Imaging Pearls ❯ Vascular ❯ Genetic Vascular Disease
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- “Thoracic aortic diseases (TAD) encompass both dilation as well as aneurysms and dissections of the ascending or descending thoracic aorta. Population-based studies estimate an annual incidence of 6 to 16 cases per 100,000, and aortic dissection is the most devastating complication of TAD. Clinical studies have long suggested a familial predisposition for TAD, estimating that 20% of cases are caused by genetic factors.”
A decade of discovery in the genetic understanding of thoracic aortic disease Andellfinger G, Loeys B, Dietz H Canadian Journal of Cardiology (in press) doi:10.1016/j.cjca.2015.10.017 - “As more genes are identified causing an inherited predisposition for TAD, it is becoming progressively more important to adapt clinical management according to the underlying gene mutation. The rationale for this approach are the genotype-phenotype relationships that have emerged over the last years and that have flown into treatment guidelines endorsed by medical societies. The two most immediate consequences of gene discovery in TAD, to date, are gene-specific guidance for surgical intervention, as well as genetic diagnosis in family members.”
A decade of discovery in the genetic understanding of thoracic aortic disease Andellfinger G, Loeys B, Dietz H Canadian Journal of Cardiology (in press) doi:10.1016/j.cjca.2015.10.017 - “For several non-syndromic and syndromic forms of thoracic aortic disease, a genetic basis has now been identified, with three main pathomechanisms emerging: perturbation of the TGF-β signalling pathway, disruption of the vascular smooth muscle cell contractile apparatus, and impairment of extracellular matrix synthesis. Since smooth muscle cells and proteins of the extracellular matrix directly regulate TGF-β signalling, this latter pathway emerges as a key component of thoracic aortic disease initiation and progression.”
A decade of discovery in the genetic understanding of thoracic aortic disease Andellfinger G, Loeys B, Dietz H Canadian Journal of Cardiology (in press) doi:10.1016/j.cjca.2015.10.017
- “Loeys–Dietz syndrome (LDS), an autosomal-dominant connective tissue disorder first characterized by aortic aneurysms and generalized arterial tortuosity, hypertelorism, and bifid/ broad uvula or cleft palate, was first described in 2005.With variable expression, mutations in the transforming growth factor ? receptor I (TGFBR1) and transforming growth factor ? receptor II (TGFBR2) genes were discovered to be the first reported genetic causes of LDS. Subsequently, gene mutations in the mothers against decapentaplegic homolog 3 (SMAD3) gene and the transforming growth factor ? 2 ligand gene (TGFB2) were associated with phenotypes showing typical manifestations of LDS.”
- “Loeys–Dietz syndrome (LDS), an autosomal-dominant connective tissue disorder first characterized by aortic aneurysms and generalized arterial tortuosity, hypertelorism, and bifid/ broad uvula or cleft palate, was first described in 2005.”
Loeys–Dietz syndrome: a primer for diagnosis and management
Gretchen MacCarrick et al.
Genet Med 2014: vol 16: 8:576-587 - “With variable expression, mutations in the transforming growth factor ? receptor I (TGFBR1) and transforming growth factor ? receptor II (TGFBR2) genes were discovered to be the first reported genetic causes of LDS. Subsequently, gene mutations in the mothers against decapentaplegic homolog 3 (SMAD3) gene and the transforming growth factor ? 2 ligand gene (TGFB2) were associated with phenotypes showing typical manifestations of LDS.”
Loeys–Dietz syndrome: a primer for diagnosis and management
Gretchen MacCarrick et al.
Genet Med 2014: vol 16: 8:576-587 - “Mutations in all four genes show similarly altered transforming growth factor-? (TGF-?) signaling, and individuals show similar cardiovascular, craniofacial, cutaneous, and skeletal features. Most importantly, affected individuals show widespread arterial involvement, with vascular tortuosity, a high risk of aneurysms and dissections throughout the arterial tree, and an aggressive vascular course. No specific clinical criteria exist, as the diagnosis is confirmed by a molecular test. ”
Loeys–Dietz syndrome: a primer for diagnosis and management
Gretchen MacCarrick et al.
Genet Med 2014: vol 16: 8:576-587 - “We propose that a mutation in any of these four genes in combination with arterial aneurysm or dissection or family history of documented LDS should be sufficient to estab- lish the diagnosis. These diagnostic procedures may ultimately be applicable to newly discovered genes that directly influence the TGF-? signaling cascade and result in widespread and/or aggressive vascular disease. ”
Loeys–Dietz syndrome: a primer for diagnosis and management
Gretchen MacCarrick et al.
Genet Med 2014: vol 16: 8:576-587 - “In view of the aggressive nature of the vascular disease and the low rate of complications associated with valve-sparing aortic root replacement surgery at experienced centers, surgery is being recommended at or around these dimensions. For adults with LDS 1 or 2, this includes surgical repair of the aortic root once the maximal dimension of the aortic root reaches 4.0 cm. Valve-sparing surgery is recommended to avoid the need for anticoagulation.”
Loeys–Dietz syndrome: a primer for diagnosis and management
Gretchen MacCarrick et al.
Genet Med 2014: vol 16: 8:576-587 - “Diagnostic or baseline vascular imaging through magnetic resonance angiography or computerized tomography angiography with three-dimensional reconstruction of the head, neck, chest, abdomen, and pelvis should be performed to assess for aneurysms throughout the aorta and arterial tree and arterial tortuosity. Aneurysmal disease (including dissection) is not limited to the aortic root and has been reported in all other portions of the aorta and arterial branches of the head, neck, and thoracic and abdominal aorta.”
Loeys–Dietz syndrome: a primer for diagnosis and management
Gretchen MacCarrick et al.
Genet Med 2014: vol 16: 8:576-587 
- The decision to undergo aortic surgery is typically based on the absolute dimension of the aorta, rate of progression, valve function, severity of noncardiac features, family history, and infor-mation about genotype. Unlike the increased risk of aortic dissection at or above the 5.0-cm aortic root dimension in Marfan syndrome, dissections have occurred in individuals with LDS 1, 2, or 3 at aortic dimensions of 3.9–4.0 cm and has been reported in LDS 4 at a dimension <5.0 cm.
Loeys–Dietz syndrome: a primer for diagnosis and management
Gretchen MacCarrick et al.
Genet Med 2014: vol 16: 8:576-587 
- “Diagnostic or baseline vascular imaging through magnetic resonance angiography or computerized tomography angiography with three-dimensional reconstruction of the head, neck, chest, abdomen, and pelvis should be performed to assess for aneurysms throughout the aorta and arterial tree and arterial tortuosity . Aneurysmal disease (including dissection) is not limited to the aortic root and has been reported in all other portions of the aorta and arterial branches of the head, neck, and thoracic and abdominal aorta.”
Loeys–Dietz syndrome: a primer for diagnosis and management
Gretchen MacCarrick et al.
Genet Med 2014: vol 16: 8:576-587 - “Full vascular imaging should be performed on initial evaluation and at about a 2-year interval if there are no identified aneurysms or dissections (H. Dietz and B. Loeys, personal communication).”
Loeys–Dietz syndrome: a primer for diagnosis and management
Gretchen MacCarrick et al.
Genet Med 2014: vol 16: 8:576-587 - “ Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome represent the more common heritable connective tissue diseases that may manifest with life-threatening cardiovascular conditions. Although these syndromes share some overlapping features, they have discriminating clinical and imaging features, and knowledge of these features enables the radiologist to aid the referring clinician in making the correct diagnosis.”
CT Angiographic Evaluation of Genetic Vascular Disease:
Role in Detection, Staging, and Management of Complex Vascular Pathologic Conditions
Chu LC , Johnson PT, Dietz HC, Fishman EK
AJR 2014; 202:1120–1129 - “Marfan syndrome is an autosomal-dominant connective tissue disorder that occurs in approximately 1 in 20,000 individuals . It is caused by mutations in the FBN1 gene, which encodes for fibrillin-1, an important extracel- lular matrix protein . Marfan syndrome is a multisystem disorder affecting the cardiovascular, ocular, and skeletal systems.”
CT Angiographic Evaluation of Genetic Vascular Disease:
Role in Detection, Staging, and Management of Complex Vascular Pathologic Conditions
Chu LC , Johnson PT, Dietz HC, Fishman EK
AJR 2014; 202:1120–1129 - “Loeys-Dietz syndrome, first described in 2005, is an autosomal-dominant connective tissue disorder caused by mutations in either of the two genes encoding subunits of the trans- forming growth factor–? (TGF-?) receptor: TGFBR1 or TGFBR2, causing Loeys-Dietz syndrome type 1 or type 2, respectively [10]. More recently, it was shown that mutations in the genes encoding the TGF-? signaling effector SMAD3 or the TGF-? ligand TGF-?2 can also cause Loeys-Dietz syndrome (Loeys- Dietz syndrome type 3 and type 4, respectively).”
CT Angiographic Evaluation of Genetic Vascular Disease:
Role in Detection, Staging, and Management of Complex Vascular Pathologic Conditions
Chu LC , Johnson PT, Dietz HC, Fishman EK
AJR 2014; 202:1120–1129 - “Aortic root aneurysms are present in up to 98% of patients with Loeys-Dietz syndrome, with thoracic aortic dissection being the leading cause of death (67%), followed by abdominal aortic dissection (22%) and cerebral hemorrhage (7%) . Arterial tortuosity is a distinguishing feature of Loeys- Dietz syndrome, and there is a propensity for involvement of the extracranial carotid arteries and vertebral arteries.”
CT Angiographic Evaluation of Genetic Vascular Disease:
Role in Detection, Staging, and Management of Complex Vascular Pathologic Conditions
Chu LC , Johnson PT, Dietz HC, Fishman EK
AJR 2014; 202:1120–1129 - “The most common spinal abnormality in Loeys-Dietz syndrome is scoliosis, which can be seen in 50–55% of patients. Pectus deformities are present in 68–77% of patients, with pectus excavatum being more common than pectus carinatum. Other musculoskeletal findings that have been described include dural ectasia; dolichostenomelia; arachnodactyly; camptodactyly; protrusio acetabuli; developmental dysplasia of the hip; and foot deformities, including talipes equinovarus, forefoot varus, hindfoot valgus, and pes planus.”
CT Angiographic Evaluation of Genetic Vascular Disease:
Role in Detection, Staging, and Management of Complex Vascular Pathologic Conditions
Chu LC , Johnson PT, Dietz HC, Fishman EK
AJR 2014; 202:1120–1129 - “The more common vascular complications in vascular Ehlers-Danlos syndrome include aneurysm, dissection, or rupture of medium- sized abdominal arteries (i.e., iliac, renal, and mesenteric arteries) and the abdominal aorta, although aneurysms and dissections can occur throughout the arterial tree . Unlike Marfan syndrome or Loeys-Dietz syndrome, there is not a predisposition for involvement of the aortic root in vascular Ehlers- Danlos syndrome. The characteristic manifestation is arterial aneurysms or dissections involving multiple arteries in different vascular segments. Preexisting aneurysms tend to progress over time, and new aneurysms can also develop over time because of the underlying tissue fragility.”
CT Angiographic Evaluation of Genetic Vascular Disease:
Role in Detection, Staging, and Management of Complex Vascular Pathologic Conditions
Chu LC , Johnson PT, Dietz HC, Fishman EK
AJR 2014; 202:1120–1129 - “Intestinal perforation is another common complication of vascular Ehlers-Danlos syn-
drome because the intestinal walls are rich in type III collagen. Bowel complications most frequently affect the colon, especially the sigmoid colon . Perforations of the small bowel and stomach are much less common. ”
CT Angiographic Evaluation of Genetic Vascular Disease:
Role in Detection, Staging, and Management of Complex Vascular Pathologic Conditions
Chu LC , Johnson PT, Dietz HC, Fishman EK
AJR 2014; 202:1120–1129 - “CT protocols must be optimized for identification of vascular abnormalities in smaller arteries, necessitating submillimeter detector sections, accurately timed studies performed with high infusion rates (5–8 mL/s; total dose, 100–120 mL), and interpretation with interactive 2D multi- planar reconstructions and 3D rendering. ECG-gated CT is particularly useful in evaluating aortic root dissection and aneurysm, and ECG gating should be performed in patients with a high clinical suspicion of aortic root dissection. ”
CT Angiographic Evaluation of Genetic Vascular Disease:
Role in Detection, Staging, and Management of Complex Vascular Pathologic Conditions
Chu LC , Johnson PT, Dietz HC, Fishman EK
AJR 2014; 202:1120–1129 - “The advantage of MR angiography is the absence of radiation exposure, which is an important consideration in young patients who need to undergo serial examinations. Aneurysms and dissections of the aorta and ma jor branch vessels are well depicted by contrast-enhanced MR angiography. However, because of lower spatial resolution, MR an- giography may not show focal dissections in medium-to-small arterial branches as clearly as CT angiography.”
CT Angiographic Evaluation of Genetic Vascular Disease:
Role in Detection, Staging, and Management of Complex Vascular Pathologic Conditions
Chu LC , Johnson PT, Dietz HC, Fishman EK
AJR 2014; 202:1120–1129 - “The standard medical therapy for patients with Marfan syndrome and Loeys-Dietz syndrome is ?-blockers . Recent research has shown that mutations underlying both Marfan and Loeys-Dietz syndromes result in dysregulation of the TGF-? signaling pathway. This finding led to hopes that losartan, an angiotensin II receptor blocker that can significantly attenuate TGF-? signaling, may be able to alter the natural history of Marfan and Loeys-Dietz syndromes. Losartan has been shown to decrease the rate of progression of aortic root dilatation in mouse models of Marfan syndrome and in a small observational cohort of patients with Marfan syndrome. Currently, several randomized controlled trials are in progress to evaluate the effectiveness of losartan in delaying the aortic root growth rate in patients with Marfan syndrome.”
CT Angiographic Evaluation of Genetic Vascular Disease:
Role in Detection, Staging, and Management of Complex Vascular Pathologic Conditions
Chu LC , Johnson PT, Dietz HC, Fishman EK
AJR 2014; 202:1120–1129 - “Congenital pelvic AVM are considered to be focal remaining, primitive, vascular channels. Extrauterine lesions seem to have a particular angioarchitecture. This consists of numerous communications between the anterior branches of the IIA and venous ectasies draining to the IIV. The nidus appears in the wall of the vein like AV shunts also described in the area of lateral dural sinus (vein of Galen malformations).”
Curative Treatment of Pelvic Arteriovenous Malformation – An Alternative Strategy: Transvenous Intra-operative Embolisation
Mallios A et al.
European Journal of Vascular and Endovascular Surgery
Volume 41, Issue 4, Pages 548–553, April 2011 - “Complete surgical excision of pelvic AVMs is not always possible. Embolisation does not offer a permanent cure. Intra-operative transvenous embolisation of persisting complex AVMs appears to be an alternative approach with good immediate and long-term results. Ethylene glycol appears to be the most suitable agent.”
Curative Treatment of Pelvic Arteriovenous Malformation – An Alternative Strategy: Transvenous Intra-operative Embolisation
Mallios A et al.
European Journal of Vascular and Endovascular Surgery
Volume 41, Issue 4, Pages 548–553, April 2011
- “Genetic studies over the past several decades have helped to better elucidate the genomics and inheritance of thoracic aortic diseases. Seminal work from various researchers have identified several genetic factors and mutations that predispose to aortic aneurysms, which will aid in better screening and early intervention, resulting in better clinical outcomes. Syndromic aneurysms have been associated with Marfan syndrome, Loeys-Dietz syndrome, aneurysm osteoarthritis syndrome, arterial tortuosity syndrome, Ehlers-Danlos Syndrome, and TGF- mutation. Mutations in MYH11, TGF-R1, TGF-R2, MYLK, and ACTA2 genes have been linked to familial non-syndromic cases, although linkage analysis is limited by incomplete penetrance and/or locus heterogeneity. This overview presents a summary of key genetic and genomic factors that are associated with thoracic aortic diseases.”
The genetics and genomics of thoracic aortic disease
Pomianowski P, Elefteriades JA
Ann Cardiothorac Surg 2013;2(3):271-279 - “Syndromic aneurysms have been associated with Marfan syndrome, Loeys-Dietz syndrome, aneurysm osteoarthritis syndrome, arterial tortuosity syndrome, Ehlers-Danlos Syndrome, and TGF- mutation. Mutations in MYH11, TGF-R1, TGF-R2, MYLK, and ACTA2 genes have been linked to familial non-syndromic cases, although linkage analysis is limited by incomplete penetrance and/or locus heterogeneity. This overview presents a summary of key genetic and genomic factors that are associated with thoracic aortic diseases.”
The genetics and genomics of thoracic aortic disease
Pomianowski P, Elefteriades JA
Ann Cardiothorac Surg 2013;2(3):271-279 - “Hippocrates first described a clinical syndrome consistent with Ehler-Danlos and its accompanying easy bruising and bleeding as far back as 400 BC. Writing in his “Airs, Waters, and Places”, he noted that Nomads and Scythians had lax joints and easy bruising. The Danish dermatologist Ehler in 1901 and the French physician Danlos in 1908 then refined the clinical description of the disorder. Several years earlier, Antoine Marfan, a French pediatrician, had described a hereditary connective tissue disorder which came to bear his name. His report was made in 1896 in the Bulletin of the Medical Society of Paris and described a five-year-old girl with long limbs and digits. It was not until over 50 years later that the syndrome was fully described, including the involvement of aneurysms of the ascending aorta. In 2006, Loeys and Dietz described the syndrome of early, malignant arterial dilatations and unique facial features which characterize the syndrome that bears their names. These were the first clinical reports of recognizing the genetically heterogenous nature of thoracic aorta aneurysms.”
The genetics and genomics of thoracic aortic disease
Pomianowski P, Elefteriades JA
Ann Cardiothorac Surg 2013;2(3):271-279 - “ The Danish dermatologist Ehler in 1901 and the French physician Danlos in 1908 then refined the clinical description of the disorder. Several years earlier, Antoine Marfan, a French pediatrician, had described a hereditary connective tissue disorder which came to bear his name. His report was made in 1896 in the Bulletin of the Medical Society of Paris and described a five-year-old girl with long limbs and digits. It was not until over 50 years later that the syndrome was fully described, including the involvement of aneurysms of the ascending aorta. In 2006, Loeys and Dietz described the syndrome of early, malignant arterial dilatations and unique facial features which characterize the syndrome that bears their names. These were the first clinical reports of recognizing the genetically heterogenous nature of thoracic aorta aneurysms.”
The genetics and genomics of thoracic aortic disease
Pomianowski P, Elefteriades JA
Ann Cardiothorac Surg 2013;2(3):271-279 - “Medical science has made substantial progress in elucidating the genetic basis of aortic diseases since Marfan's original observations a century ago. The identification of specific mutations underlying syndromic and non-syndromic thoracic aortic aneurysms now permits precise identification of affected patients and confirmation of clinical diagnoses. Further, it is becoming clear that specific mutations lead to subtly different patterns of disease progression. Soon, we will enter an era of personalized aneurysm care, in which specific mutations will determine the appropriate size criterion for surgical intervention.”
The genetics and genomics of thoracic aortic disease
Pomianowski P, Elefteriades JA
Ann Cardiothorac Surg 2013;2(3):271-279 - “Syndromic aortic aneurysms occur in patients with:
Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), aneurysm osteoarthritis syndrome (AOS), arterial tortuosity syndrome (ATS), Ehlers-Danlos Syndrome (EDS) and TGF- mutations. Many of the syndromic aneurysms can be diagnosed by their characteristic dysmorphic features and gene testing.”
The genetics and genomics of thoracic aortic disease
Pomianowski P, Elefteriades JA
Ann Cardiothorac Surg 2013;2(3):271-279 - “LDS is caused by a heterozygous mutation in one of the transforming growth factor beta receptor genes (TGF-R1 or TGF-R2). TGF-R2 mutations on chromosome 3 (3p24.1) account for the majority of LDS mutations (75%), and TGF-R1 mutations on chromosome 9 (9q22.33) account for the remaining 25% (12). Direct sequencing of both TGF-R1 and TGF-R2 allows for the identification of a causal mutation in more than 95% of individuals.”
The genetics and genomics of thoracic aortic disease
Pomianowski P, Elefteriades JA
Ann Cardiothorac Surg 2013;2(3):271-279 
The genetics and genomics of thoracic aortic disease
Pomianowski P, Elefteriades JA
Ann Cardiothorac Surg 2013;2(3):271-279
The genetics and genomics of thoracic aortic disease
Pomianowski P, Elefteriades JA
Ann Cardiothorac Surg 2013;2(3):271-279- Ehlers Danlos Syndrome Type IV: Facts
- autosomal dominant disorder with a prevalence of 1:10,000-25,000 in the US caused by highly penetrant mutations in COL3A1 (2q32.2).
- Characterized by cutaneous findings (thin translucent skin, easy bruising) and arterial, intestinal, or uterine rupture.
- Vascular aneurysms/dissections or gastrointestinal perforation constitutes the presenting signs in a majority of adults with EDS IV.
- The average age for the first major arterial or gastrointestinal complication is 23 years. - Ehlers Danlos Syndrome Type IV: Facts
- Among patients with EDS IV ascertained because of a medical complication associated with the disorder, in 25% the complication was present by age 20 and in 80% by age 40
- The median age of death in patients with EDS IV is 48 years
- The diagnosis of EDS IV is made on clinical grounds (using major and minor diagnostic criteria) and is confirmed by genetic or protein-based testing
- Surgical intervention is notoriously dangerous in EDS IV due to excess vessel fragility - Loeys-Dietz Syndrome (LDS): Facts
- LDS is an autosomal dominant disorder of connective tissue with multisystem involvement
- Patients with typical dysmorphic features (hypertelorism, craniosynostoses, cleft palate) are classified as LDS type 1; those with mild dysmorphic features (only hypertelorism) without other dysmorphic findings but with velvety, translucent skin, easy bruising, and atrophic scars are classified as LDS type 2
- The natural history of both types of LDS is marked by early and rapid onset of thoracic aortic aneurysms (originating at the level of the sinuses of Valsalva) and death at an early age (mean age reported at 26.1 years) - Loeys-Dietz Syndrome (LDS): Facts
- LDS is caused by a heterozygous mutation in one of the transforming growth factor beta receptor genes (TGF-R1 or TGF-R2). TGF-R2 mutations on chromosome 3 (3p24.1) account for the majority of LDS mutations (75%), and TGF-R1 mutations on chromosome 9 (9q22.33) account for the remaining 25% . Direct sequencing of both TGF-R1 and TGF-R2 allows for the identification of a causal mutation in more than 95% of individuals. - “ Assessment of aortic volume is highly reproducible and may be suited for use in the detection of aortic expansion in patients with Marfan syndrome.”
Aortic Disease in Patients with Marfan Syndrome: Aortic Volume Assessment for Surveillance
den Hartog AW et al.
Radiology 2013; 269:370-377 - “ Total aortic dilation rate can be detected more accurately by using aortic volume assessment (root to bifurcation) than by using mean aortic diameter assessment.”
Aortic Disease in Patients with Marfan Syndrome: Aortic Volume Assessment for Surveillance
den Hartog AW et al.
Radiology 2013; 269:370-377 - “ Overall, the most common causes of sudden cardiac deaths in young adults are, in descending order of frequency, hypertrophic cardiomyopathy, coronary artery anomalies with an interarterial or intramural course, and ARVC (arrhythmogenic right ventricular cardiomyopathy).”
Congenital and Hereditary Causes of Sudden Cardiac Death in Young Adults: Diagnosis, Differential Diagnosis, and Risk Stratification
Stojanovska J et al.
RadioGraphics 2013;33:1977-2001
- " The manifestation of vascular Ehlers-Danlos syndrome frequently involves multiple vascular segments, with aneurysms and dissections being the most common imaging findings. The traditional practice of avoiding surgery until complications develop is being modified in select cases."
Vascular Complications of Ehlers-Danlos Syndrome: CT Findings
Chu LC, Johnson PT, Dietz HC, Black JH, Fishman EK
AJR (2012,in press) - Ehlers-Danlos Syndrome:Vascular Pathologies
- Aneurysms (single or multiple)
- Dissections (single or multiple)
- Vessel occlusion (single or multiple) - Vascular Ehlers-Danlos Syndrome: Facts
- Previously known as type IV Ehlers-Danlos syndrome
- autosomal-dominant disorder resulting from a mutation in the COL3A1 gene encoding for type III procollagen synthesis
- Clinical diagnosis made on basis of at least two of four major criteria;
- thin translucent skin
- fragility or rupture of the arteries, intestines, or uterus
- extensive bruising
- characteristic facial appearance - Vascular Ehlers-Danlos Syndrome: Facts
- Excessive tissue fragility predisposes patients with vascular Ehlers-Danlos syndrome to premature arterial, intestinal, or uterine rupture
- More than 80% of patients will have a complication by age 40 and this complication is the first sign of disease in many cases - Vascular Imaging Protocols
- Injection protocols
- Scan acquisition protocols
- Data analysis protocols
- Final analysis and consultation - Ehlers Danlos Syndrome: Time Course of Vascular lesions
- Lesions tend to progress over time
- New lesions develop over time
- Patients with aneurysms are at risk for complications like rupture and hemoperitoneum
- Patients with progression of arterial dissection can result in vascular compromise and infarcts - Vascular Ehlers Danlos Syndrome: Complications
- Preexisting aneurysms progress over time
- New aneurysms develop over time
- Aneurysms are at risk for spontaneous rupture (chest or abdomen)
- Arterial dissection can result in vascular compromise and infarction - Vascular Ehlers Danlos Syndrome: Treatment
- Careful monitoring of imaging findings with echocardiography, CT and/or MRI
- Surgery is more complicated in these patients because of high morbidity and mortality (up to 65%) due to vessel fragility
- Embolization can be helpful in select cases but catheter angiography is associated with major complications in up to 67% of patients and mortality rates of up to 17% - Vascular Ehlers Danlos Syndrome: Stent Graft Therapy
- The current consensus is that stent graft therapy should be avoided in patients with vascular Ehlers-Danlos syndrome and in those with other connective tissue disorders
- Society of Thoracic Surgeons Endovascular Surgery Task Force. Expert consensus document on the treatment of descending thoracic aortic disease using endovascular stent-grafts.
- Svensson LG, Kouchoukos NT, Miller DC, et al.;
- Ann ThoracSurg 2008; 85(suppl 1):S1–S41 - "The elective surgical management of vascular disorders in EDS patients using open and endovascular procedures has been associated with good outcomes. Our results suggest that vascular interventions in these EDS patients can be safely performed and should not be withheld until rupture or acute symptoms arise."
Contemporary management of vascular complications associated with Ehlers-Danlos syndrome.
Brooke BS, Amaoutakis G, McDonnell NB, Black JH III
J Vasc Surg 2010 Jan;51(1):131-8 - " Arterial abnormalities in patients with vascular Ehlers-Danlos syndrome frequently involve multiple vascular segments. Patients should undergo routine surveillance by noninvasive imaging of the chest, abdomen, and pelvis to monitor the progression of vascular complications. New management algorithms are being defined that support the strategy of performing surgical intervention in some patients before catastrophic complications develop.“
Vascular Complications of Ehlers-Danlos Syndrome: CT Findings
Chu LC, Johnson PT, Dietz HC, Black JH, Fishman EK
AJR (2012,in press) - " Spontaneous coronary artery dissection usually results from extension of a dissection from the proximal aorta, which has been reported in patients with connective tissue diseases such as Marfan syndrome or Ehlers-Danlos syndrome, as well as atherosclerotic aortic dissection."
Less Common Causes of Disease Involving the Coronary Arteries: MDCT Findings
Kim JA et al.
AJR 2011;197:125-130 
- Genetic Vascular Diseases
- Marfan Syndrome
- Ehlers Danlos Syndrome
- Loeys Dietz Syndrome - "Spinal and foot abnormalities were the most clinically important skeletal findings. Eleven patients had talipes equinovarus, and nineteen patients had cervical anomalies and instability. Thirty patients had scoliosis (mean Cobb angle [and standard deviation], 30 degrees +/- 18 degrees ). Two patients had spondylolisthesis, and twenty-two of thirty-three who had computed tomography scans had dural ectasia. Thirty-five patients had pectus excavatum, and eight had pectus carinatum. Combined thumb and wrist signs were present in approximately one-fourth of the patients. Acetabular protrusion was present in approximately one-third of the patients and was usually mild.“
Musculoskeletal findings of Loeys-Dietz Syndrome
Erkula G et al.
J Bone Joint Surg Am 2010 Aug 4; 92(9);1876-1883 - "Loeys-Dietz syndrome is a recently recognized multisystemic disorder caused by mutations in the genes encoding the transforming growth factor-beta receptor. It is characterized by aggressive aneurysm formation and vascular tortuosity. We report the musculoskeletal demographic, clinical, and imaging findings of this syndrome to aid in its diagnosis and treatment.“
Musculoskeletal findings of Loeys-Dietz Syndrome
Erkula G et al.
J Bone Joint Surg Am 2010 Aug 4; 92(9);1876-1883 - " Characterized by a unique constellation of clinical and pathologic findings, Loeys-Dietz syndrome manifests with aggressive vascular pathology. Aneurysms may form at a young age and have a propensity for arterial dissection. In addition, aneurysms rupture at diameters smaller than those used to dictate surgical intervention for other syndromes and disorders."
Loeys-Dietz Syndrome: MDCT Angiography Findings
Johnson PT, Chen JK, Loeys BL, Diets HC, Fishman EK
AJR 2007; 189:W29-W35 - " For patients with Loeys Dietz syndrome, early diagnosis and rapid intervention are instrumental in averting catastrophic events. Serial imaging assessment by radiologists."
Loeys-Dietz Syndrome: MDCT Angiography Findings
Johnson PT, Chen JK, Loeys BL, Diets HC, Fishman EK
AJR 2007; 189:W29-W35 - Marfans Syndrome vs Loeys-Dietz Syndrome
- Marfans has aortic root dilatation and it is the leading cause of morbidity and mortality. Loeys Dietz also has ortic root dilatation but aneurysms dissect at a smaller size and earlier age
- Pulmonary artery dilatation occurs in both Marfans syndrome and Loeys-Dietz syndrome
- Marfans patient may get extension of aortic dissection post repair while in Loeys-Dietz syndrome many other vessels are involved - Vascular Ehlers Danlos vs Loeys-Dietz Syndrome
- Loeys Dietz type II and Vascular Ehlers Danlos are similar in that spontaneous rupture of bowel, uterus and arteries can happen in both.
- Loeys Dietz patient do better with surgery than the Ehlers Danlos patients with less tha 5% mortality rate and so a more aggressive management style is usually warranted - An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. For the latter a new scoring system has been designed. In this revised nosology, FBN1 testing, although not mandatory, has greater weight in the diagnostic assessment. Special considerations are given to the diagnosis of MFS in children and alternative diagnoses in adults. We anticipate that these new guidelines may delay a definitive diagnosis of MFS but will decrease the risk of premature or misdiagnosis and facilitate worldwide discussion of risk and follow-up/management guidelines."
- "An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. For the latter a new scoring system has been designed. In this revised nosology, FBN1 testing, although not mandatory, has greater weight in the diagnostic assessment."
The revised Ghent nosology for the Marfan Syndrome
Loeys BL, Dietz HC, Braverman AC et al
J Med Genet 2010 Jul;47(7);475-485 - "An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required."
The revised Ghent nosology for the Marfan Syndrome
Loeys BL, Dietz HC, Braverman AC et al
J Med Genet 2010 Jul;47(7);475-485 - " Established linear methods for aortic measurement yield different results that impact surgical eligibility. DO (double oblique plane) yielded improved agreement with planimetry and differed with axial in proportion to aortic geometric obliquity. Findings support DO measurements for imaging evaluation of subects with TAA."
Impact of image analysis methodology on diagnostic and surgical classifcation of patients with thoracic aortic aneurysms
Mendoza DD et al.
Ann Thorac Surg 2011 Sep;92(3):913
- “ The manifestation of vascular Ehlers-Danlos syndrome frequently involves
multiple vascular segments, with aneurysms and dissections being the most common imaging findings. The traditional practice of avoiding surgery until complications develop is being modified in select cases.”
Vascular Complications of Ehlers-Danlos Syndrome: CT Findings
Chu LC, Johnson PT, Dietz HC, Black JH, Fishman EK
AJR (2012,in press) - Ehlers-Danlos Syndrome:Vascular Pathologies
- Aneurysms (single or multiple)
- Dissections (single or multiple)
- Vessel occlusion (single or multiple) - Vascular Ehlers-Danlos Syndrome: Facts
-Previously known as type IV Ehlers-Danlos syndrome
- autosomal-dominant disorder resulting from a mutation in the COL3A1 gene encoding for type III procollagen synthesis
- Clinical diagnosis made on basis of at least two of four major criteria;
- 1. thin translucent skin
- 2. fragility or rupture of the arteries, intestines, or uterus
- 3. extensive bruising
- 4. characteristic facial appearance - Vascular Ehlers-Danlos Syndrome: Facts
- Excessive tissue fragility predisposes patients with vascular Ehlers-Danlos syndrome to premature arterial, intestinal, or uterine rupture
- More than 80% of patients will have a complication by age 40 and this complication is the first sign of disease in many cases - Vascular Imaging Protocols
-Injection protocols
-Scan acquisition protocols
-Data analysis protocols
-Final analysis and consultation - Ehlers Danlos Syndrome: Time Course of Vascular lesions
- Lesions tend to progress over time
- New lesions develop over time
- Patients with aneurysms are at risk for complications like rupture and hemoperitoneum
- Patients with progression of arterial dissection can result in vascular compromise and infarcts - Vascular Ehlers Danlos Syndrome: Complications
- Preexisting aneurysms progress over time
- New aneurysms develop over time
- Aneurysms are at risk for spontaneous rupture (chest or abdomen)
- Arterial dissection can result in vascular compromise and infarction - Vascular Ehlers Danlos Syndrome: Treatment
- Careful monitoring of imaging findings with echocardiography, CT and/or MRI
- Surgery is more complicated in these patients because of high morbidity and mortality (up to 65%) due to vessel fragility
- Embolization can be helpful in select cases but catheter angiography is associated with major complications in up to 67% of patients and mortality rates of up to 17% - Vascular Ehlers Danlos Syndrome: Stent Graft Therapy
- The current consensus is that stent graft therapy should be avoided in patients with vascular Ehlers-Danlos syndrome and in those with other connective tissue disorders
- Society of Thoracic Surgeons Endovascular Surgery Task Force. Expert consensus document on the treatment of descending thoracic aortic disease using endovascular stent-grafts.
- Svensson LG, Kouchoukos NT, Miller DC, et al.;
- Ann ThoracSurg 2008; 85(suppl 1):S1–S41 - “The elective surgical management of vascular disorders in EDS patients using open and endovascular procedures has been associated with good outcomes. Our results suggest that vascular interventions in these EDS patients can be safely performed and should not be withheld until rupture or acute symptoms arise.”
Contemporary management of vascular complications associated with Ehlers-Danlos syndrome.
Brooke BS, Amaoutakis G, McDonnell NB, Black JH III
J Vasc Surg 2010 Jan;51(1):131-8 - “ Arterial abnormalities in patients with vascular Ehlers-Danlos syndrome frequently involve multiple vascular segments. Patients
should undergo routine surveillance by noninvasive imaging of the chest, abdomen, and pelvis to monitor the progression of vascular complications. New management algorithms are being defined that support the strategy of performing surgical intervention in some patients before catastrophic complications develop.”
Vascular Complications of Ehlers-Danlos Syndrome: CT Findings
Chu LC, Johnson PT, Dietz HC, Black JH, Fishman EK
AJR (2012,in press) - “ Spontaneous coronary artery dissection usually results from extension of a dissection from the proximal aorta, which has been reported in patients with connective tissue diseases such as Marfan syndrome or Ehlers-Danlos syndrome, as well as atherosclerotic aortic dissection.”
Less Common Causes of Disease Involving the Coronary Arteries: MDCT Findings
Kim JA et al.
AJR 2011;197:125-130 - Genetic Vascular Diseases
- Marfan Syndrome
- Ehlers Danlos Syndrome
- Loeys Dietz Syndrome - “Spinal and foot abnormalities were the most clinically important skeletal findings. Eleven patients had talipes equinovarus, and nineteen patients had cervical anomalies and instability. Thirty patients had scoliosis (mean Cobb angle [and standard deviation], 30 degrees +/- 18 degrees ). Two patients had spondylolisthesis, and twenty-two of thirty-three who had computed tomography scans had dural ectasia. Thirty-five patients had pectus excavatum, and eight had pectus carinatum. Combined thumb and wrist signs were present in approximately one-fourth of the patients. Acetabular protrusion was present in approximately one-third of the patients and was usually mild.”
Musculoskeletal findings of Loeys-Dietz Syndrome
Erkula G et al.
J Bone Joint Surg Am 2010 Aug 4; 92(9);1876-1883 - “Loeys-Dietz syndrome is a recently recognized multisystemic disorder caused by mutations in the genes encoding the transforming growth factor-beta receptor. It is characterized by aggressive aneurysm formation and vascular tortuosity. We report the musculoskeletal demographic, clinical, and imaging findings of this syndrome to aid in its diagnosis and treatment.”
Musculoskeletal findings of Loeys-Dietz Syndrome
Erkula G et al.
J Bone Joint Surg Am 2010 Aug 4; 92(9);1876-1883 - “ Characterized by a unique constellation of clinical and pathologic findings, Loeys-Dietz syndrome manifests with aggressive vascular pathology. Aneurysms may form at a young age and have a propensity for arterial dissection. In addition, aneurysms rupture at diameters smaller than those used to dictate surgical intervention for other syndromes and disorders.”
Loeys-Dietz Syndrome: MDCT Angiography Findings
Johnson PT, Chen JK, Loeys BL, Diets HC, Fishman EK
AJR 2007; 189:W29-W35 - “ For patients with Loeys Dietz syndrome, early diagnosis and rapid intervention are instrumental in averting catastrophic events. Serial imaging assessment by radiologists.”
Loeys-Dietz Syndrome: MDCT Angiography Findings
Johnson PT, Chen JK, Loeys BL, Diets HC, Fishman EK
AJR 2007; 189:W29-W35 - Marfans Syndrome vs Loeys-Dietz Syndrome
- Marfans has aortic root dilatation and it is the leading cause of morbidity and mortality. Loeys Dietz also has ortic root dilatation but aneurysms dissect at a smaller size and earlier age
- Pulmonary artery dilatation occurs in both Marfans syndrome and Loeys-Dietz syndrome
- Marfans patient may get extension of aortic dissection post repair while in Loeys-Dietz syndrome many other vessels are involved - Vascular Ehlers Danlos vs Loeys-Dietz Syndrome
- Loeys Dietz type II and Vascular Ehlers Danlos are similar in that spontaneous rupture of bowel, uterus and arteries can happen in both.
- Loeys Dietz patient do better with surgery than the Ehlers Danlos patients with less tha 5% mortality rate and so a more aggressive management style is usually warranted - "An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. For the latter a new scoring system has been designed. In this revised nosology, FBN1 testing, although not mandatory, has greater weight in the diagnostic assessment. Special considerations are given to the diagnosis of MFS in children and alternative diagnoses in adults. We anticipate that these new guidelines may delay a definitive diagnosis of MFS but will decrease the risk of premature or misdiagnosis and facilitate worldwide discussion of risk and follow-up/management guidelines.”
- “An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. For the latter a new scoring system has been designed. In this revised nosology, FBN1 testing, although not mandatory, has greater weight in the diagnostic assessment.”
The revised Ghent nosology for the Marfan Syndrome
Loeys BL, Dietz HC, Braverman AC et al
J Med Genet 2010 Jul;47(7);475-485 - “An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required.”
The revised Ghent nosology for the Marfan Syndrome
Loeys BL, Dietz HC, Braverman AC et al
J Med Genet 2010 Jul;47(7);475-485 - “ Established linear methods for aortic measurement yield different results that impact surgical eligibility. DO (double oblique plane) yielded improved agreement with planimetry and differed with axial in proportion to aortic geometric obliquity. Findings support DO measurements for imaging evaluation of subects with TAA.”
Impact of image analysis methodology on diagnostic and surgical classifcation of patients with thoracic aortic aneurysms
Mendoza DD et al.
Ann Thorac Surg 2011 Sep;92(3):913