Abstract
Ehlers-Danlos syndrome type IV (EDS IV) is caused by mutation within the COL3A1 gene, resulting in the disorder of type III procollagen. The diagnosis is confirmed by demonstrating the synthesis of abnormal type III procollagen molecules from cultured dermal fibroblasts or by identifying the mutation in the COL3A1 gene.
The authors report a case of EDS IV caused by a novel point mutation in the COL3A1 gene in a 16-yr-old female. Recurrent haemoptysis and cavitary formation of the lung were evidence of pulmonary involvement. However, extrathoracic manifestations of EDS IV were mostly absent.
To the best of the authors' knowledge, all previously reported Ehlers-Danlos syndrome IV patients with respiratory disease had the characteristic findings or histories of Ehlers-Danlos syndrome IV. In the present case, connective tissue friability was suspected due to tissue laceration observed in the biopsied lung specimen, and the diagnosis was made beginning from this pivotal finding.
- Cavitary formation in the lung
- Ehlers-Danlos syndrome type IV
- friability of lung tissue
- massive haemoptysis
Ehlers-Danlos syndrome type IV (EDS IV), the vascular type, is the most severe form of Ehlers-Danlos syndromes 1. It is characterized by four diagnostic criteria: easy bruising, thin transparent skin, characteristic facial features, and fatal rupture of the arteries, uterus or intestines, which usually occur at a young age 2, 3. The diagnosis is often made following a catastrophic complication or at post mortem examination 4.
Several cases of EDS IV with respiratory manifestations have been reported 5–9. All of these cases, to the best of the authors' knowledge, were accompanied by such clinical features as characteristic facies, translucent skin, excessive bruising, or a familial history. Described here is the case of a 16-yr-old female with EDS IV for whom the correct diagnosis was difficult to make because of a paucity of extrathoracic findings.
Case report
A 16-yr-old female, who had been in good health, was referred from another hospital because of recurrent haemoptysis. Her facies and skin were normal. Her parents and brother were also in good health. From 6 months prior to hospitalization, she had experienced recurrent haemoptysis approximately once a month, but there was no relationship to menstruation, and transient numbness of the right side of her body was an accompanying symptom.
Haematological studies showed mild anaemia (haemoglobin concentration was 11.4 g·dL−1), and coagulation studies, including bleeding time, were normal. Chest radiography and computed tomography demonstrated a cavitary lesion in the right lung field (fig. 1⇓), but 1-month later the lesion had spontaneously disappeared (fig. 2⇓). Neurological examinations including brain magnetic resonance imaging and electroencephalography failed to reveal any abnormalities. Pulmonary arteriography was performed to detect any abnormalities in the pulmonary vessels, but the results were negative.
Subsequently, wedge arteriography of the right A9 was performed. Immediately after this procedure, haemothorax and massive haemoptysis developed, which were treated with thoracic drainage and transfusion. The haemothorax caused a residual haematoma and accompanying atelectasis in the right lower lobe. The differential diagnosis included trauma, neoplasm, autoimmune diseases, haematologic disorders, and collagen vascular diseases. Two weeks later, thoracotomy was performed for removal of the haematoma and for open lung biopsy.
The biopsied lung specimen revealed marked diffuse haemorrhage, haemosiderosis, and fibrosis with osseous metaplasia. In the areas of the fibrosis, elastic tissue was lacerated and had already disappeared (fig. 3⇓). There was no evidence of vasculitis or bronchiectasis.
These findings indicated the fragility of the lung tissue. Based on this, a connective tissue disorder was suspected and, after obtaining informed consent, biochemical study of biopsied skin tissue was performed.
Analysis of collagen synthesis using dermal fibroblasts was performed as previously described 10. The production of normal type III procollagen was remarkably decreased (fig. 4⇓). Genetic analysis was then carried out by examining the coding sequence of messenger ribonucleic acid (mRNA) of cultured dermal fibroblasts as described 11. A missense base mutation was revealed in the COL3A1 gene heterozygously, which converted the glycine codon GGT at amino acid position 727 to the codon GAT which codes for aspartate. Based on these findings, a diagnosis of EDS IV was made. Mutation at this location had not been previously reported as a cause of this disorder 12. Unfortunately, due to the ethical regulations of the authors' institution, confirmation of the genetic status of the patient's parents could not be carried out.
The patient's postoperative course was uneventful. Five months later, she experienced haemothorax again, but she improved by the use of only conservative therapies.
Discussion
Respiratory system involvement is not common in EDS IV, but when present, pneumothoraces are the most common respiratory complications 6. Haemoptysis, bulla formation, cavitary pulmonary lesions, and fibrous pseudotumour have also been described 5–9. This case was distinctive because all previously reported patients had family histories strongly suggestive of EDS IV, physical findings characteristic of the disorder, or episodes of arterial, intestinal or organ rupture.
Neurological complications including epilepsy 13 and temporary hemiparesis 5 developing in patients with EDS IV have also been reported. It has been suggested that some cases of EDS IV have such neurovascular diseases as microangiopathy and various congenital malformations including cortical dysgenesis, which are difficult to detect with the current conventional neuroimaging techniques 13, 14. The numbness of the body experienced by the patient studied here might be ascribed to such a disorder.
EDS IV results from mutations in the COL3A1 gene which encodes type III procollagen 1, 2, which is a major component of blood vessels, uterus, and intestines 1,15. Fibroblastic cells in the skin of affected individuals have dilated rough endoplasmic reticulum (RER) containing abnormal type III procollagen molecules; in such patients the diameter of collagen fibrils in the skin is small 16. Type III procollagen is a homotrimer of three identical α1-chains. Therefore, by the heterozygous mutation of COL3A1 gene, wild-type homotrimers comprise only one-eighth of the type III procollagen molecules produced 1.
Pepin et al. 4 suggested that there was no apparent relationship between the type of complication and the location of mutations. However, it has also been suggested that the nature of the mutation can relate to phenotype 16–23. Mutations at the very 3' end of the gene generally produce a severe form of the disease, with arterial rupture and markedly reduced life expectancy, and mutations located in the middle part or at the 5' end produce more variable phenotypes and milder variants 1, 17, 18. Smith et al. 16 notes that RER dilation and small collagen fibrils in the dermis are more common with mutation near the C-terminal end of the triple helix, whereas variable fibril diameters reflect mutations more toward the N-terminal in the triple helical domain. However, mutation at the very N-terminal end can produce severe vascular involvement 1, 4. EDS IV is almost uniformly fatal because even a single arterial rupture is often lethal.
Many types of mutations in the gene have already been reported 12, but the present mutation (Gly727Asp, the middle part of the protein molecule) has not been previously documented. At a speculative level, if the parents, whose phenotypes are apparently normal, had been available for examination (they were not, for ethical reasons), and no mutations had been found, it could be concluded that the clinical features seen in the present case were due to the uniqueness of the mutation. A complete map of all the mutations and analyses of the clinical features of this disease will be indispensable for eventually proving this hypothesis.
Acknowledgments
The authors would like to thank A. Sugito, H. Kawana and A. Watanabe.
- Received February 27, 2001.
- Accepted July 3, 2001.
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