Familial Syndromic and Non-Syndromic Aortopathy

Written by Mr Niall Khan, Specialist Registrar in Cardiothoracic Surgery, St James’s Hospital & Mr Saleem Jahangeer, Consultant Cardiothoracic and Aortic Surgeon- aorta@stjames.ie

Introduction: Aortopathy is a term which encompasses all disorders of the aortic wall, not solely aneurysm, acknowledging that size is not the sole contributor to aortic complications. The commonest, and potentially preventable, cause of death in aortopathy is acute aortic dissection. This arises when regional wall stress leads to intimal disruption, separation of the intima and media, and development of a false lumen. Subsequent complications such as aortic rupture or acute aortic valve insufficiency contribute to the considerable mortality rate associated with this condition.

Approximately 25% of aortic dissections have an identifiable genetic basis. Individuals with familial aortopathy may present with a syndromic (associated with a phenotypic presentation) or nonsyndromic (pure vascular type) variant. In syndromic aortopathies, aortic disease is an overwhelming contributor to morbidity and mortality. For example, over 90% of Marfan syndrome (MFS) deaths relate to aortic complications. Familial aortopathies account for the majority of aortic dissections in younger age groups (<40s). Current management includes surveillance, lifestyle adjustment, pharmacological therapies, and prophylactic or emergent aortic surgery. Genetic counselling plays an additional role.

In general, prophylactic aortic surgery is indicated at established size thresholds when the perceived risk of spontaneous complications is estimated to outweigh that of the elective repair. Outcomes for elective surgery are superior to those of emergency repair. A proportion of those experiencing acute aortic complications may also succumb before reaching the operating table.

Unfortunately, current guidelines for prophylactic aortic surgery are imperfect. Acute aortic syndromes continue to occur in those below guideline’s thresholds. This phenomenon is particularly pronounced in those with familial aortopathy, in whom further contributors to aortic wall weakness exist, independent of size alone. Due to the relative rarity of these conditions, reliable thresholds for intervention have been difficult to determine, and a personalized approach must often be employed.

This article will review the most well described familial aortopathies and provide an overview of their management.

Syndromic AortopathiesMarfan Syndrome

First described in 1896 by French paediatrician Antoine Bernard- Jean Marfan, this syndrome represents the commonest form of syndromic aortopathy. It is an autosomal dominant disorder caused by mutations in the FBN-1 gene encoding fibrillin-1. Fibrillin-1 is a large, extracellular matrix glycoprotein that serves as a structural component of microfibrils. These forcebearing support structures are widely distributed in elastic and nonelastic tissues.

MFS affects 0.5-1 in 10,000 live births with a uniform sex distribution. Diagnosis is via the Ghent nosology (Table 1), within which the typical clinical features are well described (Table 2). Clinical diagnosis with the Ghent nosology appears to correlate well with the presence of FBN-1 gene mutations. Central to the diagnosis are the findings of a positive family history, aortic root dilatation (Figure 1), or ectopia lentis.

Individuals affected by MFS are subject to an increased rate of aortic dilatation compared to the general population, as well as an increased risk of acute aortic events at any given aortic diameter. Aortic dissection most commonly occurs in the third decade and a significant proportion of remaining individuals will have undergone prophylactic aortic surgery by this age.

Current guidelines for prophylactic aortic surgery include an ascending aortic or root diameter ≥50mm (ESC(1) and ACCF/ AHA(2)), ≥45mm in the presence of additional risk factors (ESC and ACCF/AHA) or ≥40mm if considering pregnancy (ACCF/ AHA). Unfortunately, present data indicate that as many as 15% of individuals experience acute aortic syndromes while outside of these thresholds. The identification of individuals at increased risk, despite a lower aortic diameter, represents an important priority for future investigation.

Loeys-Dietz syndrome

Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described by Bart Loeys and Harry C Dietz in 2005. This autosomal dominant condition is characterized by aortic aneurysms, generalized arterial tortuosity, hypertelorism, bifid uvula or cleft palate. Five genes are implicated, all affecting the signalling of transforming growth factor β (TGFβ). The 5 subtypes of LDS (LDS 1-5) are respectively named according to the gene involved; TGFBR1, TGFBR2, SMAD3, TGFB2 and TGFB3. The disorder is rare, with an estimated prevalence of <1 in 100,000. LDS 1 and 2 appear to be the commonest and are associated with significant cardiovascular involvement.

The aortopathy in LDS leads to rapidly progressive aneurysmal disease. Congenital heart disease is a further association, including conditions such as bicuspid aortic valve, atrial septal defect, and persistent ductus arteriosus. The presence of such conditions further contributes to the progression of aortopathy. Aortic dissection is frequent and has been reported in individuals as young as three months of age.

Given the relative rarity of these disorders, data to support specific indications for prophylactic surgery are lacking. The ESC does not make any specific recommendation in the case of LDS, but highlight a need for individualized decision making. The ACCF/AHA recommend intervention at an aortic diameter of ≥42mm on transoesophageal echocardiogram; or ≥44-46mm on CT/MRI, acknowledging the limited quality of available evidence.

Notably, MacCarrick and colleagues at John’s Hopkins University, describe their approach to the management of LDS (3). Children with rapidly progressive aneurysms in the >99th percentile are repaired at a root diameter of 20-22mm, so that an adult sized graft may be accommodated. Root aneurysms in children that are slowly progressive are repaired at 40mm. In adults, root aneurysms are also repaired at 40mm, or if the growth rate exceeds 5mm per year. In adults, the descending aorta is repaired when diameter exceeds 45-50mm, or if growth rate exceeds 10mm per year.

Turner Syndrome

Turner syndrome (TS) results from complete or partial absence of the second X chromosome, occurring in 1 in 2500 live-born females. Mosaicism may also occur. It is one of the commonest human chromosomal abnormalities. Characteristic features include short stature, primary ovarian failure, lymphoedema, and congenital heart disease (affecting over 50%). The TIMP1 and TIMP3 genes have recently been implicated in the aortopathy associated with TS. These genes encode proteins which inhibit matrix metalloproteinases, a group of compounds involved in the breakdown of extracellular matrix.

Cardiovascular manifestations are common in TS, and include bicuspid aortic valve (30%), coarctation of the aorta (12%), thoracic aortic aneurysm (30%) and aortic dissection. The incidence of aortic dissection is up to 100 times more frequent in TS compared to the general population, occurring most commonly in the third decade. Hypertension is frequent, with multiple driving factors, and contributes to increased aortic wall stress. As with MFS and LDS, cardiovascular disease is the leading cause of mortality in individuals affected by TS.

Figure 1: Cardiac MR images showing the characteristic pearshaped aorta seen in Marfan syndrome. Image used with permission from Treasure T, Takkenberg JJ, Pepper J. Surgical management of aortic root disease in Marfan syndrome and other congenital disorders associated with aortic root aneurysms. Heart. 2014;100(20):1571-6.

Aortic dissection in TS appears to occur at lower aortic diameters than in other aortopathies. Given the typical short stature of these individuals, there is a need to use thresholds indexed for body size. Aortic size index (ASI) has emerged as the leading method for guiding intervention, and describes the ratio of aortic diameter to body surface area. However, ASI presents its own limitations. It is unreliable in females below the age of sixteen. Furthermore, the use of TS-specific Z scores has been proposed, given limitations associated with comparing this group to the general population.

The ESC and ACCF/AHA do not make specific recommendations for TS in their respective guidelines. However, for individuals with short stature in general, the ESC recommends intervention at an ASI ≥27.5mm/ m2 for the ascending aorta or root. The ACCF/AHA recommend intervention when the crosssectional aortic area divided by height exceeds 10cm2/m. The International Turner Syndrome Consensus group published broad guidance in 2017. They recommend intervention in individuals ≥16 years of age with an ascending ASI ≥2.5cm/m2 and associated risk factors for aortic dissection, including bicuspid aortic valve, elongation of the transverse aorta, coarctation of the aorta and/or hypertension.

Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome (EDS) refers to a broad group of fourteen connective tissue disorders. Mutations in genes affecting collagen are prominent, with aortopathy primarily seen in vascular EDS (previously known as type 4 EDS). This group have mutations of the COL3A1 gene, which encodes type 3 collagen. Affected individuals may have short stature, thin scalp hair, characteristic facial features (such as large eyes, small chin, and thin nose and lips).

The aortic wall is composed of type 1 and 3 collagen, which have a high resistance to biomechanical forces and contribute significantly to the force-bearing capability of the aortic wall. The aortic wall in those with vascular EDS is therefore fragile and prone to dilatation, rupture and dissection. Indeed, aortic dissection occurs at an increased rate in vascular EDS, even in the absence of pre-existing aortic dilatation. The median survival of these individuals is 48 years, with arterial rupture representing the primary cause of mortality.

The role of prophylactic surgery in vascular EDS is the least well established. In addition to a lack of clear data, the friability of the tissues and associated potential for haemorrhage mean that surgery, even in the elective setting, is fraught with risk. Consequently, the ESC and ACCF/AHA do not make specific recommendations to support the role of prophylactic aortic surgery in this group.

Aneurysms-Osteoarthritis Syndrome

Aneurysms-osteoarthritis syndrome (AOS) is an autosomal disorder which represents 2% of syndromic aortopathies. Implicating the SMAD3 gene. Syndromic features include craniofacial dysmorphism, cutaneous anomalies, and mild skeletal features. Osteoarthritis and other joint disorders such as osteochondritis dissecans occur at an early age.

Arterial involvement is characterised by tortuosity, aneurysms and dissections which may involve any segment of the arterial tree. Optimal management has yet to be established given the relative novelty of this condition. Therefore, many clinicians choose strategies based on those used in MFS and LDS.

Arterial Tortuosity Syndrome

Arterial tortuosity syndrome is a very rare syndromic aortopathy, displaying an autosomal recessive pattern of inheritance. The SLC2A10 gene is implicated. Phenotypic features include craniofacial dysmorphism (elongated face, beaked nose, micrognathia, high arched palate), hyper-extensible skin, and skeletal features (arachnodactyly, chest wall deformities).

The vascular component is characterised by elongated, tortuous arteries which are prone to both stenosis and aneurysm. Large and medium sized vessels are typically affected, especially the aorta and pulmonary artery. Given the rarity of this condition, incidence rates of complications such as aortic dissection are not well understood. Management protocols have yet to be borne out in the literature and at present, are individualised.

Non-Syndromic Aortopathies

Non-syndromic familial aortopathies represent a heterogeneous group wherein there is familial clustering of aortic disease, typically presenting at a young age, in the absence of syndromic features. While syndromic aortopathies account for around 5% of thoracic aortic disease, non-syndromic familial aortopathies account for a further 20% based on currently known culprit genes. Given the lack of phenotypic features, these individuals often come to attention later in life, potentially in the setting of a presentation with an acute aortic syndrome. At least 30 genes have been identified, generally encoding proteins involved in extracellular matrix, vascular smooth muscle cell function, or TGFβ signaling (Table 3). Many of these genes are also associated with syndromic aortopathies, but presenting in the absence of typical phenotypic features.

Emerging recognition of these genes is anticipated to change future practice. For example, the ACTA2 gene (one of the commonest to be detected) and the MYLK genes are associated with aortic dissection at diameters <5cm, suggesting a possible need for earlier prophylactic surgery in this cohort. Whole exome sequencing is being utilized in some international centres with a special interest in this area (4). This allows detection of culprit genes in the proband, followed potentially by assessment of relatives with more specific gene sequencing panels targeted to the culprit gene. Crucially, this practice continues to enable the detection of novel culprit genes.

Clinical guidelines have yet to provide specific recommendations for intervention in individuals with non-syndromic familial aortopathy. However, as understanding of the gene-disease association for familial aortopathy improves, a more personalized approach may become available to these families.

Management of Familial Aortopathies

Surveillance

Surveillance represents a cornerstone of management for individuals with aortopathy. Regular surveillance is critical for monitoring the progression of aortic dilatation and the development of associated complications such as aortic incompetence. In the absence of widely accessible, reliable biomarkers; imaging remains the sole means of guiding intervention.

Surveillance may include transthoracic echocardiogram to assess the aortic valve, root, and proximal ascending aorta. CT and MRI provide accurate imaging of the entire aorta and its branches. MRI is often favoured in a younger cohort. Ideally, surveillance is carried out at a dedicated centre where expertise in aortic imaging is available. This uniformity enables reliability in serial measurements and minimizes inter-observer error.

Imaging is carried out at regular intervals based on the individual risk profile, typically 6 to 12 monthly. Factors contributing to this risk profile include those relating to the underlying genetic disorder, family history of aortic dissection or rupture, increased rate of progression (>3mm per year for example), or increased baseline diameter.

Close surveillance is critical even after aortic repair, to monitor for disease progression in the remaining native aorta.

Counselling

Individuals with a high suspicion of a familial aortopathy should be referred to a clinical geneticist (ESC) for family testing and molecular investigation. As age of onset is variable, even healthy ‘at-risk’ relatives require regular screening at five-year intervals until a diagnosis is ruled out or established (ESC).

Pre-pregnancy counselling is another important area. Aortic wall stress is significantly elevated in pregnancy, with increased cardiac output being a key driver. The risk of aortic dissection is therefore raised, occurring most commonly in the third trimester. Those planning pregnancy may require prophylactic aortic surgery at lower thresholds.

Lifestyle Intervention

Individuals should be counselled on monitoring for the signs and symptoms of acute aortic syndromes. In those with aneurysmal disease, avoidance of high intensity isometric exercise is essential to avoid sudden increases in wall stress. Strict adherence to prescribed anti-hypertensive medication must be maintained. Sudden hypertension in the setting of missed medications is a potential precipitating event for acute complications.

An MDT approach is indispensable in the management of those with syndromic aortopathy. These multisystem disorders require organised, comprehensive care; potentially delivered through specialised clinics, encompassing all relevant caregivers at a single visit.

Medical Intervention

Beta blockers are used to reduce aortic wall stress. More recently, angiotensin receptor blockers are being used in MFS to reduce the rate of progression of aneurysmal disease. This practice is occasionally employed in other disorders such as LDS, inferring from the positive experience in MFS populations. It has recently emerged that certain medications may have an adverse effect on the natural history of aortopathy. Calcium channel blockers may increase wall stress through a reduction in cardiac afterload. Fluoroquinolones have been positively associated with aortopathy, potentially through their adverse effect on extracellular matrix, and should be avoided.

Surgical Intervention

Surgical options are varied and depend on the morphology of the aorta. Replacement of the diseased aortic segment provides definitive treatment for the diseased segment. Given the younger age of this cohort of patients, valve-preserving procedures are preferred.

The role of endovascular strategies is debated and there have been concerns regarding long-term outcome. These relate to the landing of stent grafts into segments of aorta in which the wall may be inherently abnormal, or be subject to progressive dilatation.

Regardless of the mode of intervention, these patients require life-long surveillance as other segments of the aorta tend to dilate over time.

Conclusion

Recent advances in our understanding of aortic disease have revealed an increasingly prominent role of genetics in the development of aortopathy. The natural history of familial aortopathy is less predictable than in non-genetic forms.

Unlocking the genetic make-up of familial aortopathy will allow us in the future to offer a completely personalised management for those patients, especially regarding personalised thresholds for interventions.

References available on request

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