Cardiovascular Management of Aortopathy in Children: A Scientific Statement From the American Heart Association.

Aortopathy encompasses a spectrum of conditions predisposing to dilation, aneurysm, dissection, or rupture of the aorta and other blood vessels. Aortopathy is diagnosed commonly in children, from infancy through adolescence, primarily affecting the thoracic aorta, with variable involvement of the peripheral vasculature. Pathogeneses include connective tissue disorders, smooth muscle contraction disorders, and congenital heart disease, including bicuspid aortic valve, among others. The American Heart Association has published guidelines for diagnosis and management of thoracic aortic disease. However, these guidelines are predominantly focused on adults and cannot be applied adeptly to growing children with emerging features, growth and developmental changes, including puberty, and different risk profiles compared with adults. Management to reduce risk of progressive aortic dilation and dissection or rupture in children is complex and involves genetic testing, cardiovascular imaging, medical therapy, lifestyle modifications, and surgical guidance that differ in many ways from adult management. Pediatric practice varies widely, likely because aortopathy is pathogenically heterogeneous, including genetic and nongenetic conditions, and there is limited published evidence to guide care in children. To optimize care and reduce variation in management, experts in pediatric aortopathy convened to generate this scientific statement regarding the cardiovascular care of children with aortopathy. Available evidence and expert consensus were combined to create this scientific statement. The most common causes of pediatric aortopathy are reviewed. This document provides a general framework for cardiovascular management of aortopathy in children, while allowing for modification based on the personal and familial characteristics of each child and family.

Spontaneous pneumothorax and hemothorax frequently precede the arterial and intestinal complications of vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (vEDS) is a connective tissue disorder due to defective type III collagen production and is associated with arterial rupture, spontaneous intestinal perforation, and gravid uterine rupture. Spontaneous pneumothorax and/or hemothorax (P/HTX) also occurs in vEDS patients. The temporal relation of pulmonary manifestations to arterial and intestinal complications in vEDS has not been well described. This was investigated in a multi-institutional retrospective case series of vEDS patients with confirmatory testing for COL3A1 mutation between 2000 and 2012. Data abstracted included demographics, family histories, presentation, and management of associated complications. Ninety-six cases (39% males, mean age 38.6 ± 15.5 years, range 8-79) had confirmatory testing for vEDS. P/HTX was documented in 17 (17.7%) cases. Most P/HTX preceded the diagnosis of vEDS (81%). Diagnosis of vEDS was made after arterial or intestinal complications at a mean of 7 years (range 0-26) post the initial P/HTX. In conclusion, spontaneous P/HTX is an early manifestation of vEDS frequently preceding an arterial complication or intestinal perforation. Thus, a spontaneous P/HTX in a young patient should trigger a differential diagnosis that includes vEDS. This should lead to an investigation of other vEDS features and subsequent genetic testing if vEDS features are present.

Clinical, structural, biochemical and X-ray crystallographic correlates of pathogenicity for variants in the C-propeptide region of the COL3A1 gene.

Vascular Ehlers-Danlos syndrome (vEDS) is a heritable disorder of connective tissue caused by pathological variants in the COL3A1 gene, which encodes the α1 chain of type III collagen. Type III collagen is a major component of skin, arterial walls, and the gastrointestinal tract. Collagen III protein deficiency manifests as an increased risk of rupture, perforation, and dissection of these structures. The most disruptive gene variants affect the collagen helix via glycine substitutions or splice donor site mutations. The C-propeptide region of COL3A1 includes exons 49-52 and has a crucial role in initiating the C-terminal assembly of procollagen monomers in the early stages of collagen biosynthesis. Nineteen COL3A1 variants have previously been reported in these exons, of which four were associated with a severe vEDS phenotype. We identified two novel C-propeptide missense variants; p.Pro1440Leu, p.Arg1432Leu, and a non-stop mutation, c.4400A > T, p. (*1467Leuext*45). These variants produce variable phenotypes ranging from obvious acrogeria to classical or hypermobile EDS. A previously reported variant p.Lys1313Arg is of unknown clinical significance but likely benign, based on this study. Assigning disease pathogenicity remains complex, clinical phenotyping and crystal structure evidence being crucial. We briefly compare reported phenotypes for patients with missense variants in the C-propeptide domain for other human collagen disorders including COL1A1 and COL1A2 (osteogenesis imperfecta).

Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease. METHODS: Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination. RESULTS: A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03). CONCLUSIONS: Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.

Case Report: Hybrid approach as a Rescue Treatment in a patient with vascular Ehlers-Danlos Syndrome.

Vascular Ehlers-Danlos Syndrome (vEDS) is a rare connective tissue disorder associated with COL3A1 gene mutation encoding type III collagen. Given the possible fatal prognosis if not treated timely, it is important to suspect and diagnose as soon as possible. Despite advances in endovascular technique, access point complications remain a serious challenge in patients with vEDS. Here, we describe a 30-year-old male patient who was diagnosed with vEDS after consecutive events of bilateral iliac vessels at an interval of 3 months: (1) spontaneous dissecting aneurysm of right iliac artery and (2) arteriovenous fistula between left internal iliac artery (IIA) and left common iliac vein. This patient was treated with iliac stent-grafts and overlapping femoral interposition graft (Dacron) in the 1st operation and access artery repair with surgical dissection after coil embolization of IIA and stent-graft insertion into left common to external iliac arteries in the 2nd operation. The patient has been treated with beta-blockers and anticoagulants for the management of vEDS and postoperative deep vein thrombosis, respectively. The stent-grafts in both iliac arteries and the access sites have been well-tolerated without any adverse effects for 14 months following the 2nd operation. In conclusion, given the vascular fragility and the potential for future events, additional vascular manipulation should be avoided unless it is in a life-threatening condition. In particular, meticulous hybrid interventions can be effective treatments.

Clinically Suspected Exercise-Induced Myocarditis in a Patient With Vascular Ehlers-Danlos Syndrome.

Ehlers-Danlos syndrome (EDS) is an inherited condition that affects connective tissue structures throughout the body. EDS type IV is a specific subset of EDS that targets vascular structures. Patients with EDS type IV can have a wide range of vascular disorders such as myocarditis and are advised to refrain from participating in contact sports and high-intensity physical exercises to avoid life-threatening cardiovascular conditions such as arterial dissection or rupture. In this report, we present the case of an EDS type IV patient with myocarditis secondary to exercise. The patient received supportive treatment including beta-blockers, bed rest, and refraining from intense physical exertion.

Successful Prophylactic Endovascular Therapy for a Rapidly Expanding Hepatic Arterial Aneurysm in a Patient with Vascular Ehlers-Danlos Syndrome.

Vascular Ehlers-Danlos syndrome (vEDS) causes fatal vascular complications due to vascular fragility. However, invasive therapeutic procedures are generally avoided except in emergencies. We report a case of vEDS presenting with rapid expansion of a hepatic arterial aneurysm successfully treated using prophylactic endovascular therapy. A 43-year-old woman with vEDS confirmed by genetic testing was hospitalized for a symptomatic hepatic arterial aneurysm that expanded rapidly within a week. Prophylactic coil embolization was then successfully performed. Although the general applicability of this approach cannot be determined, prophylactic endovascular therapy can clearly be an option for arterial aneurysms at high risk of rupture.

Ehlers-Danlos syndrome type IV: a case report of a rare cause of spontaneous sigmoid perforation and enteroatmospheric fistulae in a child.

BACKGROUND: Ehlers-Danlos syndrome (EDS) type IV is a rare subtype of EDS, but has important surgical implications. Case presentation Here, we present a case of a spontaneous sigmoid perforation in a 14-year-old boy. He was initially treated with laparotomy, oversew of the sigmoid perforation and a diverting ileostomy. He developed a complete wound dehiscence and enteroatmospheric fistulae. These were managed with a combination of negative pressure wound therapy and Eakin (TG Eakin™) pouch changes. We discuss the clinical features and presentation of EDS type IV, the surgical implications of managing patients with the condition, and the challenges in management of enteroatmospheric fistulae in children. CONCLUSIONS: Ehlers-Danlos syndrome type IV should be considered as a cause of any spontaneous colonic perforation in children.

Renal Artery Dissection in a Young Woman: Diagnoses Beyond Fibromuscular Dysplasia.

A 31-year-old woman presented at the emergency room after experiencing colic pain in the right iliac fossa for 5 days. She had previously consulted another center, where deterioration of renal function had been identified and abdominal computed tomography (CT) angiography had shown a dissection of the right renal artery, with areas suggestive of infarction in the right kidney, as well as an aneurysm in the left renal artery and a smaller left kidney. The patient had no relevant family or personal history except posttraumatic carotid-cavernous fistula in 2014, which had been treated with embolization. In our hospital, the patient was hypertensive and acute renal failure was confirmed, accompanied by an increase in lactate dehydrogenase and isomorphic microhematuria. After a new CT Scan, in addition to the lesions described in the renal arteries, another aneurysm in the splenic artery and an aneurysm of the right femoral artery were identified. Antihypertensive treatment was initiated with calcium antagonists and anticoagulation. Subsequent renal arteriography confirmed the dissection of the right renal artery, which could not be repaired, and a coated stent was placed in the left renal artery to exclude the aneurysm. The splenic artery lesion was treated 2 months later. The etiological diagnosis in this young woman was challenging. The presence of visceral aneurysms suggested a differential diagnosis comprising fibromuscular dysplasia, vasculitis, and collagenopathies. Using a multidisciplinary approach and directed anamnesis, the presence of frequent sprains, joint hypermobility, and skin fragility was confirmed. Blood immunology and CT angiography including the thoracic and cervical territories were normal. Echocardiography revealed tricuspid insufficiency. All these data suggested the presence of a collagen-like Ehlers-Danlos syndrome (vascular form). The diagnosis was confirmed by the genetic study, which showed a pathogenic mutation in the COL3A1 gene. Currently, the patient is asymptomatic with recovered renal function following treatment with a beta-blocker and antiplatelet therapy.

Vascular Ehlers-Danlos Syndrome With a Novel Missense COL3A1 Mutation Present With Pulmonary Complications and Iliac Arterial Dissection.

Vascular Ehlers-Danlos syndrome (vEDS) is a life-threatening connective tissue disorder due to its high tendency of arterial and organ rupture. Pulmonary complications in vEDS are rare. We present a young male patient with vEDS who developed severe pulmonary complications and severe rupture of the iliac artery at different stages of his life. Vascular Ehlers-Danlos syndrome was diagnosed based on clinical manifestations and confirmed by the identification of COL3A1 gene mutation. Due to high bleeding tendency and weak cardiopulmonary capacity, conservative treatment was taken for him. To our knowledge, this is the first report of vEDS case in which the patient developed both pulmonary complications and dissection of large arteries. Our report emphasizes the importance of considering vEDS when an adolescent develops unexplained pulmonary cysts with fragility of lung tissues. Genetic counseling and close monitoring should be performed for earlier diagnosis and prevention of severe complications of large arteries. The typical presentations of vEDS were also discussed by means of a review of case reports on vEDS with pulmonary complications.

Aggressive change of a carotid-cavernous fistula in a patient with Ehlers-Danlos syndrome type IV.

The authors report a rare case of a carotid-cavernous fistula (CCF) secondary to Ehlers-Danlos syndrome (EDS) type IV which showed an aggressive angiographical change.A 59-year-old woman presented with headache, right pulsatile tinnitus, and diplopia on the right side. The diagnostic angiography demonstrated a right CCF. Accordingly transarterial embolization of the fistula was attempted 5 days later. The initial right internal carotid angiography showed an aneurysm on the petrous portion of the internal carotid artery (ICA) which was not recognized in the diagnostic angiography. Spontaneous reduction of the shunt flow and long dissection of the ICA were also revealed. The aneurysm was successfully occluded with coils, and only minor shunt flow was shown on the final angiogram. EDS type IV was diagnosed with a skin biopsy for a collagen abnormality. After the operation, the stenosis of the right ICA gradually progressed, although there was no recurrence of the CCF.Interventional treatment for patients with EDS can cause devastating vascular complication. We should be aware of the possibility of EDS type IV when a spontaneous CCF shows unusual angiographical change because early diagnosis of EDS type IV is crucial for determination of the optimum treatment option.

Secondary publication Sudden Aortic Rupture in Ehlers-Danlos Syndrome Type IV / 대한법의학회지

Ehlers-Danlos syndrome type IV (EDS IV) is a hereditary disorder of the connective tissue, characterized by easy bruising, thin skin with visible veins, and spontaneous rupture of the large arteries, uterus, or bowel. EDS IV is caused by mutations of the gene for type III procollagen (COL3A1), resulting in insufficient collagen production or a defect in the structure of collagen. EDS IV can have fatal complications such as the rupture of great vessels or organs, which can cause hemorrhaging and sudden unexpected death. Here, we report a case of a 43-year-old female who collapsed after a struggle with a neighbor. In this patient, the bifurcation of the bilateral common iliac artery ruptured, with no evidence of trauma, inflammation, or atherosclerosis. Genetic analysis of COL3A1 showed the presence of a c.2771G>A (p.Gly924Arg) mutation, which may be associated with EDS IV. The forensic pathologist should consider the possibility that the spontaneous visceral or arterial rupture was caused by EDS IV. Genetic analysis is not currently a routine procedure during autopsy. However, in this case, we suggest that the patient possibly had an underlying EDS IV condition, and we recommended family members of the deceased to seek genetic analysis and counseling.

Ehlers-Danlos Syndrome Type IV and the Management of Its Vascular Complication / 대한혈관외과학회지

Ehlers-Danlos syndrome type IV (EDS IV), the vascular type of EDS, is an inherited connective tissue disorder due to abnormal procollagen III synthesis by mutation of the COL3A1 gene. EDS is classified into 6 types based on clinical, biochemical, and molecular characteristics. Among them, EDS IV has the worst prognosis because of the major vascular catastrophes and the difficulty of vascular repair due to fragile connective tissue. Arterial, digestive, or uterine ruptures are the main lethal symptoms of EDS IV, and thin translucent skin, extensive bruising, and characteristic facial appearance are the other major symptoms. Although many successful results have been reported after open surgery or endovascular repair for EDS IV, surgical or endovascular procedures are still challenging to perform and sometimes are associated with serious hemorrhagic complications in EDS IV patients. In general, open surgery is not recommended except in an emergency situation, and conservative treatment is the preferred strategy for the treatment of vascular complications in EDS IV. Aneurismal diseases are observed in many EDS IV patients, and abdominal aortic aneurysm and iliac arterial aneurysm are the frequent presentations. Therefore, when treating patients with aneurysms, the vascular surgeon should consider the high possibility of connective tissue disease, especially EDS IV. Without the preoperative recognition of EDS IV, routine surgical or endovascular procedures may result in major bleeding and subsequent increased morbidity and mortality. In this article, the characteristics, clinical outcomes, and treatment strategies of EDS IV are reviewed.

Genetic Analysis of Three Korean Patients with Clinical Features of Ehlers-Danlos Syndrome Type IV

Ehlers-Danlos syndrome (EDS) is a hereditary disorder of the connective tissue. EDS type IV (EDS IV), the vascular type of the disease, is characterized by easy bruising, thin skin with visible veins, and spontaneous rupture of the large arteries, uterus, or bowel. EDS IV is caused by mutations in the gene for type III procollagen (COL3A1). However, recent studies suggest that the causative mutation of EDS IV is not homogeneous. We report our experience with three patients presenting with clinical features of type IV EDS. A 48-yr-old woman presented with acute aortic dissection (patient 1) and 36-yr-old and 21-yr-old women presented with carotidcavernous fistula (patients 2 and 3, respectively). All three patients bruised easily. Two patients (patients 1 and 3) had thin transparent skin with visible veins. Genetic analysis of COL3A1 revealed a Gly732Val (c.2195G>T) mutation in patient 1 and a duplication of 15 base pairs (c.3221_3235dup) which resulted in an interposition of five amino acids (p.Gly1074_Pro1078dup) in patient 2. However, no mutations were observed in COL3A1 or transforming growth factor beta receptors 1 and 2 in patients 3, which might be either due to a deletion of single or multiple exons in the COL3A1 gene or due to a genetic heterogeneity. This is the first report of genetically confirmed cases of EDS IV in Korea.