Approximately 98% of vEDS cases are caused by a mutation in the COL3A1 gene. COL3A1 is composed of 52 exons, and is expressed in the arteries, intestines, lungs and the uterus . Mutations of this gene cause aortic aneurysms, aortic dissection and rupture, gastrointestinal hemorrhage and perforation, uterine rupture, pneumothorax, hemothorax, and, in some cases, sudden death . In most cases, because the glycine that is present in the COL3A1 gene is substituted for other amino acids, the generation of the normal type III collagen is inhibited, and vEDS develops . In our study, our patients also showed a mutation in exon 36 of the COL3A1 gene. This is the first time this heterozygous missense mutation, c.2411 G>T p.Gly804Val (exon 36), has been reported. Although this mutation, c.2411G>T p. G804V, is novel, mutation in the same gene of the same amino acid, c.2410G>A p.G804S, has been reported before .
In adults, symptoms of vEDS are mostly manifested in the cardiovascular system, respiratory system and digestive organs, where this gene is expressed, and are often observed during pregnancy and childbirth. Arterial rupture, arterial dissection and aneurysms are the cardiovascular symptoms reported in 77% of patients . Arterial rupture may occur spontaneously in the thorax or abdomen in 50% of patients . Intestinal rupture, mostly sigmoid, has been reported in 25% of patients with vEDS . Hemopneumothorax, hemoptysis and alveolar hemorrhage have been found in 51% of patients, and have been reported to be the first symptom in 45% of patients . Kawabata et al. previously reported that most pulmonary lesions consist of idiopathic lung tissue lacerations . Chest CT has been reported to show ground glass opacity due to bleeding, a tumor-like shadow due to the presence of a hematoma, a cavernous opacity following the formation of the hematoma, or a cystic shadow and a calcified opacity [6, 8, 11, 12]. In addition, most pleural lesions have been reported to consist of pneumothorax and hemothorax caused by weakening of the pleura and vascular fragility [2, 6, 11–13]. Our patient had gastrointestinal perforation and hemothorax, which are very similar to the complications associated with vEDS.
vEDS is associated with a maximal mortality risk of 12% due to uterine rupture before or after childbirth . Thus, most symptoms of vEDS found in adulthood are severe; one quarter of patients will have experienced symptoms by the age of 20 years, and 80% of patients by the age of 40 years. The average age at the time of death has been reported to be 48 years [2, 4]. In our case, the bleeding following childbirth at the age of 26 years is now believed to be caused by vEDS. Compared to the average age at the time of death reported thus far, our patient has a relatively long-term survival period, the reason for which is unknown. Pepin et al. reported that the complications of vEDS were not associated with specific mutations in COL3A1. In our case, except for the fact that our patient was initially diagnosed at an advanced stage, there was no particularly unusual clinical phenotype.
No causal treatment for vEDS is available, and the current treatment consists mainly of the prevention of complications, as well as symptomatic treatment, including surgery and catheterization . Because catheterization and surgical treatment are highly invasive , conservative treatment is preferred where possible, and when surgery is inevitable the procedure is performed cautiously. The postoperative monitoring needs to be prolonged. Any kind of elective surgery, for example, stripping of varicose veins, is contraindicated. Arteriograms and endoscopies should be avoided . However, because we unfortunately did not notice the presence of vEDS at the time of admission, an emergent surgery for hemopneumothorax was performed, and our patient was consequently correctly diagnosed with vEDS based on the operative and pathological findings. At the time of the second admission, we believe that the emergent operation was absolutely necessary to rescue this patient from life-threatening acute peritonitis due to perforation of her digestive tract. Celiprolol has recently been reported to be effective in the prevention of arterial complications; it is a β1 receptor antagonist that is widely used in the treatment of hypertension. In a report on 53 patients with vEDS divided into a celiprolol administration group (25 patients) and a non-administration group (28 patients), the incidence of arterial ruptures caused by aortic dissection was 20% in the celiprolol group and 50% in the control group, and the hazard ratio was 0.36. Celiprolol was found to have a preventive effect on arterial rupture and aortic dissection that is brought about via an increase in type III collagen production via transforming growth factor-beta (TGFβ) stimulation or activation of intrinsic TGFβ . However, the role of the TGFβ signal pathway in the treatment of vEDS using celiprolol is still debatable. Our patient was not given celiprolol, but her blood pressure was consistently maintained at a lower level. Thus, hemodynamic control may also be important for the treatment of vEDS.
In addition, because vEDS is an autosomal dominant inherited disorder, taking the next generation into consideration is necessary. To this end, psychosocial support and genetic counseling are of crucial importance. We conducted a genetic test for vEDS and found that the daughter carried the same genetic mutation as her mother. Because of this diagnosis, a systemic search for the lesion caused by vEDS and counseling by a specialized counselor were provided to the daughter.