Chest Imaging Findings and Tissue Biopsy Experience in a Patient with Type IV Ehlers-Danlos Syndrome: A Case Report

Abstract

Vascular Ehlers-Danlos syndrome (EDS) is a rare genetic connective tissue disorder caused by abnormalities in extracellular matrix components, such as collagen. Among the six subtypes of EDS, type IV is known to have the worst prognosis. However, owing to its low prevalence (approximately 4%), diagnosis is often delayed, leading to fatal complications such as bleeding. We report a case of an 18-year-old male who presented with hemoptysis. CT revealed cavitary nodules and signs of bleeding. A biopsy was attempted, during which the bleeding tendency of the patient was noted, and a rapidly progressing pneumothorax developed in both lungs. This led us to suspect a diagnosis of type IV EDS. This case highlights the importance of considering type IV EDS as a differential diagnosis in patients with cavitary nodules and ground-glass opacities on imaging, especially in the presence of increasing pneumothorax and a tendency to bleed.

INTRODUCTION

Ehlers-Danlos Syndrome (EDS) is a rare genetic connective tissue disorder caused by abnormalities in extracellular matrix (ECM) components such as collagen. EDS is classified into six types based on clinical features, inheritance patterns, biochemical characteristics, and molecular biology (1). Among these types, the vascular type, type IV, is known to have the poorest prognosis and is caused by a single allele mutation in the COL3A1 gene, which encodes type III collagen. Patients with this condition have highly fragile blood vessel walls, internal organs, and uterine walls, making them prone to rupture. Unlike other types of EDS, joint hypermobility is rare in type IV, often leading to delayed diagnosis and, consequently, fatal complications such as arterial rupture and bowel perforation are frequently reported (1).

Here, we report a case of an 18-year-old male patient with type IV EDS, in whom a CT-guided lung biopsy was attempted. We aim to share our experience with the CT imaging findings and tissue biopsy in the patient with type IV EDS.

CASE REPORT

An 18-year-old male presented to our hospital with hemoptysis. His past medical history was notable only for Achilles tendon rupture surgery performed approximately 10 years ago. The patient presented with a history of severe vomiting and diarrhea several days before admission. Upon admission, his coagulation tests, blood tests, and vital signs were all within normal ranges. However, elevated cardiac enzymes were observed, with creatine phosphokinase at 2,493 U/L, creatine kinase-MB at 170 ng/mL, and troponin I at 115.0 ng/mL. Notably, no evidence suggestive of acute coronary syndrome was observed using electrocardiography. To identify the cause of the hemoptysis, a chest CT was performed. The CT revealed a cavitary nodule with surrounding ground-glass opacity and consolidation in the left lower lobe. Diffuse ground-glass opacity was also observed around the lesion, and consolidation was noted in the periphery of the lungs. Similarly, a cavitary nodule with surrounding ground-glass opacity was noted in the right lower lobe (Fig. 1). Based on these imaging findings, we first considered the possibility of vasculitis with pulmonary hemorrhage and atypical pneumonia as a differential diagnosis. Considering the clinical presentation, imaging findings, hemoptysis, diarrhea, and the age of the patient, vasculitis-induced hemoptysis and myocarditis were suspected. To eliminate vasculitis, tests for rheumatoid factor, antinuclear antibody, and antineutrophil cytoplasmic antibodies (ANCA) were conducted, all of which were negative. However, as a negative ANCA result does not entirely exclude the possibility of vasculitis, further diagnostic evaluation was required. Multidisciplinary discussion highlighted that a relatively large specimen, such as one obtained through surgical lung biopsy, is recommended for a definitive diagnosis of vasculitis. Simultaneously, considering the negative ANCA result, the possibility of other diseases such as atypical pneumonia could not be excluded. To address both scenarios, a CT-guided percutaneous needle biopsy was planned as the initial diagnostic step, with surgical biopsy reserved as a subsequent option if needle biopsy failed to provide a conclusive diagnosis.

Fig. 1. Chest CT images of an 18-year-old male with type IV Ehlers-Danlos syndrome.

A–F. (A, B) CT axial images show cavitary nodules with surrounding ground glass opacity in both lower lobes (white arrows). Subpleural and parenchymal consolidation with ground glass opacity is noted at left lower lobe. (C–F) CT images taken during a CT guided biopsy. (C) Prior to intervention, CT examination of the lung with grid was performed to determine the optimal direct biopsy route in the prone position. A small cavitary nodule with ground glass opacity was still noted in the left lower lobe. (D, E) A 20 G coaxial needle was advanced at the planned puncture site. Immediate after the coaxial needle passed through the pleura, a small amount of left pneumothorax occurred, despite the needle’s swift passage. A right pneumothorax also developed. Additionally, motion artifacts were noted. (F) Follow-up CT was performed to verify the needle placement and concluding the procedure. The image revealed a significant increase in bilateral pneumothorax, along with an exacerbation of motion artifacts. Due to the rapid increase in bilateral pneumothorax and significant motion artifacts on the CT image, if was no longer feasible to continue the procedure. Consequently, the biopsy needle was not inserted into the coaxial needle, and the procedure was terminated.

To further investigate the cause, a tissue biopsy of the cavitary nodule in the left lower lobe was planned. The biopsy was performed using a core needle biopsy technique under CT guidance, using the coaxial needle method. Despite the patient having normal coagulation and platelet levels, there was a tendency for bleeding. This bleeding was excessive and difficult to control upon lidocaine injection (10 cc syringe, 23-gauge needle) for local anesthesia. A 20-gauge, 20 mm Mission Disposable Core Biopsy Instrument (Bard, Inc. Covington, UK) was used for the lung biopsy. The guiding needle was inserted into the left lower lobe, and a small pneumothorax was detected in the left lung immediately after the needle traversed the pleura on the CT scan. Subsequent CT imaging showed a rapid increase in the size of the pneumothorax. In addition, spontaneous and recurrent pneumothorax was also observed in the right lung, which had not been present on the CT scan taken the previous day. Moreover, the size of the right pneumothorax increased rapidly (Fig. 1). Although the oxygen saturation of the patient was 98%–99%, the rapidly increasing pneumothorax and significant motion artifacts on the CT scan made it impossible to continue the procedure. Therefore, the needle was removed without performing the biopsy.

After the procedure, considering the bleeding tendency of the patient and the occurrence of spontaneous and recurrent pneumothorax in the contralateral lung, type IV EDS was suspected.

The patient revealed no significant family history during clinical interviews. However, his skin was extensible and thin enough to reveal subcutaneous vessels, and joint hypermobility was noted (Supplementary Fig. 1). The history of Achilles tendon surgery was also consistent with the clinical features of EDS (consistent with tendon/muscle rupture, which is one of the minor diagnostic criteria of type IV EDS). Under the strong expectation of type IV EDS, we conducted a genetic test, which confirmed a COL3A1 gene LPV mutation. The patient was ultimately diagnosed with type IV EDS.

Following the diagnosis, bilateral chest tubes were inserted to treat the pneumothorax, which subsequently improved, and antifibrinolytic agents were administered for hemoptysis, resulting in the improvement of symptoms. However, the cavitary nodules and pulmonary consolidation persisted. The patient was discharged with plans for regular follow-up.

This study was approved by our Institutional Review Board (IRB No. 2024-07-010). Given the retrospective nature of the study, the need for informed consent was waived.

DISCUSSION

EDS is a hereditary disorder that affects connective tissue due to mutations in genes responsible for the structure and biosynthesis of collagen, a key component of the ECM (2). The incidence is reported to be 1/10,000–1/25,000, and is characterized by skin hyperextensibility, joint hypermobility, and general connective tissue fragility (3). EDS is classified into six subtypes, with type IV, the vascular type, accounting for approximately 4% of cases. This type is known to have the worst prognosis (4).

Type IV EDS is an autosomal dominant disorder caused by defects in the COL3A1 gene, leading to abnormalities in type III collagen protein (5). Patients frequently present with arterial diseases such as aneurysms, arterial dissections, and arterial dilatations across various vascular sites. Unlike other types, joint hypermobility is rarely observed in type IV (6). Despite normal coagulation profiles, patients may exhibit a bleeding tendency, manifesting as gum bleeding, prolonged post-operative bleeding, extended menstrual bleeding, or widespread bruising. Cases of uterine, visceral organ, and arterial rupture are also frequently reported (7).

Clinically, type IV EDS is characterized by four major features: 1) distinctive facial appearance (acrogeria), 2) thin, translucent skin with visible subcutaneous vessels, 3) easy bruising, and 4) complications involving arteries, internal organs, and the uterus. A clinical diagnosis of type IV EDS can be made if two of these criteria are met. The final diagnosis requires confirmation of a COL3A1 gene mutation through tissue biopsy or molecular biology techniques (8).

Type IV EDS has a high risk of fatal complications, including cerebral hemorrhage, bowel rupture, and uterine rupture during pregnancy. However, type IV accounts for approximately 4% of all EDS cases, making it rare and often resulting in delayed diagnosis. Invasive diagnostic procedures can result in life-threatening complications such as bleeding (8). Surgery should be reserved for emergencies, such as uncontrollable bleeding or rapidly enlarging aneurysms, and conservative management should be prioritized. Patients are advised to avoid strenuous physical activities and contact sports that may cause pressure on the body, such as scuba diving (8). Overall, rapid and non-invasive diagnosis is crucial to prevent fatal complications.

According to a previous study, 57% of patients with type IV EDS exhibited pulmonary abnormalities. The most common abnormalities were emphysema, cavitary nodules, calcified micro-nodules, and hemothorax or pneumothorax (6). The cavitary nodules observed on imaging are likely hematomas resulting from spontaneous rupture of small arteries due to connective tissue fragility, which progress to fibrous nodules and eventually to calcified micronodules (6). Although type IV EDS is a rare condition, pulmonary manifestations are not uncommon. Therefore, it is essential to be familiar with the imaging findings associated with this condition.

Due to the rarity of type IV EDS, studies on the mechanisms underlying the occurrence of pneumothorax are limited. One study reported in 1980 showed a connection between spontaneous pneumothorax and type III collagen deficiency. Subsequent studies have since suggested that pneumothorax arises from pleural weakening and arterial fragility, as large areas of ecchymosis in the thoracic cavity are frequently observed (9). Another study involving autopsies of nine patients with type IV EDS showed that most pulmonary lesions were idiopathic lung tissue lacerations owing to the fragility of the alveolar walls containing type III collagen, which is likely a major factor contributing to parenchymal and pleural damage (10).

This case involves a young male who presented with hemoptysis and exhibited cavitary nodules and ground-glass opacities on CT imaging, suggesting hemorrhage. During the biopsy, the bleeding tendency of the patient was confirmed, and simultaneous pneumothorax developed easily on both sides, leading to the consideration of type IV EDS as a differential diagnosis. The final diagnosis was confirmed through clinical findings, family history, and genetic testing. If this condition had not been recognized and an invasive surgical biopsy had been performed, or if the patient had been followed up only after treatment for pneumothorax and hemoptysis, the outcome may have been fatal. Since genetic mutation testing is a lengthy process, it is crucial to consider this diagnosis as a differential based on imaging findings before reaching a final diagnosis.

In conclusion, when encountering a patient with cavitary nodules and ground-glass opacities on imaging, along with rapidly increasing pneumothorax and bleeding tendencies, type IV EDS should be considered as a differential diagnosis. Overall, prompt diagnosis can significantly reduce the risk of potentially fatal complications in these patients.

Supplementary Materials

Supplementary Fig. 1

Clinical appearance of our patient. Note that extensible and thin, translucent skin (A) and hypermobility of small joint (B).