎と細い鼻の鳥様顔貌,眼球突出を認めた.そのほかに,軽度の皮膚の非薄化・血管透見,萎縮を認め,また軽度の小関節の過可動も見られた.しかし,これらの所見は皮膚生検のために皮膚科を受診した際,皮膚科医によって初めて気付かれた所見であり,当初の診療を行っていた呼吸器チームではまったく見逃していた所見であった.喀血,肺裂傷様の胸部CT像をみた場合はこれらの身体所見にも注意すべきであろう.肺の結合組織は,主に I型および III 型コラーゲンに
確認するための生化学的検査および遺伝学的検査か解析が必要であり,本症例では獨協医科大学皮膚科学教室で行った,培養線維芽細胞の III 型コラーゲン産生能の著しい低下および COL3A1の変異を証明し,血管型EDSと確定診断した.本例では関節の過可動,皮膚の菲薄化,顔貌異常などに気付いていなかったため,EDSを疑って III 型コラーゲンの異常や遺伝子変異の検索を行った動機はすべて肺病理所見からであった.若年者の喀血,頻回な気胸,出現・消退・変形する結節影などを認めた時には,Ehlers-Danlos 症候群も鑑別診断に含めるべきである.血管型EDSの致命的な合併症を避けるための注意事
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日呼吸会誌 47(8),2009.710
Abstract
A case of Ehlers-Danlos syndrome suspected from pulmonary hematomadue to disruption of the lung
1)Respiratory Medicine, Saitama Cardiovascular and Respiratory Center2)Division of Pathology, Saitama Cardiovascular and Respiratory Center
3)Department of Dermatology, Dokkyo Medical University
A 20-year-old man was referred to our hospital due to hemoptysis. Chest CT showed a ground-glass opacity,suggesting pulmonary bleeding ; however, a diagnosis was not obtained. At a follow-up examination after 2months, Chest CT showed improvement of the ground-glass opacity, however a cavitary nodule had newly ap-peared. Four months later, another new nodule was found on chest X-ray film. Video-assisted thoracoscopic lungbiopsy was performed for pathological diagnosis ; disruption of the pleural, lung and blood vessels, and pulmonaryhematoma were found. We thought of the fragility of the pleuro-pulmonary connective tissue and also thought ofthe probability of Ehlers-Danlos syndrome (EDS). A biochemical analysis of cultured dermal fibroblasts and mo-lecular biological examination revealed decreased production of type III collagen in fibroblasts and COL3A1 muta-tion. We diagnosed this case as vascular EDS. EDS is one of the differential diagnoses in patients presenting he-moptysis and pulmonary hematoma due to disruption of the lung.