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 Table of Contents  
Year : 2019  |  Volume : 4  |  Issue : 2  |  Page : 27-31

A four-generation pedigree of vascular-type Ehlers–Danlos syndrome with spontaneous aortic dissections and multiple aneurysms: A case report and literature review

1 Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
2 Mckusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China

Date of Submission08-Sep-2019
Date of Decision20-Sep-2019
Date of Acceptance19-Oct-2019
Date of Web Publication27-Nov-2019

Correspondence Address:
Yue Hong Zheng
Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ts.ts_12_19

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Ehlers-Danlos syndrome (EDS) is a rare, heritable connective tissue disorder disease . Among the subtypes of EDS, vascular type EDS (VEDS), is the most catastrophic one which can lead to aortic aneurysm, aortic dissection and even aortic rupture. We report a four-generation pedigree of VEDS. We give the propositus and her sister a DNA Test and made a literature review about the treatment of VEDS. The diagnosis turned out to be VEDS, which is caused by mutations in COL3A1(c.2221G>A, p.G741S), The patient received conservative treatment and her family got the medical instructions. Although EDS is rarely seen, it is necessary to be aware of this disease to make the right diagnosis and chose the appropriate treatment strategy, Doctors' unfamiliarity with this disease may compromise care.

Keywords: Abdominal aortic aneurysm, Ehlers–Danlos syndrome, endovascular, pedigree

How to cite this article:
Zhang X, Si N, Li Y, Liang M, Zheng YH. A four-generation pedigree of vascular-type Ehlers–Danlos syndrome with spontaneous aortic dissections and multiple aneurysms: A case report and literature review. Transl Surg 2019;4:27-31

How to cite this URL:
Zhang X, Si N, Li Y, Liang M, Zheng YH. A four-generation pedigree of vascular-type Ehlers–Danlos syndrome with spontaneous aortic dissections and multiple aneurysms: A case report and literature review. Transl Surg [serial online] 2019 [cited 2020 Aug 12];4:27-31. Available from: http://www.translsurg.com/text.asp?2019/4/2/27/271820

  Introduction Top

Ehlers–Danlos syndrome (EDS) is a rare, heritable connective tissue disease, which is first portrayed by Ehlers and Danlos in 1901. Taking the clinical manifestation and its underlying pathogenic genes into account, 13 subtypes of EDS have been classified so far.[1] Among the subtypes of EDS, vascular type EDS(VEDS), is the most dangerous one can lead to catastrophic results. Although EDS is rarely seen, it is necessary to be aware of this disease to make the right diagnosis and chose the appropriate treatment strategy, Because the deficiency of Type III collagen in vascular leads to results that surgery treatment is unsatisfactory and the incidence of mortality is very high (overall mortality was about 39%).[2],[3] In general, the treatment of VEDS still remains a challenge.[4] In our case, we report a four-generation pedigree of VEDS. The propositus is diagnosed with Type B aortic dissections, abdominal aortic aneurysm, and multiple intracranial and extracranial aneurysms, and several elder generation members of this family all died in their 40s due to aortic rupture, but they had not been diagnosed with EDS before. Doctors' unfamiliarity with this disease may compromise care. We highlight our management strategy changeover during the treatment process and give a literature review about the treatment of VEDS.

  Case Presentation Top

A 38-year-old female was referred to our emergency department due to a severe, sharp thoracic–abdominal pain which radiated to the hip. Her electrocardiogram and blood cardiac biomarkers were normal and blood pressure was 145/90 mmHg. The aortic computed tomography angiography showed thoracic–abdominal aortic dissections (from the seventh thoracic vertebra level to iliac artery, celiac trunk, superior mesenteric artery, and renal artery from true lumen) and abdominal aortic aneurysms (from the first lumbar to the fifth lumbar, diameter 58 mm) [Figure 1]a and [Figure 1]b. The patient's medical history was clear, except hypertension Stage 1 and tendency of skin bruises. Emergency surgery seemed to be necessary, but she was found to have multiple intracranial and extracranial aneurysms, located in common carotid artery bifurcation, internal carotid, vertebral artery, and middle cerebral artery [Figure 1]c.
Figure 1: (a and b) Aortic dissections from the seventh thoracic vertebra level to iliac artery, celiac trunk, superior mesenteric artery, and renal artery from true lumen; abdominal aortic aneurysm from the first lumbar to the fifth lumbar. (c) There are multiple intracranial and extracranial aneurysms, located in bilateral common carotid artery bifurcation, internal carotid, vertebral artery, and middle cerebral artery

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Patient' family history also captured our attention. The patient's grandmother died of thoracic aortic rupture at young age. Her father, uncle, and aunt all died of spontaneous thoracic–abdominal aortic rupture in their 40s. Her cousin, the daughter of her aunt, died at the age of 30 years due to rupture of multiple intracranial aneurysms. Her brother was diagnosed with abdominal aortic aneurysm. Her sister had no clinical manifestation [Figure 2]. By the time of her presentation, her children had no similar symptoms.
Figure 2: Normal male: , Normal female: , EDS male: , EDS female: , Pass away: , Propositus:

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Considering the clinical manifestations and family history, we established the diagnosis of VEDS.[1],[5] There is a significant clinical overlap between VEDS and other heritable connective tissue disorders, such as classic-type EDS, hypermobility-type EDS, Marfan syndrome, Loeys–Dietz syndrome, osteogenesis imperfecta, arterial tortuosity syndrome, and lateral meningocele syndrome.[6] There had no physical signs been found such as disproportionate tall stature, dislocation of the lens, pectus carinatum, arachnodactyly, hypertelorism, and cleft palate.

Then, DNA sequencing was ordered for the patient and her sister to confirm the mutation. Targeted genes were captured by Illumina TruSight One Sequencing panel (Illumina, USA) and sequenced on Illumina MiSeq platform. A missense mutation in the gene COL3A1 (c.2221G>A, p. G741S) was detected in the patient, but not in her unaffected sister [Figure 3]. This mutation has been reported and documented as pathogenic for VEDS in Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php). The patient and her sister had signed informed consent, and the experiment was approved by the Peking Union Medical College Hospital's Ethical Community.
Figure 3: The patient mutation gene is located in COL3A1:c.2221G>A, p. G741S. The sister is normal

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Because the patient was diagnosed with VEDS, the treatment strategy switched from emergency surgery to conservative treatment, including bed rest, vital sign monitoring, and antihypertensive medication (β receptor blocker; blood pressure was maintained at 120–130/70–80 mmHg).

  Discussion Top

EDS' prevalence is about 1/10,000–1/25,000. VEDS is even rarer, accounting for 5% of EDS cases.[7],[8] Pepin et al. summarized the characteristics of 220 EDS patients and concluded that 25% of the index patients had their first presentation before 20, and over 80% had had at least one attack by the age of 40[9] and VEDS is associated with higher mortality than other subtypes. The most common cause of death in VEDS patients is arterial rupture.[10] The mutant gene COL3A1 causes mal-synthesized Type III collagen in vascular wall and hollow organs,[11] resulting in life-threating complication.[12]

Due to its low prevalence and various clinical manifestations, EDS is easily missed or misdiagnosed. Adequate knowledge of EDS and complete summary of the patient history is an important step to make the right diagnosis. The diagnosis of VEDS is made based on clinical criteria, abnormal procollagen production, and genetic tests. The major diagnostic criteria for VEDS include family history of VEDS 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 pathogenesis, uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears, and carotid-cavernous sinus fistula formation in the absence of trauma. EDS should be suspected when the patient or family members meet the criteria.[1] When EDS is suspected, a skin biopsy for electron microscopy is recommend. Cultures of fibroblasts and genetic tests can confirm the diagnosis. Genetic counseling should be suggested for other family members.[13],[14] Hence, we recommended genetic tests for other family member and their children to facilitate early detection and management.

The treatment of EDS still remains a big challenge in both medicine and surgery aspect. In medicine treatment, Ong et al. found that β receptor blocker, celiprolol, could reduce the incidence of aortic dissection or aortic rupture in EDS patients in a randomized, multicenter, open-labeled trial over 4 years.[15] Mast et al. suggested that desmopressin can normalize the bleeding time in EDS children with bleeding symptom.[16]

Regarding surgical treatment, due to the fragile vessels and tissues, the incidence of postoperative bleeding complications and late graft-related problem was significant and shortened the EDS patients' survival time.[17] Some patients' deaths are directly associated with surgery complications.[2] Therefore, selection of treatment requires thorough consideration, and invasive operations may not be the first choice.[18] If the condition of the patient is stable, conservative treatment should be recommended.[19],[20] If life-threating complications are present, emergency surgery should be performed.[9] The surgery should be performed by experienced surgeons.[4] The operator should handle the vessels and tissues softly to avoid extra injuries, as ruptured artery is very difficult to manage.[21] During the surgery, vascular clamps, embolectomy, or thrombectomy with Fogarty balloon catheter should be avoided. When placing vascular grafts, interrupted sutures could reduce tearing.[2] In total, the incidence of mortality is high and prognosis of VEDS is poor.[22]

On the other hand, Brooke et al. retrospectively reviewed 40 patients who received surgery in their medical center from 1994 to 2009; the rate of survival free of any complications at 5 years was 85% and 54% following endovascular and open procedures.[23] This result inspired that sufficient preparation may bring a good outcome for elective surgery in EDS patients, and that endovascular repair may have lower incidence of complication. Other successful cases of endovascular intervention have also been reported, including endovascular coil embolization for spontaneous splenic and hepatic arterial tears,[17] coil embolization of vertebral artery and hepatic artery aneurysms,[24],[25] and balloon occlusion of spontaneous carotid cavernous fistulae, endovascular abdominal aortic aneurysm repair, and thoracic endovascular aortic repair.[26],[27]

Educating patients about EDS is an important element of treatment. EDS patients should wear bracelets with disease information. It is recommended for patients to stay away from physical confrontative sports. Antiplatelet and anticoagulation medicine should be avoided unless necessary.[28] Murray et al. reported that pregnancy-related death and life-threatening incidents in women with EDS are higher than normal women. Thus, women with VEDS should be involved in a shared decision-making process when contemplating pregnancy and pregnancy management.[29]

  Conclusion Top

At present, the outcome of VEDS treatment is still unsatisfied with the high surgery complication rate and mortality; the management strategies for patients with or without EDS are totally different; and the invasive treatment should be avoided as could as possible. When we encounter young patients with spontaneous aortic dissection or aneurysm or artery-venous fistula in emergency department, it is necessary to attach importance to patients' and their family medical history, in case of missing the diagnosis of VEDS, which may bring catastrophic results.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

The CAMS Innovation Fund for Medical Sciences (CIFMS) (Grant number: 2016-I2M-1-002).

Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3]


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