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A 22-year-old man presented to the hospital with a 3-day history of scant hemoptysis, cough, and dyspnea on exertion. He denied any constitutional symptoms. He had no history of infectious contacts, foreign travel, or occupational exposures. He had a history of prior pneumothoraces. Three years ago, a right-sided pneumothorax had been managed with an intercostal chest drain; 1 year ago, a left-sided pneumothorax was managed conservatively. Both occurrences were diagnosed as primary spontaneous pneumothorax. Other past medical history included keratoconus of the left eye that was surgically corrected. He smoked a half-pack of cigarettes daily for 4 years. Both his maternal grandmother and mother had died suddenly during their fourth decade of life of unknown cardiovascular events. He was not taking any prescribed medications.
Physical examination revealed a man in mild respiratory distress with a temperature of 37.8°C, heart rate of 115 beats/min, blood pressure 118/80 mm Hg, respiratory rate of 18/min, and pulse oximetry 91% on room air. He was 184 cm tall with a slender build, prominent eyes, and a thin nose. The skin was subtly translucent, with visible veins over his chest. There were reduced breath sounds auscultated over the right apex. The clinical examination was otherwise normal.
A chest radiograph revealed a small right-sided cavity, and a subsequent computed tomography (CT) scan demonstrated several cavitating lesions and a small right-sided pneumothorax but no evidence of blebs or emphysema (Figure 1). Laboratory work revealed a mild leukocytosis with neutrophilia. Blood and sputum bacterial cultures and human immunodeficiency virus test were negative. Laboratory tests for connective tissue disease with antinuclear antibodies and antineutrophil cytoplasmic antibody were unremarkable.
Figure 1. Computed tomography imaging of the chest, axial section demonstrating right-sided pneumothorax (thin arrow) and cavitary lesion (thick arrow).
[More] [Minimize]The patient received antibiotics and an intercostal chest drain was inserted, with complete resolution of the pneumothorax. He was later discharged with follow-up at the local pneumothorax clinic. During outpatient assessment, a repeat CT scan of the chest showed resolution of most of the previous cavities, but several new cavitating lesions surrounded by ground glass were seen. He proceeded to have a video-assisted thoracoscopic lung biopsy along with right-sided pleural abrasion. Histopathology did not find any evidence of vasculitis; stains for mycobacteria and fungi were negative. The lung biopsy specimen had irregular fibroblastic nodules, osseous metaplasia, and hemosiderin-laden macrophages suggesting recent alveolar hemorrhage (Figure 2).
Figure 2. Histopathology of lung biopsy. (A) Region of reactive pleural and subpleural fibrosis, secondary to previous rupture of bullous/cystically dilated airspaces, and adjacent intra-alveolar hemosiderin-containing macrophages indicative of previous hemorrhage. Magnification ×16. (B) Zoom of A. Note the collections of hemosiderin-laden intra-alveolar macrophages, suggesting previous pulmonary hemorrhage, and foci of intra-alveolar organization with fibrosis. (Lung periphery stained with hematoxylin and eosin. Magnification ×50). (C) Perls’ Elastic Van Giesson (EVG) stain of adjacent section to A at similar magnification. Note iron-containing macrophages staining blue.
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1. What is the most likely diagnosis?
2. How would you confirm the diagnosis?
3. What other potential complications should this patient be screened for?
The differential diagnosis for pneumothorax is extensive (Table 1); however, the patient’s recurrent pneumothorax, physical appearance, and family history of sudden death led to the suspicion of vascular Ehlers-Danlos syndrome (vEDS). In addition, keratoconus is associated with some diseases of altered immunity and connective tissue disorders, including vEDS (1). He did not exhibit the hypermobility of classic Ehlers-Danlos syndrome or the musculoskeletal features or aortic root enlargement of Marfan syndrome. He was referred to medical genetics for COL3A1 gene sequencing, which revealed a novel missense mutation (Gly651Glu) confirming the diagnosis of vEDS.
| Primary spontaneous pneumothorax | |
|---|---|
| Associated with male sex, increased height, thin body habitus, and smoking. | |
| Secondary pneumothorax | |
| Airway diseases | Chronic obstructive pulmonary disease |
| Cystic fibrosis | |
| Asthma | |
| Infectious causes | Tuberculosis |
| Pneumocystis jirovecii pneumonia | |
| Necrotizing bacterial pneumonia | |
| Interstitial lung disease | Idiopathic pulmonary fibrosis |
| Lymphangioleiomyomatosis | |
| Langerhans cell histiocytosis | |
| Lymphocytic interstitial pneumonia | |
| Sarcoidosis | |
| Connective tissue disease | Ankylosing spondylitis |
| Sjögren syndrome | |
| Rheumatoid arthritis | |
| Scleroderma | |
| Marfan syndrome | |
| Ehlers-Danlos syndrome | |
| Neoplasm | Bronchogenic carcinoma |
| Metastatic disease | |
| Sarcoma | |
| Miscellaneous | Catamenial pneumothorax |
| Birt-Hogg-Dubé syndrome | |
Ehlers-Danlos syndrome comprises a group of rare inherited genetic disorders of collagen synthesis characterized by several features, such as skin hyperextensibility, joint hypermobility, and tissue brittleness (2). The subtypes are distinguished from one another by the associated genetic mutation, family history, and clinical criteria. The clinical criteria differentially involve the skin, joints, skeleton, and vasculature to varying degrees (2, 3). vEDS is rare, with an estimated prevalence of 1 in 150,000 (4). Because of the association with catastrophic acute viscus and vascular ruptures, vEDS has the worst prognosis of the 13 subtypes (5). The median life span ranges from approximately 48 to 54 years (5, 6). As outlined in Table 2, the 2017 International Classification for vEDS includes major and minor clinical criteria that are suggestive of the diagnosis. In those with a family history of vEDS, arterial rupture or dissection before the age of 40 years, unexplained sigmoid colon rupture, spontaneous pneumothorax with other features of vEDS, or a mix of minor criteria, further work-up for vEDS is required (2).
| Major criteria |
| Family history of vascular Ehlers-Danlos syndrome with documented causative variant in COL3A1 |
| Arterial rupture at a young age |
| Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology |
| Uterine rupture during the third trimester in the absence of previous Cesarean section and/or severe peripartum perineum tears |
| Carotid–cavernous sinus fistular formation in absence of trauma |
| Minor criteria |
| Bruising unrelated to identified trauma and/or in unusual sites, such as cheeks and back |
| Thin, translucent skin with increased venous visibility |
| Characteristic facial appearance (prominent eyes, thin nose, lobeless ears) |
| Spontaneous pneumothorax |
| Acrogeria |
| Talipes equinovarus |
| Congenital hip dislocation |
| Hypermobility of small joints |
| Tendon and muscle rupture |
| Keratoconus |
| Gingival recession and gingival fragility |
| Early-onset varicose veins (younger than age 30 years and nulliparous female) |
Sequence analysis of the COL3A1 gene confirms the diagnosis in more than 95% of cases (5), and reduced type III procollagen production from fibroblasts can also be seen (1). To date, there are at least 600 mutations described in the COL3A1 gene (7), which is normally responsible for generating type III collagen in arteries, lungs, intestines, and uterus. Rare variants in COL1A1 have been reported to cause a phenotype similar to vEDS (2). This autosomal dominant disease can sometimes arise from de novo mutations (8). There is not a clear correlation between genotype and phenotype, although the majority of missense mutations affect the glycine residue in the Gly-X-Y triplet of the major triple helical domain (5). It has also been established that individuals with haploinsufficiency mutations have a lower risk of rupture and a delay in the occurrence of major complications in comparison to individuals with missense and skip mutations (9).
Up to 80% of patients with vEDS may have a life-threatening viscus or vascular rupture before the age of 40 years (5). Prevention and management strategies include avoidance of contact and collision sports and genetic counseling during family planning. There is no consensus on the frequency of surveillance to look for arterial aneurysms; however, scanning of the neck, thorax, and abdominal vessels is recommended on diagnosis and at minimum every few years (1, 6). The optimal time to surgically intervene on an asymptomatic enlarging aneurysm is not currently known (6). Celiprolol is a unique β-blocker with β1-adrenoceptor antagonism and partial β2-agonist activity that leads to lower pulsatile pressure and heart rate. In the only randomized controlled trial ever conducted in vEDS to date, celiprolol demonstrated delayed time to vascular complications compared with placebo (10).
Pulmonary complications are less common, but the incidence of pneumothorax ranges from 16% to 40% (6, 11). The pathophysiology likely relates to injury of alveolar or vessel walls (11). Hemoptysis and lung cavitation can mimic a vasculitic or infectious process. Particularly in this case, where the patient was tall, slender, and an active smoker, the diagnosis of inheritable causes of pneumothorax can often be delayed. This case illustrates the importance of always considering secondary causes of pneumothorax, as failure to diagnose inherited disorders such as vEDS may have catastrophic implications for patients who require screening and treatment for multisystem complications.
1. What is the most likely diagnosis?
vEDS.
2. How would you confirm the diagnosis?
Because of the phenotypic variability and implications of this diagnosis, definitive confirmation requires molecular confirmation of a mutation in the COL3A1 gene.
3. What other potential complications should this patient be screened for?
He should be screened for vascular aneurysms at time of diagnosis and intermittently thereafter, as arterial rupture or dissection is a common cause of death.
The patient had magnetic resonance angiography of his head, chest, and abdomen, which identified a 2.8 × 2.6-cm fusiform abdominal aortic aneurysm. Celiprolol is not currently available in Canada; therefore, he was initiated on bisoprolol for β-adrenergic receptor blockade. He was counseled on the importance of family planning and avoiding contact sports and instructed to wear a medical alert bracelet, as even nonspecific presentations such as abdominal pain should prompt an expedited work-up for visceral or vascular ruptures. At this time, he remains well.
| • | vEDS is a rare but existing cause of pneumothorax, particularly among young people. Prompt diagnosis is critical. | ||||
| • | In those suspected to have vEDS, a COL3A1 gene mutation should be sought. | ||||
| • | All patients with confirmed vEDS should undergo screening for vascular aneurysms and avoid contact sports. Providers taking care of patients with vEDS should be aware of the risk of vascular and viscus ruptures as well as pulmonary complications. | ||||
| • | Screening should be offered to first-degree family members, as vEDS is inherited in an autosomal dominant fashion. | ||||
| 1 . | Byers PH, Belmont J, Black J, De Backer J, Frank M, Jeunemaitre X, et al. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet 2017;175:40–47. |
| 2 . | Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 2017;175:8–26. |
| 3 . | Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ; Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet 1998;77:31–37. |
| 4 . | Cortini F, Marinelli B, Seia M, De Giorgio B, Pesatori AC, Montano N, et al. Next-generation sequencing and a novel COL3A1 mutation associated with vascular Ehlers-Danlos syndrome with severe intestinal involvement: a case report. J Med Case Reports 2016;10:303. |
| 5 . | Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000;342:673–680. |
| 6 . | Oderich GS, Panneton JM, Bower TC, Lindor NM, Cherry KJ, Noel AA, et al. The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience. J Vasc Surg 2005;42:98–106. |
| 7 . | Dalgleish R. Ehlers Danlos syndrome variant database; [revised 2017 April; accessed 2017 Dec 31]. Available from: https://eds.gene.le.ac.uk/home.php?select_db=COL3A1. |
| 8 . | Shalhub S, Black JH III, Cecchi AC, Xu Z, Griswold BF, Safi HJ, et al. Molecular diagnosis in vascular Ehlers-Danlos syndrome predicts pattern of arterial involvement and outcomes. J Vasc Surg 2014;60:160–169. |
| 9 . | Schwarze U, Schievink WI, Petty E, Jaff MR, Babovic-Vuksanovic D, Cherry KJ, et al. Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV. Am J Hum Genet 2001;69:989–1001. |
| 10 . | Ong KT, Perdu J, De Backer J, Bozec E, Collignon P, Emmerich J, et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet 2010;376:1476–1484. [Published erratum appears in Lancet 388:564.] |
| 11 . | Shimaoka Y, Kosho T, Wataya-Kaneda M, Funakoshi M, Suzuki T, Hayashi S, et al. Clinical and genetic features of 20 Japanese patients with vascular-type Ehlers-Danlos syndrome. Br J Dermatol 2010;163:704–710. |
Author disclosures are available with the text of this article at www.atsjournals.org.
