Update on the Diagnosis and Management of Inherited Aortopathies, Including Marfan Syndrome.

Abstract

1.A number of inherited conditions can predispose the aorta, and less commonly other blood vessels, to dilatation and/ or rupture.2.Broadly speaking, these conditions are recognised as syndromic when accompanied by a number of systemic features or non-syndromic when the aortic dilatation appears to exist in isolation.3.The commonest syndromic aortopathy is Marfan syndrome and the commonest non-syndromic aortopathy is that which accompanies congenital bicuspid aortic valve.4.Mutations in a number of genes have been identified, particularly in syndromic aortopathy.5.Although genotype-phenotype relationships exist, the phenotypes of the syndromic aortopathies may have significant overlap.6.When a syndromic aortopathy is suspected, review by a clinical geneticist is instrumental in characterising the clinical signs and the family history.7.Confirmation of a diagnosis (either clinically or by gene testing) allows identification of individuals at increased risk of aortic sequelae who will benefit from active medical management.8.Medical management is usually undertaken by a cardiologist with referral to other specialists (eg cardiothoracic surgeons) as appropriate.9.At risk family members should be offered predictive testing if a mutation is identified, and should otherwise be screened in keeping with the presumptive clinical diagnosis and assessment of risk.10.Pregnancy and the post-partum period confer a higher risk for aortic complications:a.Women with a personal or family history of aortopathy need appropriate pre-conception screening and counselling.b.Intervention may be required pre-conception and they should be managed closely throughout pregnancy, ideally in a high-risk obstetric clinic, with joint management by an obstetrician and a cardiologist.c.Management may include appropriate cessation and commencement/continuation of medication ((ACE inhibitors and ARB are teratogenic and contraindicated in pregnancy, beta blockers can be used in pregnancy) and should include involvement of a cardiologist in the management during pregnancy and decision making for delivery.11.A clinical diagnosis of an inherited aortopathy can be made in the absence of a positive genetic test if the systemic features are consistent with a specific syndromic aortopathy. A familial history of aortic dissection in the absence of both a positive gene test and systemic examination findings may be more difficult to manage without a working clinical diagnosis. However, an inherited risk of dissection should nonetheless be considered in this setting, particularly if the process has affected young individuals and/or in the absence of traditional risk factors. The aortopathies encompass a number of conditions that result in an aorta that is structurally more susceptible to both dilatation and/or dissection. There is no accepted definition for the term and it is broadly applicable to both inherited and acquired conditions. This update concentrates on the inherited syndromic and non-syndromic aortopathies. Acquired thoracic and abdominal aortic aneurysm and dissection occur particularly in the elderly; are associated with cardiac risk factors, especially hypertension and cigarette smoking; and not considered further in this document [1Pape L.A. Awais M. Woznicki E.M. Suzuki T. Trimarchi S. Evangelista A. et al.Presentation, Diagnosis, and Outcomes of Acute Aortic Dissection: 17-Year Trends From the International Registry of Acute Aortic Dissection.J Am Coll Cardiol. 2015; 66: 350-358Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar, 2Goldfinger J.Z. Halperin J.L. Marin M.L. Stewart A.S. Eagle K.A. Fuster V. Thoracic aortic aneurysm and dissection.J Am Coll Cardiol. 2014; 64: 1725-1739Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 3Saratzis A. Bown M.J. The genetic basis for aortic aneurysmal disease.Heart. 2014; 100: 916-922Crossref PubMed Scopus (53) Google Scholar]. This update is intended as an overview, not an exhaustive literature review. Where guidelines exist, regardless of the often-limited evidence base, these will be recommended. Extensive discussion of each condition is also beyond the scope of the update and interested readers may find the references a useful resource. This term includes, and this update will briefly discuss, Marfan syndrome (MFS), Turner syndrome (TS), Loeys Dietz syndrome (LDS), Ehlers-Danlos, particularly type IV (vascular subtype), and arterial tortuosity syndrome (ATS). Most of these conditions are characterised by autosomal dominant inheritance. Turner syndrome is due to sex chromosome aneuploidy with the loss of one of the X chromosomes (45,X). Arterial tortuosity syndrome is a rare autosomal recessive condition. The most serious complication of an aortopathy is an aortic dissection. Aortic dissection due to an underlying heritable disorder (whether syndromic or non-syndromic) presents in the same way as aortic dissection in the general community. Guidelines are available regarding investigation, diagnosis and treatment of this potentially life-threatening complication [[4]Erbel R. Aboyans V. Boileau C. Bossone E. Bartolomeo R.D. Eggebrecht H. et al.2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC).Eur Heart J. 2014; 35: 2873-2926Crossref PubMed Scopus (2737) Google Scholar]. Consideration of an underlying heritable disorder should be given particularly in the setting of occurrence at a young age (<50), dissection during pregnancy or post-partum, when clinical examination uncovers clinical signs in keeping with one of the syndromic conditions (see below), or when there is a family history of dissection. A positive family history is an important clue. Taking a full family history is an essential part of clinical care, including following an emergent presentation. The conditions that cause syndromic aortopathies may present to the clinician in a variety of other clinical settings reflecting other affected organ systems. It is important to note that the clinical features described below can occur in a spectrum from mild to severe, and a clinical cardiac genetic service may be best placed to make a detailed assessment of the patient and family. This is the best known and characterised inherited aortopathy. It is also the one most often genotypically positive in the setting of clinically diagnostic features. The revised Ghent Criteria [[5]Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar] (see Table 1 below) allows a diagnosis to be made according to the presence or absence of family history and taking into account the aortic root size, ectopia lentis, a number of systemic features and the identification of an FBN1 mutation.Table 1Revised Ghent Criteria for diagnosis of Marfan syndrome (MFS) (see original article for description of differential diagnoses [5]Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar).No family history (a)Family history (b)1. AoD (Z ≥ 2) and EL = MFS1. EL + FH* MFS = MFSDiagnosis of MFS2. AoD (Z ≥ 2) and FBN1 = MFS2. Syst ≥ 7 = MFS + FH* MFS = MFS3. AoD (Z ≥ 2) and Syst ≥ 7 = MFS3. AoD (Z ≥ 2 if adult, Z ≥ 3 if < 20 yoa + FH* MFS = MFS4. EL + FBN1 + known AoD = MFSClinical signScore1. Wrist + Thumb sign32. Wrist OR Thumb sign13. Hindfoot deformity2Systemic (syst)4. Flat feet1features and scores5. Pneumothorax2for each feature6. Myopia (> 3 dioptres)1(maximum 20)7. Mitral valve prolapse18. Facial features (≥ 3/5) (dolicopcephaly, enopthalmus, downslanting palpebral fissures, malar hypoplasia, retrognathia)19. Pectus carinatum210. Pectus excavatum or chest asymmetry111. Reduced US/LS AND increased AS/Ht (in the absence of severe scoliosis)112. Scoliosis, thoracolumbar kyphosis113. Reduced elbow extension114. Skin striae115. Dural ectasia216. Protrusio acetabuli2FH* = Family history of MFS, where diagnosis fulfils criteria in column titled (a)AoD = aortic root dilatationZ = Z-score, derived from the internet z score calculator: http://www.marfan.orgSyst = systemic featuresEL = ectopia lentisFBN1 = fibrillin-1 mutationyoa = years of ageUS/LS = upper span: lower span ratioAS/Ht = arm span: height ratio Open table in a new tab FH* = Family history of MFS, where diagnosis fulfils criteria in column titled (a) AoD = aortic root dilatation Z = Z-score, derived from the internet z score calculator: http://www.marfan.org Syst = systemic features EL = ectopia lentis FBN1 = fibrillin-1 mutation yoa = years of age US/LS = upper span: lower span ratio AS/Ht = arm span: height ratio Loeys Dietz syndrome was described recently, and clinically may appear as MFS or a marfanoid-like condition. It is understood to be a clinical continuum due to dysregulation of TGF beta (TGFβ) signalling. Clinical features are present in the vascular, skeletal, craniofacial and cutaneous systems [[6]Loeys B.L. Schwarze U. Holm T. Callewaert B.L. Thomas G.H. Pannu H. et al.Aneurysm syndromes caused by mutations in the TGF-beta receptor.N Engl J Med. 2006; 355: 788-798Crossref PubMed Scopus (1254) Google Scholar]. The vascular disease is widespread and manifests as arterial tortuosity, aneurysm formation and dissection. Early reports suggesting almost ubiquitous aortic root dilatation likely reflect ascertainment bias [[6]Loeys B.L. Schwarze U. Holm T. Callewaert B.L. Thomas G.H. Pannu H. et al.Aneurysm syndromes caused by mutations in the TGF-beta receptor.N Engl J Med. 2006; 355: 788-798Crossref PubMed Scopus (1254) Google Scholar]. Skeletal involvement overlaps with the skeletal features of MFS and additionally may manifest as early onset osteoarthritis. Craniofacial features include hypertelorism, bifid uvula (see Figure 1), cleft palate, craniosynostosis and structural brain anomalies. Intellectual disability has been reported in severely affected children. Cutaneous features include hyperelastic and/or translucent skin, easy bruising and dystrophic scars. The Ehlers Danlos syndrome are characterised by joint hypermobility, skin hyperextensibility and tissue fragility [[7]Beighton P. De Paepe A. Steinmann B. Tsipouras P. Wenstrup R.J. Ehlers-Danlos syndromes: revised nosology. Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK).Am J Med Genet. 1998; 77: 31-37Crossref PubMed Scopus (1366) Google Scholar]. Ehlers Danlos syndromes Type IV (vascular subtype), is associated with rupture of organs and normally sized blood vessels, including the aorta [[8]Sobey G. Ehlers-Danlos syndrome: how to diagnose and when to perform genetic tests.Arch Dis Child. 2015; 100: 57-61Crossref PubMed Scopus (52) Google Scholar]. Clinically, important clues are a history of an arterial/ intestinal/ uterine rupture, incidentally noted organ tissue fragility at operation and extensive easy bruising and translucent (thin) skin. Guidelines recommend surgical intervention in EDS Type IV only in the setting of life-threatening complications due to the increased surgical risk [[4]Erbel R. Aboyans V. Boileau C. Bossone E. Bartolomeo R.D. Eggebrecht H. et al.2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC).Eur Heart J. 2014; 35: 2873-2926Crossref PubMed Scopus (2737) Google Scholar]. Aortic dilatation has been reported in the classic and hypermobile subtypes. However, most subtypes of EDS are a more benign condition with respect to aortic dissection risk [[9]Atzinger C.L. Meyer R.A. Khoury P.R. Gao Z. Tinkle B.T. Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome.J Pediatr. 2011; 158 (826-30 e1)Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. The rarer (autosomal recessive) kyphoscoliotic subtype of EDS has also been associated with vascular rupture[[8]Sobey G. Ehlers-Danlos syndrome: how to diagnose and when to perform genetic tests.Arch Dis Child. 2015; 100: 57-61Crossref PubMed Scopus (52) Google Scholar]. This is a very rare condition with marfanoid appearance, cutis laxa, hyperelastic soft skin, joint hypermobility and dislocations and herniae. Imaging reveals more widespread and tortuous involvement of the arterial tree [[10]Ritelli M. Chiarelli N. Dordoni C. Reffo E. Venturini M. Quinzani S. et al.Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review.BMC Med Genet. 2014; 15: 122Crossref PubMed Scopus (25) Google Scholar]. Turner syndrome is characterised by a woman of short stature who may present with delayed puberty and either reduced fertility or infertility. The incidence of bicuspid aortic valve (BAV) and coarctation of the aorta, as well as hypertension, are overrepresented in these women [11Turtle E.J. Sule A.A. Webb D.J. Bath L.E. Aortic dissection in children and adolescents with Turner syndrome: risk factors and management recommendations.Arch Dis Child. 2015; 100: 662-666Crossref PubMed Scopus (24) Google Scholar, 12Matura L.A. Ho V.B. Rosing D.R. Bondy C.A. Aortic dilatation and dissection in Turner syndrome.Circulation. 2007; 116: 1663-1670Crossref PubMed Scopus (284) Google Scholar]. A number of other genetic syndromes have been reported in association with aortic disease, including but not limited to: Weill-Marchesani syndrome (ADAMTS10 and FBN1)[[13]Le Goff C. Cormier-Daire V. From tall to short: the role of TGFbeta signaling in growth and its disorders.Am J Med Genet C Semin Med Genet. 2012; 160C: 145-153Crossref PubMed Scopus (63) Google Scholar]; congenital contractural arachnodactyly (resembles MFS, is characterised by crumpled ears, scoliosis, joint contractures and FBN2 mutations)[[14]Callewaert B.L. Willaert A. Kerstjens-Frederikse W.S. De Backer J. Devriendt K. Albrecht B. et al.Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families.Hum Mutat. 2008; 29: 150-158Crossref PubMed Scopus (141) Google Scholar]; Noonan syndrome (mutations in the RAS–MAPK signalling pathway) [15Cornwall J.W. Green R.S. Nielsen J.C. Gelb B.D. Frequency of aortic dilation in Noonan syndrome.Am J Cardiol. 2014; 113: 368-371Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 16Roberts A.E. Allanson J.E. Tartaglia M. Gelb B.D. Noonan syndrome.Lancet. 2013; 381: 333-342Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar]; Alagille syndrome (JAG1)[[17]Kamath B.M. Spinner N.B. Emerick K.M. Chudley A.E. Booth C. Piccoli D.A. et al.Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality.Circulation. 2004; 109: 1354-1358Crossref PubMed Scopus (264) Google Scholar]; X-linked dominant periventricular nodular heteropia, EDS variant (FLNA)[[18]Reinstein E. Frentz S. Morgan T. Garcia-Minaur S. Leventer R.J. McGillivray G. et al.Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A.Eur J Hum Genet. 2013; 21: 494-502Crossref PubMed Scopus (73) Google Scholar] and Shprintzen-Goldberg syndrome (SK1) [[19]Doyle A.J. Doyle J.J. Bessling S.L. Maragh S. Lindsay M.E. Schepers D. et al.Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.Nat Genet. 2012; 44: 1249-1254Crossref PubMed Scopus (193) Google Scholar]. Non-syndromic TAAD is recognised by the clustering of aortic sequelae in a family [[20]Luyckx I. Loeys B.L. Curriculum topic: The genetic architecture of non-syndromic thoracic aortic aneurysm.Heart. 2015; 101: 1678-1684Crossref PubMed Scopus (21) Google Scholar]. By definition, the clinical phenotype is otherwise normal. To date, mutations in these families have been identified in a number of genes (see Table 1, below). The proportion of families who will have an identifiable genetic mutation is unknown. Therefore, a positive family history is always significant even in the absence of a putative gene mutation. Bicuspid aortic valve is the commonest condition in our community (1% prevalence) that can develop aortic dilatation and aneurysm formation (approximately 20–30% of subjects with BAV [[21]Michelena H.I. Corte A.D. Prakash S.K. Milewicz D.M. Evangelista A. Enriquez-Sarano M. Bicuspid aortic valve aortopathy in adults: Incidence, etiology, and clinical significance.Int J Cardiol. 2015; 201: 400-407Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar]). Though usually a sporadic finding, it can be inherited [20Luyckx I. Loeys B.L. Curriculum topic: The genetic architecture of non-syndromic thoracic aortic aneurysm.Heart. 2015; 101: 1678-1684Crossref PubMed Scopus (21) Google Scholar, 22Prakash S.K. Bosse Y. Muehlschlegel J.D. Michelena H.I. Limongelli G. Della Corte A. et al.A roadmap to investigate the genetic basis of bicuspid aortic valve and its complications: insights from the International BAVCon (Bicuspid Aortic Valve Consortium).J Am Coll Cardiol. 2014; 64: 832-839Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar], and thus guidelines recommend echocardiographic screening first-degree relatives to determine whether the aortic valve is bicuspid or tricuspid [[23]Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.M. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology. Society of Thoracic Surgeons, and Society for Vascular Medicine.Circulation. 2010; 121: e266-e369Crossref PubMed Scopus (1917) Google Scholar]. Ideally, consideration of an inherited aortopathy should prompt referral to a clinical or cardiac genetics service for a thorough specialised examination. Standardised examination protocols exist for determining the likelihood clinically of MFS [[5]Loeys B.L. Dietz H.C. Braverman A.C. Callewaert B.L. De Backer J. Devereux R.B. et al.The revised Ghent nosology for the Marfan syndrome.J Med Genet. 2010; 47: 476-485Crossref PubMed Scopus (1339) Google Scholar] and EDS [[24]Malfait F. Wenstrup R.J. De Paepe A. Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type.Genet Med. 2010; 12: 597-605Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar]. Assessment of the aortic root and ascending aorta is essential if there is clinical suspicion of an inherited aortopathy. Aortic root involvement is classically seen in MFS and EDS, but may also occur in the other syndromic aortopathies (Figure 2). The ascending aorta is the usual site of dilatation in BAV, TS and the non-syndromic aortopathies, but also may occur in other conditions, including MFS (Figure 3). Abdominal aortic aneurysms have been reported in both MFS and LDS. Involvement of vasculature throughout the body, including cerebral vessels, occurs in LDS [6Loeys B.L. Schwarze U. Holm T. Callewaert B.L. Thomas G.H. Pannu H. et al.Aneurysm syndromes caused by mutations in the TGF-beta receptor.N Engl J Med. 2006; 355: 788-798Crossref PubMed Scopus (1254) Google Scholar, 25MacCarrick G. Black 3rd, J.H. Bowdin S. El-Hamamsy I. Frischmeyer-Guerrerio P.A. Guerrerio A.L. et al.Loeys-Dietz syndrome: a primer for diagnosis and management.Genet Med. 2014; 16: 576-587Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar].Figure 3Dilated ascending aorta associated with a bicuspid aortic valve.Show full captionTransthoracic echocardiography long axis parasternal view showing a dilated ascending aorta (5.0 cm) in the setting of a bicuspid aortic valve with mild stenosis (mean gradient 13 mmHg) in a 40-year-old woman. Note the relative preservation of the aortic sinus compared to the dilatation seen with MFS.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Transthoracic echocardiography long axis parasternal view showing a dilated ascending aorta (5.0 cm) in the setting of a bicuspid aortic valve with mild stenosis (mean gradient 13 mmHg) in a 40-year-old woman. Note the relative preservation of the aortic sinus compared to the dilatation seen with MFS. Clinical symptoms in other vascular beds should lead to directed imaging. Once a diagnosis of syndromic subtype is made, then imaging will need to be considered accordingly (see Management). It appears prudent to image the entire aorta, though no evidence regarding the optimal interval between screenings is available. Involvement of other specialists will need to be considered on a case-by-case basis according to the likely diagnosis. A detailed (three generation pedigree) family history is essential. A reported clinical or genetic diagnosis in a family member should be verified by obtaining relevant documentation, with consent as appropriate. Molecular confirmation of a suspected clinical diagnosis is increasingly important for guiding patient management. As an example, an individual who looks marfanoid will have more extensive arterial imaging screening if identified to have a SMAD3 mutation as opposed to an FBN1 mutation. Table 2 lists the genes identified most commonly for specific clinical phenotypes. The genotype-phenotype relationship is not absolute. Mutations in the same gene can cause variable clinical phenotypes. Fulfilment of the modified Ghent criteria does not necessarily imply a diagnosis of MFS, as patients with LDS may fulfil these criteria as well.Table 2Gene(s) most commonly identified for the different clinical ‘classical’ aortopathy diagnoses.ConditionGeneReferenceMarfan syndromeFBN1[26]Proost D. Vandeweyer G. Meester J.A. Salemink S. Kempers M. Ingram C. et al.Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes.Hum Mutat. 2015; 36: 808-814Crossref PubMed Scopus (80) Google ScholarLoeys-Dietz syndromeTGFBR2[25]MacCarrick G. Black 3rd, J.H. Bowdin S. El-Hamamsy I. Frischmeyer-Guerrerio P.A. Guerrerio A.L. et al.Loeys-Dietz syndrome: a primer for diagnosis and management.Genet Med. 2014; 16: 576-587Abstract Full Text Full Text PDF PubMed Scopus (314) Google ScholarTGFBR1SMAD3TGFB2Ehlers Danlos syndrome (vascular subtype)COL3A1[27]Germain D.P. Ehlers-Danlos syndrome type IV.Orphanet J Rare Dis. 2007; 2: 32Crossref PubMed Scopus (213) Google ScholarArterial tortuosity syndromeSLC2A10[10]Ritelli M. Chiarelli N. Dordoni C. Reffo E. Venturini M. Quinzani S. et al.Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review.BMC Med Genet. 2014; 15: 122Crossref PubMed Scopus (25) Google ScholarNon-syndromic TAADACTA2[28]Milewicz D.M. Guo D.C. Tran-Fadulu V. Lafont A.L. Papke C.L. Inamoto S. et al.Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction.Annu Rev Genomics Hum Genet. 2008; 9: 283-302Crossref PubMed Scopus (315) Google Scholar[29]Guo D.C. Regalado E. Casteel D.E. Santos-Cortez R.L. Gong L. Kim J.J. et al.Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.Am J Hum Genet. 2013; 93: 398-404Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar[30]Wang L. Guo D.C. Cao J. Gong L. Kamm K.E. Regalado E. et al.Mutations in myosin light chain kinase cause familial aortic dissections.Am J Hum Genet. 2010; 87: 701-707Abstract Full Text Full Text PDF PubMed Scopus (220) Google ScholarMYH11*May be associated with a patent ductus arteriosus # Non-syndromic TAAD genes have been identified in individuals with BAV and aortic dilatation ^ Accounts for a small proportion of patients with BAV(Mutations in many of the genes identified in this table as causing syndromic aortopathy have also been identified in cases of non-syndromic aortopathy)PRKG1MYLKBicuspid aortic valve#NOTCH1^[22]Prakash S.K. Bosse Y. Muehlschlegel J.D. Michelena H.I. Limongelli G. Della Corte A. et al.A roadmap to investigate the genetic basis of bicuspid aortic valve and its complications: insights from the International BAVCon (Bicuspid Aortic Valve Consortium).J Am Coll Cardiol. 2014; 64: 832-839Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar* May be associated with a patent ductus arteriosus# Non-syndromic TAAD genes have been identified in individuals with BAV and aortic dilatation^ Accounts for a small proportion of patients with BAV Open table in a new tab A definitive molecular genetic diagnosis can clarify an equivocal clinical picture or result in a diagnosis in an apparently phenotypically normal individual. It is unknown at this stage what proportion of patients with these different genetic mutations will develop aortic dilatation or dissection. Identification of a causal mutation allows for the provision of accurate genetic counselling, the screening of at-risk family members and offers the possibility of accurate prenatal or preimplantation genetic diagnosis. Sanger sequencing may be considered when there is no doubt about the clinical diagnosis. Despite clinical certainty however, a pathogenic mutation may not be found. Typically, exonic or whole-gene deletions and/or duplications are not detected by this method and require alternative technology e.g. quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes the relevant gene/chromosome segment. There are intrinsic hurdles, not least of all cost, of Sanger sequencing of consecutive candidate genes compared to multi-gene panel testing. Many clinical laboratories offer a multi-gene MFS/LDS/familial TAAD panel that includes FBN1 and numerous other genes associated with aortic aneurysm and dissection disorders. This approach may be advantageous, given the known clinical and genetic heterogeneity of these disorders. It is important to recognise that no testing method guarantees a molecular diagnosis. The described limitation of Sanger sequencing to detect deletions and/or duplications may also occur in panel testing and should be discussed with the testing laboratory as appropriate. Both methodologies described above may result in the finding of a variant of uncertain/ unknown significance (VUS). Ideally, family studies to track the VUS genotype with phenotype may assist with clarification. Practically, however, this can prove difficult. Whilst functional studies to determine the molecular effect of the mutation may assist in interpretation of a VUS, these studies are not readily available. Management of acute dissection is not dealt with in this document. Broadly speaking, management of patients at risk of aortic dilatation and dissection falls into the following categories:1.Consideration of medical therapya.There is data regarding medical prophylaxis of aortic dilatation, largely limited to individuals with MFS.b.A number of trials have shown a positive effect on reducing aortic growth with the use of beta blockers, angiotensin receptor blockers (ARB) or angiotensin converting enzyme inhibitors (ACEI) [31Thakur V. Rankin K.N. Hartling L. Mackie A.S. A systematic review of the pharmacological management of aortic root dilation in Marfan syndrome.Cardiol Young. 2013; 23: 568-581Crossref PubMed Scopus (12) Google Scholar, 32Attenhofer Jost C.H. Greutmann M. Connolly H.M. Weber R. Rohrbach M. Oxenius A. et al.Medical treatment of aortic aneurysms in Marfan syndrome and other heritable conditions.Curr Cardiol Rev. 2014; 10: 161-171Crossref PubMed Google Scholar]. We are not aware of currently available data regarding the effect of medical therapy on mortality.c.Superiority of a medication class has not been established, and treatment should be individualised as tolerated. Future recommendations may suggest concomitant use of more than one class of medication.d.It is unknown whether clinicians should aim for the dose used in trials or measure effect on a physiological variable (e.g. heart rate at submaximal exercise) or both.2.Surveillance for aortic dilatationa.Usual practice is clinical review with yearly echocardiogram in MFS.b.Six-monthly echocardiogram if the aortic root is either close to surgical threshold or has increased significantly in size between prior imaging interval (≥0.3 cm/year).c.If there is significant valvular disease (eg aortic or mitral regurgitation), then imaging frequency may be further individualised.d.Computed tomography angiography or MRI of the entire aorta should be undertaken in MFS. The interval for repeat screening of a normally sized aorta is not stipulated in most publications [4Erbel R. Aboyans V. Boileau C. Bossone E. Bartolomeo R.D. Eggebrecht H. et al.201