NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Heritable Thoracic Aortic Disease Overview

, MD, PhD
Division of Medical Genetics
Department of Internal Medicine
University of Texas Health Science Center at Houston McGovern Medical School
Houston, Texas
, MS, CGC
Division of Medical Genetics
Department of Internal Medicine
University of Texas Health Science Center at Houston McGovern Medical School
Houston, Texas

Initial Posting: ; Last Revision: December 14, 2017.

Summary

Purpose.

The goals of this overview on heritable thoracic aortic aneurysms and dissections (shortened in this GeneReview to heritable thoracic aortic disease) are the following:

Goal 1.

To describe the clinical characteristics of thoracic aortic disease

Goal 2.

To review the causes of heritable thoracic aortic disease and risk assessment for thoracic aortic aneurysm and dissection by gene

Goal 5.

To inform (when possible) management regarding, surveillance for thoracic aortic aneurysm, and medical/surgical intervention based on the genetic cause

Clinical Characteristics: Heritable Thoracic Aortic Disease

Thoracic aortic disease, for the purpose of this GeneReview, refers to thoracic aortic aneurysms and aortic dissections (TAAD).

Heritable thoracic aortic disease (HTAD) refers to thoracic aortic disease caused by mutation of a gene that confers a high risk for TAAD (see Causes).

A thoracic aortic aneurysm is a permanent, localized dilatation of the thoracic aorta. Thoracic aortic aneurysms may involve different thoracic aortic segments; this review focuses on aneurysms involving the aortic root and/or ascending aorta (see Figure 1).

Figure 1.

Figure 1.

Thoracic aortic aneurysms involving the aortic root (a) and the ascending aorta (b) Printed with permission from Baylor College of Medicine, Copyright 2016

To evaluate for a thoracic aortic aneurysm, the aortic diameter is measured (perpendicular to the axis of blood flow) by echocardiography, CT, or MRI at reproducible anatomic locations. Measurements of aortic diameters obtained from transthoracic echocardiography tend to be smaller than measurements obtained from CT or MRI [Asch et al 2016]. The echocardiography convention for assessment of aortic root and ascending aortic diameters has been to measure leading edge to leading edge in end-diastole [Evangelista et al 2010]. Recent data indicate that measurements (using this convention) assessed by two-dimensional transthoracic echocardiography accurately correlate with internal diameters assessed by multidetector CT or MRI [Rodríguez-Palomares et al 2016].

Nomograms for normal aortic diameter based on age, sex, and body size have been developed for the aortic root and the ascending aorta [Devereux et al 2012, Kälsch et al 2013]. Aortic diameters that exceed the upper limit in these nomograms are considered enlarged or dilated.

Thoracic aortic aneurysms are usually asymptomatic and enlarge over time. Undiagnosed or untreated thoracic aortic aneurysms can lead to life-threatening acute ascending aortic dissections.

An aortic dissection is defined as a disruption of the medial layer of the aorta resulting in bleeding within and along the wall of the aorta and separation of the layers of the wall of the aorta. Of note, although most dissections occur in the presence of an aneurysm, dissections can occur in the absence of enlargement of the aorta.

Aortic dissections can be classified by the Stanford criteria based on the involvement of the ascending aorta:

  • Type A dissections (Figure 2a, 2b) involve the ascending aorta regardless of the site of origin and may or may not extend into the descending thoracic aorta.
  • Type B dissections (Figure 2c) originate at the descending thoracic aorta, typically distal to the left subclavian artery, and propagate variable distances down the descending thoracic aorta and abdominal aorta. Type B dissections do not involve the ascending aorta.
Figure 2.

Figure 2.

Thoracic aortic dissections: Type A (a and b) and Type B (c) Printed with permission from Baylor College of Medicine, Copyright 2016

The DeBakey classification system, which is sometimes used to classify aortic dissections, defines dissections based on the origin of the tear and extent of the dissection. Click here (pdf) to read more about the DeBakey classification system.

Natural history. Over time a thoracic aortic aneurysm asymptomatically enlarges until the aortic wall weakens and the intimal (inner) layer tears acutely at the junction between the sinuses and the tubular ascending aorta, leading to a Stanford type A dissection. With type A dissection, blood escapes through a tear in the inner wall of the ascending aorta penetrating and separating the layers of the medial (thick middle) layer, where it flows either up the ascending aorta in the direction of blood flow (anterograde dissection) or back toward the root (retrograde dissection).

While in the past, type A aortic dissections were reported to cause sudden death in up to 50% of individuals, more recent data suggest that in-hospital death rates are decreasing particularly in patients undergoing prophylactic surgical repair and early medical treatment [Mody et al 2014]. The majority of the deaths in non-hospitalized patients are due to blood dissecting retrograde and rupturing into the pericardial sac, causing pericardial tamponade.

Individuals experiencing an acute type A dissection (who have usually had a dissection that progressed through the ascending aorta and continued into the descending aorta) have a high mortality rate either acutely or following emergency surgery to repair the dissected ascending aorta [Hagan et al 2000, Hiratzka et al 2010].

Type B aortic dissections tend to be less likely to result in death and to occur with little to no enlargement of the descending aorta.

Pathology. Click here (pdf) for information about the aortic histopathology in HTAD.

Causes of Heritable Thoracic Aortic Disease

Up to 20% of individuals with TAAD who do not have a known syndrome (e.g., Marfan syndrome, vascular Ehlers Danlos syndrome, or Loeys-Dietz syndrome) have a family history of TAAD [Biddinger et al 1997].

Approximately 30% families with HTAD who do not have a clinical diagnosis of Marfan syndrome or another syndrome have a causative pathogenic variant in one of the known HTAD-related genes.

To date, 16 genes are known to predispose to TAAD (Table 1). Note that because many families with a family history of TAAD do not have a pathogenic variant in one of these 16 genes, additional HTAD-related genes are yet to be identified.

While in the past, HTAD of known genetic cause may have been considered to be either syndromic (part of a set of clinical findings) or nonsyndromic (occurring as an isolated finding), the distinction between syndromic and nonsyndromic HTAD has become increasingly blurred as it is common for pathogenic variants in a gene to result in a phenotypic spectrum that ranges from syndromic to nonsyndromic.

Heritable Thoracic Aortic Disease: Known Causes

Table 1.

HTAD-Related Genes and Phenotypes

Gene
(Locus) 1
Proportion of Families w/HTAD w/a Pathogenic Variant in This Gene 2SyndromeOther Cardiovascular Findings Observed
ACTA212%-21% 3Multisystem smooth muscle dysfunction syndrome 4See footnote 4
BGNRareMeester-Loeys syndrome (OMIM 300989)
COL3A1RareEhlers-Danlos syndrome (EDS) type IV
FBN13% 5Marfan syndrome
FOXE31.4% 6
LOX1.5% 7Bicuspid aortic valve, abdominal aortic aneurysm, hepatic artery aneurysm
MAT2A1% 8Bicuspid aortic valve
MFAP50.25% 9Atrial fibrillation, mitral valve prolapse, and arterial tortuosity in some patients
MYH111% 10Patent ductus arteriosus 11
MYLK1% 12
PRKG11% 13Coronary artery aneurysm/dissection and arterial tortuosity in some patients
TGFB21% 14Loeys-Dietz syndrome 15Abdominal aortic aneurysms and/or intracranial and other arterial aneurysms and/or dissections 16, 17, 18
TGFB32 simplex cases 19, one 3-generation family 20Rienhoff syndrome or Loeys-Dietz syndrome type 5
TGFBR13% 21Loeys-Dietz syndrome 15Abdominal aortic aneurysms and/or intracranial and other arterial aneurysms and/or dissections 16, 17, 18
TGFBR25% 22Loeys-Dietz syndrome 15
SMAD32% 23Aneurysms osteoarthritis syndrome; Loeys-Dietz syndrome 15
(AAT1 or FAA1) 24Unknown
(AAT2 or TAAD1) 24Unknown
1.

Locus is included when related gene is not known.

2.

Frequencies are based on cohorts of families with two or more members who had TAAD and did not meet clinical diagnosis criteria for Marfan syndrome, vascular Ehlers Danlos syndrome, or Loeys-Dietz syndrome. It is important to note that the frequency of variants reported in these genes varies depending on population studied.

3.
4.

TAAD cosegregating with premature coronary artery disease, ischemic stroke, and moyamoya disease have been observed in families with ACTA2 pathogenic variants, more frequently in patients with mutation of the R258, R118, and R149 residues [Guo et al 2009]. Patent ductus arteriosus, aortic coarctation, moyamoya-like cerebrovascular disease with stenosis and dilatation of cerebral vessels, retinal artery tortuosity, and brachial artery occlusion are present in patients with multisystemic smooth muscle dysfunction syndrome caused by ACTA2 R179 variants [Milewicz et al 2010].

5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.

While in the past the various clinical presentations associated with a heterozygous pathogenic variant in TGFBR1, TGFBR2, SMAD3, or TGFB2 have designated LDS types I, II, and III, it is now recognized that these phenotypes are a continuum of various combinations of clinical features. Of note, in families with mutation of one of these genes, affected family members usually have thoracic aortic disease but can also have tortuosity, aneurysms, and dissections of other vessels, including intracranial arteries.

16.
17.
18.
19.
20.
21.
22.
23.
24.

Two loci designated as AAT1 (FAA1) [Vaughan et al 2001] and AAT2 (TAAD1) [Guo et al 2001] are implicated in TAAD; the genes have not been identified.

ACTA2

Thoracic aortic aneurysms are typically fusiform and initially involve the aortic root, extending into the ascending aorta and aortic arch. Descending and abdominal aortic aneurysms are less common. See Table 2 for risks associated with thoracic aortic disease.

A subset of ACTA2 pathogenic variants predispose to early-onset stroke or coronary artery disease (i.e., age <55 years in men and <60 years in women), or Moyamoya-like cerebrovascular disease.

ACTA2 missense pathogenic variants that specifically disrupt the arginine 179 residue cause multisystem smooth-muscle dysfunction syndrome in which dysfunction of smooth muscle cells leads to severe and highly penetrant vascular diseases, pulmonary hypertension, and loss of proper smooth muscle cell contraction in other organs [Guo et al 2009, Milewicz et al 2010, Munot et al 2012]. Systemic manifestations can include:

  • Large patent ductus arteriosus
  • Aortic coarctation
  • Early-onset cerebrovascular disease with characteristic pattern of dilatation of the proximal internal carotid artery, occlusion of the cerebral arteries (mainly the terminal internal carotid arteries), and abnormally straight course of the intracranial arteries. Periventricular white-matter hyperintensities observed on brain MRI may be due to occlusion of small arteries [Munot et al 2012].
  • Pulmonary arterial hypertension
  • Brachial artery occlusion with limb ischemia [Al-Mohaissen et al 2012]
  • Tortuosity of retinal arterioles [Moller et al 2012]
  • Congenital mydriasis
  • Hypoperistalsis and malrotation of the gut
  • Hypotonic bladder that is variably associated with dilated ureters, calyces and/or renal pelvises, hydronephrosis, vesicoureteral reflux, and recurrent urinary tract infections. Prune-belly sequence has been observed [Richer et al 2012, Brodsky et al 2014].

Click here (pdf) to read more about the molecular genetics of ACTA2 that give rise to multisystem smooth-muscle dysfunction syndrome and nonsyndromic HTAD.

BGN

Meester-Loeys syndrome (OMIM 300989) is characterized by macrocephaly, frontal bossing, proptosis, hypertelorism, downslanting palpebral fissures, and malar hypoplasia and striae. Musculoskeletal findings include cervical spine instability, pectus deformities, joint hypermobility or contractures, joint dislocations, camptodactyly, short spatulate fingers, and flat feet. Affected individuals are at risk for aneurysm and/or dissection of the aortic root and ascending aorta, and (rarely) pulmonary artery aneurysm and/or cerebral aneurysm. Dilated cerebral ventricles have been reported in some individuals. Hemizygous BGN pathogenic variants are causative; inheritance is X-linked.

COL3A1

Ehlers-Danlos syndrome (EDS) type IV is characterized by thin, translucent skin, easy bruising, characteristic facial appearance, and arterial, intestinal, and/or uterine fragility. Affected individuals are at risk for arterial rupture, aneurysm, and/or dissection; gastrointestinal perforation or rupture; and uterine rupture during pregnancy. Although TAAD can be observed, it is extremely rare for more than one member of a family to have this finding as any large- to medium-sized arteries can be involved.

FBN1

The most common FBN1-related syndrome is Marfan syndrome, characterized by cardiovascular findings (dilatation of the aorta at the level of the sinuses of Valsalva, predisposition for aortic tear and rupture (see Table 2), mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery); ocular findings (myopia, ectopia lentis); and skeletal findings (disproportionately long extremities for the size of the trunk, joint laxity, pectus excavatum or carinatum, scoliosis).

FBN1 pathogenic variants can cause autosomal dominant TAAD with no ocular features and little to no skeletal or other systemic features of Marfan syndrome [Francke et al 1995, Milewicz et al 1996, Stheneur et al 2009, Regalado et al 2016], particularly in individuals of Hispanic descent who can have HTAD with fewer skeletal manifestations than individuals of European descent [Brautbar et al 2010, Villamizar et al 2010].

FOXE3

A heterozygous missense variant in FOXE3 was identified in a four-generation family with autosomal dominant inheritance of TAAD with variable clinical expressivity and reduced penetrance in women [Kuang et al 2016]. The majority of affected individuals presented with acute type A dissections at a mean age of 45 years (range 27-63 years); one individual presented with a type B dissection. Seven additional FOXE3 missense variants predicted to be pathogenic were identified in individuals with familial TAAD, but have limited family segregation or other evidence to confirm clinical significance. These variants cluster at the C-terminal end of the forkhead DNA-binding domain. Mostly homozygous pathogenic variants located in the N-terminal end or outside this domain have been associated with anterior segment dysgenesis and cataracts [Semina et al 2001, Valleix et al 2006, Anjum et al 2010, Doucette et al 2011, Khan et al 2016].

LOX

LOX heterozygous missense variants in the catalytic domain of the protein and nonsense variants were reported in seven families and cosegregated with TAAD in these families [Guo et al 2016, Lee et al 2016]. Affected individuals had ascending aortic aneurysms and type A dissections. Abdominal aortic aneurysm, hepatic artery aneurysm, and bicuspid aortic valve have been observed in some individuals. In addition, musculoskeletal manifestations of Marfan syndrome (e.g., pectus excavatum, scoliosis, arachnodactyly, high-arched palate) and skin striae were variably present in those who had an LOX pathogenic variant.

MFAP5

Loss-of-function MFAP5 pathogenic variants can cause aortic root dilation and ascending thoracic aortic dissection (see Table 2) [Barbier et al 2014]. Penetrance is reduced.

Some affected individuals have atrial fibrillation and clinical features overlapping with Marfan syndrome such as mitral valve prolapse, high-arched palate, chest deformity, and arachnodactyly.

TGFB2, TGFBR1, TGFBR2, SMAD3

Thoracic aortic aneurysms typically involve the aortic root (see Table 2).

Pathogenic variants in these genes also predispose to aneurysms and dissections in other arteries, including the abdominal aorta, arterial branches of the aorta, and intracranial arteries. Of note, although marked aortic and arterial tortuosity has been associated with mutation of these genes, aortic and arterial tortuosity is increased for the majority of HTAD-related genes [Morris et al 2011].

The phenotypes resulting from of any one of these genes can range from no to minimal features of Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome.

Loeys Dietz syndrome (LDS) is characterized by the vascular findings of early-onset aggressive thoracic aortic disease, intracranial aneurysms and dissections, aneurysms and dissections of other arteries, and vascular tortuosity. Variable findings can include systemic features of Marfan syndrome (pectus excavatum or carinatum, scoliosis, arachnodactyly, osteoarthritis, joint laxity, striae, hernias), features of vascular Ehlers-Danlos syndrome (easy bruising, thin and translucent skin, atrophic scars, uterine rupture with pregnancy), and features specific to LDS including craniofacial manifestations (ocular hypertelorism, bifid uvula/cleft palate, craniosynostosis, cervical spine instability, club foot deformity, retrognathia).

TGFB3

Rienhoff syndrome or Loeys-Dietz syndrome type 5 is characterized by either thoracic aneurysms (of the aortic root or ascending aorta) or abdominal aortic aneurysms. Both type A and type B dissections are observed [Rienhoff et al 2013, Bertoli-Avella et al 2015]. Dissections with little to no enlargement of the aorta have not been reported. Aneurysms and dissections involving other arteries are rare and the arteries are not tortuous. Penetrance of the aortic disease is reduced.

Some, but not all, affected individuals can have skeletal manifestations (dolichocephaly, high-arched palate, retrognathia, tall stature or short stature, joint hypermobility, arachnodactyly, pectus deformity), evidence of connective tissue involvement (mitral valve prolapse, inguinal hernia, cervical spine instability, and club foot deformity) and/or craniofacial involvement (hypertelorism, bifid uvula, and cleft palate).

Click here (pdf) for information about the cellular pathways involved in HTAD.

Heritable Thoracic Aortic Disease by Phenotype

The following is a list of clinical features that can be observed in persons with HTAD and the related genes:

  • Marfan syndrome type skeletal features: BGN, FBN1, LOX, MFAP5, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2
  • Marfan syndrome type skeletal features, lens dislocation: FBN1
  • Loeys-Dietz syndrome with Marfan syndrome skeletal features, craniosynostosis, cleft palate/bifid uvula: TGFBR1, TGFBR2
  • Thin, translucent skin; easy bruising; atrophic scars: COL3A1, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2
  • Gastrointestinal rupture; uterine rupture during pregnancy: COL3A1, TGFBR1, TGFBR2
  • Patent ductus arteriosus (PDA): ACTA2, MYH11,TGFBR2
  • Livedo reticularis and/or iris flocculi: ACTA2
  • Congenital mydriasis, PDA, aorto-pulmonary window, Moyamoya-like cerebrovascular disease, pulmonary hypertension, gut malrotation, hypotonic bladder: ACTA2, specifically mutation of arginine at residue 179 (Arg179)

Risk for Thoracic Aortic Aneurysm and Dissection by Gene

Table 2 presents information on risk for thoracic aortic aneurysm and dissection associated with 11 of the 16 known HTAD-related genes.

Table 2.

HTAD: Risk for Aortic Disease by Gene

CharacteristicGene
ACTA2FBN1MAT2AMFAP5MYH11MYLKPRKG1TGFB2TGFBR1TGFBR2SMAD3
Patients
assessed
Numbern=277n=965 1n=18n=10n=12n=20n=37n=23n=176n=265n=44
AgeMean: 38
(SD 20)
Mean: 22 yrs 1Median: 48 yrsMean: 32 yrsMean: 59 yrs
(SD 24)
Mean: 37 yrs
(SD 16)
Mean: 42 yrs
(SD 17)
Type A
AD
Frequency71/277 (26%)15% 1None10%2/12 (17%)7/20 (35%)11/37 (30%)3/23 (13%)31/176
(18%)
39/265 (15%)11/44 (25%)
Onset ageMean: 36 yrs
(SD 12)
Median: 35 yrs 158 yrsMean: 44 yrs (SD 6)Mean: 67 yrs
(SD 18)
Mean: 34 yrs
(SD 8)
Mean: 45 yrs
(SD 13)
Mean: 34 yrs (SD 17)Mean: 46 yrs
(SD 10)
Type B
AD
Frequency28/277 (10%)4% 1NoneNone2/12 (17%)2/20 (10%)6/37 (16%)None4/176
(2%)
16/265 (6%)2/44 (4%)
Onset ageMean: 29 yrs
(SD 12)
Median: 36 yrs 1Mean: 46 yrs (SD 13)18 & 78 yrsMean: 26 yrs
(SD 13)
Mean: 38 yrs (SD 14)Mean: 46 yrs
(SD 10)
TAA
repair
Frequency16/277 (6%)2/18 (11%)NR1/12 (8%)None5/37 (14%)2/23 (9%)35/176
(20%)
63/265 (24%)15/44 (34%)
AgeMean: 33 yrs
(SD 18)
Mean: 44 yrs22 yrsMean:43 yrs
(SD 12)
35 & 60 yrsMean: 33 yrs (SD 16)Mean: 26 yrs (SD 16)Mean: 41 yrs
(SD 11)
Aortic diameter
at which type A
ADs occurred
Median: 5.75 cm
(n=24)
Mean: 7.2 cm 2 (n=158)NANR4.4 cm
(n=1)
4.0 cm (n=1)Mean: 5.0 cm (n=2)NRMean: 6.8 cm
(n=9)
Mean: 5.2 cm
(n=13)
Range:
4.0- 6.3 cm
(n=5)
Cumulative risk of AD
or risk associated w/
prophylactic repair
76% (95% CI 64, 86) at 85 yrs74% (95% CI 67, 81)
at 60 yrs 3
NRNRNRNR86%
(95% CI 70, 95) at 55 yrs
NR100%
at 80 yrs
100%
at 90 yrs 4
NR
Cumulative risk
(95% CI) of aortic
dilatation
NR96% (94, 97)
at 60 yrs 3
NRNRNRNRNRNRNRNRNR
Frequency of
pregnancy-related
AD or sudden death
(# of pregnancies)
8/53 women
(137)
4/87 women
217.

3

NoneNone0/3 (6)None2/13 women
(41)
None1/53 women
(138)
4/69 women
178.

4

None
ReferencesRegalado et al [2014]See footnotes 1-3Guo et al [2015]Barbier et al [2014]Pannu et al [2007]Wang et al [2010]Guo et al [2013];
Authors,
unpublished
Boileau et al [2012]Jondeau et al [2016]; Jondeau, personal communicationJondeau et al [2016] 4; Jondeau, personal communicationvan der Linde et al [2012]

AD = aortic dissection

TAA = thoracic aortic aneurysm

NR = not reported

NA = not applicable

CI = confidence interval

1.
2.
3.
4.

Aortic diameters were primarily based on measurements at the time of dissection. Limited data indicate an increase in the diameter of the ascending aorta after dissection but minimal distortion of the aortic root [Rylski et al 2014].

Heritable Thoracic Aortic Disease: Unknown Causes

Approximately 70% of individuals with HTAD do not have a pathogenic variant in one of the 16 known HTAD genes. Similar to members of families with HTAD of known cause, these individuals present with aortic aneurysm of the aortic root or ascending aorta and thoracic aortic dissections.

Additional observations about these families include the following:

  • Approximately 9% have intracranial aneurysm, rupture, or hemorrhage [Regalado et al 2011].
  • In a subset, bicuspid aortic valve (BAV) cosegregates with TAAD. Of note, family members can have BAV and TAAD, TAAD with a normal aortic valve, or BAV without TAAD [Loscalzo et al 2007].
  • In some, TAAD segregates with other features, such as other arterial occlusive disease and/or congenital heart defects including PDA, aortic coarctation, and atrial septal defect [Author, personal observation].

Evaluation Strategy to Identify the Genetic Cause of Heritable Thoracic Aortic Disease in a Proband

Establishing a specific genetic cause of HTAD can aid in management of the proband and relatives at risk (i.e., risk assessment and surveillance for thoracic aortic disease and recommendations for medical or surgical intervention).

Establishing the specific genetic cause of TAAD usually involves a cardiac examination, additional vascular imaging, medical history and physical examination, family history, and molecular genetic testing.

Medical history and physical examination are directed at identifying features associated with syndromic forms of TAAD (Table 1).

Family history should include a three-generation family history with attention to aortic or other cardiovascular disease including sudden cardiac death in relatives and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing, cardiovascular and physical examinations, postmortem examination, and aortic histopathology.

Molecular genetic testing. The diagnosis of HTAD is established in a proband by identification of a heterozygous pathogenic variant in one of the 16 known HTAD genes (see Table 1). Molecular genetic testing is warranted in an individual with a thoracic aneurysm or aortic dissection when features of a syndrome are present, the family history is positive, and/or aortic disease onset is at a younger than expected age.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (comprehensive genomic sequencing).

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotypes of syndromic and nonsyndromic TAAD overlap, most individuals with HTAD are diagnosed by the following recommended testing (a multigene panel) or testing to be considered (single-gene testing or comprehensive genomic sequencing).

Recommended Testing

A multigene panel that includes some or all of the 16 genes discussed in this GeneReview may be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Testing to Consider

Single-gene testing. In a proband with TAAD and ectopia lentis, sequence analysis of FBN1 followed by FBN1 targeted deletion/duplication analysis (if no pathogenic variant has been found on sequence analysis) is warranted as the vast majority of individuals with these two findings have Marfan syndrome. Note that in all other clinical situations the recommended testing and other testing to consider are typically used in lieu of single-gene testing because of the extensive overlap of the clinical features of syndromic HTAD.

Comprehensive genomic sequencing (when available) including exome sequencing and genome sequencing may be considered if the phenotype alone is insufficient to support gene-targeted testing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Genetic Risk Assessment in Family Members of a Proband

Heritable thoracic aortic disease (HTAD) is primarily inherited in an autosomal dominant manner [Milewicz & Regalado 2015]. It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Family members of an affected individual who has a known pathogenic variant in an HTAD-related gene. Molecular genetic testing is recommended for parents, sibs, offspring, and other at-risk family members in order to clarify their genetic status, allowing:

Family members of an affected individual in whom the specific genetic cause of HTAD has not been identified. Appropriate imaging studies should be offered to parents, sibs, offspring, and other at-risk family members (see Surveillance).

Management

This section provides information regarding risk assessment for thoracic aortic aneurysm and dissection, surveillance for thoracic aortic disease, and recommendations for medical and surgical management based (when possible) on the genetic cause.

Risk Assessment for Thoracic Aortic Aneurysm and Dissection

At the time of diagnosis of HTAD appropriate imaging studies should be performed to obtain measurements of the aortic diameter at standard anatomic locations [Hiratzka et al 2010] in order to assess for associated risks (see Table 2). Nomograms have been established to predict normal aortic diameter for body surface area (BSA) and gender [Devereux et al 2012, Kälsch et al 2013]. Aortic diameters that exceed the upper limit in these nomograms are considered enlarged or dilated.

  • Echocardiography is used to detect aortic root dilation. Measurements should be taken at reproducible anatomic locations: (1) aortic valve annulus, (2) mid-sinuses of Valsalva, (3) sinotubular junction, and (4) ascending aorta [Hiratzka et al 2010].
  • CT or MRI can be used to detect dilation above the aortic root if echocardiography cannot properly evaluate these locations. Measurements should be taken at the: aortic sinuses of Valsalva, sinotubular junction, mid-ascending aorta, proximal aortic arch, mid-aortic arch, proximal descending thoracic aorta (approximately 2 cm distal to the left subclavian artery), mid-descending thoracic aorta, aorta at diaphragm, and abdominal aorta at the origin of the celiac axis.

Surveillance for Thoracic Aortic Disease

Proband. After diagnosis of aortic dilatation, aortic imaging should be repeated at standard anatomic locations in six months to assess the rate of aortic growth.

  • When the aortic diameter remains stable, repeat the examination yearly.
  • When the rate of change in the aortic diameter exceeds 0.5 cm per year, more frequent imaging should be considered
  • When the diameter of the ascending aorta and/or the aortic root exceeds about 4.0 cm in an adult, repeat the examination more frequently.

Family members who have tested positive for the HTAD-gene pathogenic variant identified in an affected relative. Surveillance is the same as for thoracic aortic disease in a proband.

First-degree relatives (i.e., parents, sibs, offspring) of an affected individual in whom the specific genetic cause of HTAD has not been identified. Perform surveillance for thoracic aortic disease using the imaging modality (echocardiography vs CT or MRI) that will best detect the type of thoracic aortic disease in the proband. For example, at-risk relatives of a proband who had an aortic root aneurysm can be screened by echocardiography; in contrast, at-risk relatives of a proband who had an ascending aortic aneurysm may need to be screened by CT or MRI (if echocardiography cannot visualize the aortic root adequately).

Recommendations for Medical and Surgical Management of Thoracic Aortic Disease

Guidelines for management of thoracic aortic disease have been published [Hiratzka et al 2010].

Management of thoracic aortic aneurysm and/or dissection requires coordinated input from a multidisciplinary team of specialists familiar with HTAD, including a clinical geneticist, cardiologist, and cardiothoracic and vascular surgeons.

Proper clinical management, including early detection through thoracic aortic imaging, surveillance for enlargement of the aortic diameter or aneurysms, medical therapy, and timely prophylactic repair of an aneurysm reduces the high morbidity and mortality associated with thoracic aortic dissections.

Accumulating data indicate that identification of the specific genetic cause of hereditary thoracic aortic disease (Table 1), and in some cases the specific pathogenic variant, can inform the risk of developing a thoracic aortic aneurysm and dissection (Table 2), the optimal range of aortic diameters for prophylactic surgical repair (Table 2), and the risk for additional vascular disease and need for vascular surveillance (see Table 1).

Medical Treatment

To reduce hemodynamic stress on the ascending aorta, beta adrenergic-blocking agents (e.g., atenolol) are routinely advised for individuals with HTAD [Shores et al 1994, Hiratzka et al 2010]. Losartan was added as an alternative to beta adrenergic-blocking agents in 2014 after studies showed its efficacy in children and young adults with Marfan syndrome who were randomly assigned to losartan or atenolol [Lacro et al 2014].

Treatment guidelines for thoracic aortic disease recommend starting medical therapies once the aorta is dilated. Initiation of these therapies in individuals with a known pathogenic variant in an HTAD-related gene and no enlargement of the aorta should also be considered, particularly when mutation of that gene is associated with aortic dissection with little to no enlargement of the aorta (see Table 2).

Hypertension should be aggressively treated and controlled in individuals with HTAD, including at-risk family members even when the specific genetic cause of HTAD has not been identified.

Other cardiovascular risk factors, including smoking and hyperlipidemia, should be addressed.

Avoidance of isometric exercises and contact sports is recommended for individuals who have aortic dilatation or a pathogenic variant in an HTAD-related gene.

Prophylactic Surgical Repair of the Aorta

Although β-blockers can slow the rate of enlargement of a thoracic aortic aneurysm, the mainstay of prevention of premature deaths from dissection of a type A thoracic aortic aneurysm is surgical repair.

Surgery is typically recommended when the diameter of the aorta is approximately twice normal. This recommendation is based on the observation that at aortic diameters greater than 5.5 to 6.0 cm the risk of an adverse event (dissection, rupture, death) exceeded the risk associated with elective repair. However, other studies showed that in up to 60% of patients with an acute type A dissection the aortic diameter was less than 5.5 cm and that some had had little to no aortic enlargement [Pape et al 2007].

When the specific cause of HTAD has been identified. The current treatment guidelines for thoracic aortic disease have made gene-specific recommendations regarding the diameter at which an aorta warrants surgical repair.

Current data for gene-specific HTAD is summarized in Table 2. It is important to note that the data in Table 2 are primarily based on measurements of aortas that have dissected. Studies have indicated that, although the aortic root is minimally distorted at the time of dissection, the ascending aorta may have further enlarged as a result of the acute dissection [Rylski et al 2014]. These observations strongly suggest that better data for gene-specific surgical management are needed.

Gene-specific recommendations exist for the four following genes; data are limited on other genes.

  • ACTA2: elective surgical repair should be considered when the aortic root or ascending aorta reaches a maximum diameter of 4.5 cm. [Regalado et al 2015].
  • FBN1: The aortic root can be monitored to 5 cm unless there is a family history of dissection at smaller diameters, rapid enlargement (i.e., greater than 0.5 cm/year), or significant aortic regurgitation [Hiratzka et al 2010].
  • TGFBR1 or TGFBR2 or Loeys Dietz syndrome: surgical management is more aggressive with aortic root repair at 4.0 cm [Williams et al 2007, MacCarrick et al 2014]. More recent data indicate that such aggressive management may not be required for all patients with TGFBR1 and TGFBR2 [Tran-Fadulu et al 2009, Jondeau et al 2016].

Other considerations in the timing of prophylactic surgical repair of the aorta. Consider repair at aortic diameters <5.0 cm in the presence of any of the following [Hiratzka et al 2010]:

  • Rapid enlargement (>0.5 cm per year)
  • A family history of aortic dissections at diameters <5.0 cm
  • Significant aortic regurgitation

When the specific cause of HTAD has not been identified, surgical repair is based on the aortic diameter at the time of type an aortic dissection in affected relatives (as determined either by imaging immediately at or prior to dissection or by postmortem findings).

References

Literature Cited

  • Al-Mohaissen M, Allanson JE, O'Connor MD, Veinot JP, Brandys TM, Maharajh G, Dennie CJ, Beauchesne LM. Brachial artery occlusion in a young adult with an ACTA2 thoracic aortic aneurysm. Vasc Med. 2012;17:326–9. [PubMed: 22946110]
  • Anjum I, Eiberg H, Baig SM, Tommerup N, Hansen L. A mutation in the FOXE3 gene causes congenital primary aphakia in an autosomal recessive consanguineous Pakistani family. Mol Vis. 2010;16:549–55. [PMC free article: PMC2846847] [PubMed: 20361012]
  • Asch FM, Yuriditsky E, Prakash SK, Roman MJ, Weinsaft JW, Weissman G, Weigold WG, Morris SA, Ravekes WJ, Holmes KW, Silberbach M, Milewski RK, Kroner BL, Whitworth R, Eagle KA, Devereux RB, Weissman NJ. GenTAC Investigators. The need for standardized methods for measuring the aorta: multimodality core lab experience from the GenTAC Registry. JACC Cardiovasc Imaging. 2016;9:219–26. [PMC free article: PMC4788536] [PubMed: 26897684]
  • Attias D, Stheneur C, Roy C, Collod-Béroud G, Detaint D, Faivre L, Delrue MA, Cohen L, Francannet C, Béroud C, Claustres M, Iserin F, Khau Van Kien P, Lacombe D, Le Merrer M, Lyonnet S, Odent S, Plauchu H, Rio M, Rossi A, Sidi D, Steg PG, Ravaud P, Boileau C, Jondeau G. Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circulation. 2009;120:2541–9. [PubMed: 19996017]
  • Barbier M, Gross MS, Aubart M, Hanna N, Kessler K, Guo DC, Tosolini L, Ho-Tin-Noe B, Regalado E, Varret M, Abifadel M, Milleron O, Odent S, Dupuis-Girod S, Faivre L, Edouard T, Dulac Y, Busa T, Gouya L, Milewicz DM, Jondeau G, Boileau C. MFAP5 Loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections. Am J Hum Genet. 2014;95:736–43. [PMC free article: PMC4259978] [PubMed: 25434006]
  • Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JM, de Graaf BM, van de Beek G, Gallo E, Kruithof BP, Venselaar H, Myers LA, Laga S, Doyle AJ, Oswald G, van Cappellen GW, Yamanaka I, van der Helm RM, Beverloo B, de Klein A, Pardo L, Lammens M, Evers C, Devriendt K, Dumoulein M, Timmermans J, Bruggenwirth HT, Verheijen F, Rodrigus I, Baynam G, Kempers M, Saenen J, Van Craenenbroeck EM, Minatoya K, Matsukawa R, Tsukube T, Kubo N, Hofstra R, Goumans MJ, Bekkers JA, Roos-Hesselink JW, van de Laar IM, Dietz HC, Van Laer L, Morisaki T, Wessels MW, Loeys BL. Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J Am Coll Cardiol. 2015;65:1324–36. [PMC free article: PMC4380321] [PubMed: 25835445]
  • Biddinger A, Rocklin M, Coselli J, Milewicz DM. Familial thoracic aortic dilatations and dissections: a case control study. J Vasc Surg. 1997;25:506–11. [PubMed: 9081132]
  • Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L, Varret M, Prakash SK, Li AH, d'Indy H, Braverman AC, Grandchamp B, Kwartler CS, Gouya L, Santos-Cortez RL, Abifadel M, Leal SM, Muti C, Shendure J, Gross MS, Rieder MJ, Vahanian A, Nickerson DA, Michel JB, Jondeau G, Milewicz DM. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 2012;44:916–921. [PMC free article: PMC4033668] [PubMed: 22772371]
  • Brautbar A, LeMaire SA, Franco LM, Coselli JS, Milewicz DM, Belmont JW. FBN1 mutations in patients with descending thoracic aortic dissections. Am J Med Genet A. 2010;152A:413–6. [PMC free article: PMC3593235] [PubMed: 20082464]
  • Brodsky MC, Turan KE, Khanna CL, Patton A, Kirmani S. Congenital mydriasis and prune belly syndrome in a child with an ACTA2 mutation. J AAPOS. 2014;18:393–5. [PubMed: 24998021]
  • Détaint D, Faivre L, Collod-Beroud G, Child AH, Loeys BL, Binquet C, Gautier E, Arbustini E, Mayer K, Arslan-Kirchner M, Stheneur C, Halliday D, Beroud C, Bonithon-Kopp C, Claustres M, Plauchu H, Robinson PN, Kiotsekoglou A, De Backer J, Adès L, Francke U, De Paepe A, Boileau C, Jondeau G. Cardiovascular manifestations in men and women carrying a FBN1 mutation. Eur Heart J. 2010;31:2223–9. [PubMed: 20709720]
  • Devereux RB, de Simone G, Arnett DK, Best LG, Boerwinkle E, Howard BV, Kitzman D, Lee ET, Mosley TH Jr, Weder A, Roman MJ. Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons ≥15 years of age. Am J Cardiol. 2012;110:1189–94. [PMC free article: PMC3462295] [PubMed: 22770936]
  • Disabella E, Grasso M, Gambarin FI, Narula N, Dore R, Favalli V, Serio A, Antoniazzi E, Mosconi M, Pasotti M, Odero A, Arbustini E. Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2). Heart. 2011;97:321–326. [PubMed: 21212136]
  • Doucette L, Green J, Fernandez B, Johnson GJ, Parfrey P, Young TL. A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly. Eur J Hum Genet. 2011;19:293–9. [PMC free article: PMC3062009] [PubMed: 21150893]
  • Evangelista A, Flachskampf FA, Erbel R, Antonini-Canterin F, Vlachopoulos C, Rocchi G, Sicari R, Nihoyannopoulos P, Zamorano J., European Association of Echocardiography. Document Reviewers:, Pepi M, Breithardt OA, Plonska-Gosciniak E. Echocardiography in aortic diseases: EAE recommendations for clinical practice. Eur J Echocardiogr. 2010;11:645–58. [PubMed: 20823280]
  • Francke U, Berg MA, Tynan K, Brenn T, Liu W, Aoyama T, Gasner C, Miller DC, Furthmayr H. A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection. Am J Hum Genet. 1995;56:1287–96. [PMC free article: PMC1801106] [PubMed: 7762551]
  • Glancy DL, Wegmann M, Dhurandhar RW. Aortic dissection and patent ductus arteriosus in three generations. Am J Cardiol. 2001;87:813–5. [PubMed: 11249915]
  • Gott VL, Greene PS, Alejo DE, Cameron DE, Naftel DC, Miller DC, Gillinov AM, Laschinger JC, Pyeritz RE. Replacement of the aortic root in patients with Marfan's syndrome. N Engl J Med. 1999;340:1307–13. [PubMed: 10219065]
  • Guo DC, Regalado ES, Gong L, Duan X, Santos-Cortez RL, Arnaud P, Ren Z, Cai B, Hostetler EM, Moran R, Liang D, Estrera A, Safi HJ. University of Washington Center for Mendelian Genomics, Leal SM, Bamshad MJ, Shendure J, Nickerson DA, Jondeau G, Boileau C, Milewicz DM. LOX mutations predispose to thoracic aortic aneurysms and dissections. Circ Res. 2016;118:928–34. [PMC free article: PMC4839295] [PubMed: 26838787]
  • Guo D, Hasham S, Kuang SQ, Vaughan CJ, Boerwinkle E, Chen H, Abuelo D, Dietz HC, Basson CT, Shete SS, Milewicz DM. Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14. Circulation. 2001;103:2461–8. [PubMed: 11369686]
  • Guo DC, Gong L, Regalado ES, Santos-Cortez RL, Zhao R, Cai B, Veeraraghavan S, Prakash SK, Johnson RJ, Muilenburg A, Willing M, Jondeau G, Boileau C, Pannu H, Moran R, DeBacker J, Bamshad MJ, Shendure J, Nickerson DA, Leal SM, Raman CS, Swindell EC, Milewicz DM. MAT2A mutations predispose individuals to thoracic aortic aneurysms. Am J Hum Genet. 2015;96:170–7. [PMC free article: PMC4289682] [PubMed: 25557781]
  • Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, Bourgeois S, Estrera AL, Safi HJ, Sparks E, Amor D, Ades L, McConnell V, Willoughby CE, Abuelo D, Willing M, Lewis RA, Kim DH, Scherer S, Tung PP, Ahn C, Buja LM, Raman CS, Shete SS, Milewicz DM. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007;39:1488–93. [PubMed: 17994018]
  • Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N, Johnson RJ, Kim DH, Pannu H, Willing MC, Sparks E, Pyeritz RE, Singh MN, Dalman RL, Grotta JC, Marian AJ, Boerwinkle EA, Frazier LQ, LeMaire SA, Coselli JS, Estrera AL, Safi HJ, Veeraraghavan S, Muzny DM, Wheeler DA, Willerson JT, Yu RK, Shete SS, Scherer SE, Raman CS, Buja LM, Milewicz DM. Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009;84:617–27. [PMC free article: PMC2680995] [PubMed: 19409525]
  • Guo DC, Regalado E, Casteel DE, Santos-Cortez RL, Gong L, Kim JJ, Dyack S, Horne SG, Chang G, Jondeau G, Boileau C, Coselli JS, Li Z, Leal SM, Shendure J, Rieder MJ, Bamshad MJ, Nickerson DA, Kim C, Milewicz DM, et al. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet. 2013;93:398–404. [PMC free article: PMC3738837] [PubMed: 23910461]
  • Hagan PG, Nienaber CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL, Evangelista A, Fattori R, Suzuki T, Oh JK, Moore AG, Malouf JF, Pape LA, Gaca C, Sechtem U, Lenferink S, Deutsch HJ, Diedrichs H, Marcos y Robles J, Llovet A, Gilon D, Das SK, Armstrong WF, Deeb GM, Eagle KA. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000;283:897–903. [PubMed: 10685714]
  • Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM, 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:e266–369. [PubMed: 20233780]
  • Hoffjan S, Waldmuller S, Blankenfeldt W, Kotting J, Gehle P, Binner P, Epplen JT, Scheffold T. Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. Eur J Hum Genet. 2011;19:520–4. [PMC free article: PMC3083620] [PubMed: 21248741]
  • Jondeau G, Ropers J, Regalado E, Braverman A, Evangelista A, Teixedo G, De Backer J, Muiño-Mosquera L, Naudion S, Zordan C, Morisaki T, Morisaki H, Von Kodolitsch Y, Dupuis-Girod S, Morris SA, Jeremy R, Odent S, Adès LC, Bakshi M, Holman K, LeMaire S, Milleron O, Langeois M, Spentchian M, Aubart M, Boileau C, Pyeritz R, Milewicz DM. International registry of patients carrying TGFBR1 or TGFBR2 mutations: results of the Montalcino Aortic Consortium. Circ Cardiovasc Genet. 2016;9:548–58. [PMC free article: PMC5177493] [PubMed: 27879313]
  • Kälsch H, Lehmann N, Mohlenkamp S, Becker A, Moebus S, Schmermund A, Stang A, Mahabadi AA, Mann K, Jockel KH, Erbel R, Eggebrecht H. Body-surface adjusted aortic reference diameters for improved identification of patients with thoracic aortic aneurysms: results from the population-based Heinz Nixdorf Recall study. Int J Cardiol. 2013;163:72–78. [PubMed: 21641667]
  • Khan SY, Vasanth S, Kabir F, Gottsch JD, Khan AO, Chaerkady R, Lee MC, Leitch CC, Ma Z, Laux J, Villasmil R, Khan SN, Riazuddin S, Akram J, Cole RN, Talbot CC, Pourmand N, Zaghloul NA, Hejtmancik JF, Riazuddin SA. FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nat Commun. 2016;7:10953. [PMC free article: PMC4820811] [PubMed: 27218149]
  • Khau Van Kien P, Mathieu F, Zhu L, Lalande A, Betard C, Lathrop M, Brunotte F, Wolf JE, Jeunemaitre X. Mapping of familial thoracic aortic aneurysm/dissection with patent ductus arteriosus to 16p12.2-p13.13. Circulation. 2005;112:200–6. [PubMed: 15998682]
  • Khau Van Kien P, Wolf JE, Mathieu F, Zhu L, Salve N, Lalande A, Bonnet C, Lesca G, Plauchu H, Dellinger A, Nivelon-Chevallier A, Brunotte F, Jeunemaitre X. Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity. Eur J Hum Genet. 2004;12:173–80. [PubMed: 14722581]
  • Kuang SQ, Medina-Martinez O, Guo DC, Gong L, Regalado ES, Reynolds CL, Boileau C, Jondeau G, Prakash SK, Kwartler CS, Zhu LY, Peters AM, Duan XY, Bamshad MJ, Shendure J, Nickerson DA, Santos-Cortez RL, Dong X, Leal SM, Majesky MW, Swindell EC, Jamrich M, Milewicz DM. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J Clin Invest. 2016;126:948–61. [PMC free article: PMC4767350] [PubMed: 26854927]
  • Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, Pearson GD, Selamet Tierney ES, Levine JC, Atz AM, Benson DW, Braverman AC, Chen S, De Backer J, Gelb BD, Grossfeld PD, Klein GL, Lai WW, Liou A, Loeys BL, Markham LW, Olson AK, Paridon SM, Pemberton VL, Pierpont ME, Pyeritz RE, Radojewski E, Roman MJ, Sharkey AM, Stylianou MP, Wechsler SB, Young LT, Mahony L., Pediatric Heart Network Investigators. Atenolol versus losartan in children and young adults with Marfan's syndrome. N Engl J Med. 2014;371:2061–71. [PMC free article: PMC4386623] [PubMed: 25405392]
  • Lee VS, Halabi CM, Hoffman EP, Carmichael N, Leshchiner I, Lian CG, Bierhals AJ, Vuzman D. Brigham Genomic Medicine, Mecham RP, Frank NY, Stitziel NO. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci U S A. 2016;113:8759–64. [PMC free article: PMC4978273] [PubMed: 27432961]
  • Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, Kempers MJ, Fishman EK, Chen Y, Myers L, Bjeda D, Oswald G, Elias AF, Levy HP, Anderlid BM, Yang MH, Bongers EM, Timmermans J, Braverman AC, Canham N, Mortier GR, Brunner HG, Byers PH, Van Eyk J, Van Laer L, Dietz HC, Loeys BL. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012;44:922–7. [PMC free article: PMC3616632] [PubMed: 22772368]
  • Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37:275–81. [PubMed: 15731757]
  • Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788–98. [PubMed: 16928994]
  • Loscalzo ML, Goh DL, Loeys B, Kent KC, Spevak PJ, Dietz HC. Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance. Am J Med Genet A. 2007;143A:1960–7. [PubMed: 17676603]
  • MacCarrick G, Black JH 3rd, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA, Guerrerio AL, Sponseller PD, Loeys B, Dietz HC 3rd. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16:576–87. [PMC free article: PMC4131122] [PubMed: 24577266]
  • Matyas G, Naef P, Tollens M, Oexle K. De novo mutation of the latency-associated peptide domain of TGFB3 in a patient with overgrowth and Loeys-Dietz syndrome features. Am J Med Genet A. 2014;164A:2141–3. [PubMed: 24798638]
  • Milewicz DM, Michael K, Fisher N, Coselli JS, Markello T, Biddinger A. Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. Circulation. 1996;94:2708–11. [PubMed: 8941093]
  • Milewicz DM, Østergaard JR, Ala-Kokko LM, Khan N, Grange DK, Mendoza-Londono R, Bradley TJ, Olney AH, Adès L, Maher JF, Guo D, Buja LM, Kim D, Hyland JC, Regalado ES. De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet A. 2010;152A:2437–43. [PMC free article: PMC3573757] [PubMed: 20734336]
  • Milewicz DM, Regalado ES. Use of genetics for personalized management of heritable thoracic aortic disease: how do we get there? J Thorac Cardiovasc Surg. 2015;149:S3–5. [PMC free article: PMC4354949] [PubMed: 25218541]
  • Mody PS, Wang Y, Geirsson A, Kim N, Desai MM, Gupta A, Dodson JA, Krumholz HM. Trends in aortic dissection hospitalizations, interventions, and outcomes among medicare beneficiaries in the United States, 2000-2011. Circ Cardiovasc Qual Outcomes. 2014;7:920–8. [PMC free article: PMC4380171] [PubMed: 25336626]
  • Moller HU, Fledelius HC, Milewicz DM, Regalado ES, Ostergaard JR. Eye features in three Danish patients with multisystemic smooth muscle dysfunction syndrome. Br J Ophthalmol. 2012;96:1227–31. [PMC free article: PMC4358743] [PubMed: 22790431]
  • Morisaki H, Akutsu K, Ogino H, Kondo N, Yamanaka I, Tsutsumi Y, Yoshimuta T, Okajima T, Matsuda H, Minatoya K, Sasaki H, Tanaka H, Ishibashi-Ueda H, Morisaki T. Mutation of ACTA2 gene as an important cause of familial and nonfamilial nonsyndromatic thoracic aortic aneurysm and/or dissection (TAAD). Hum Mutat. 2009;30:1406–11. [PubMed: 19639654]
  • Morris SA, Orbach DB, Geva T, Singh MN, Gauvreau K, Lacro RV. Increased vertebral artery tortuosity index is associated with adverse outcomes in children and young adults with connective tissue disorders. Circulation. 2011;124:388–96. [PubMed: 21730308]
  • Munot P, Saunders DE, Milewicz DM, Regalado ES, Ostergaard JR, Braun KP, Kerr T, Lichtenbelt KD, Philip S, Rittey C, Jacques TS, Cox TC, Ganesan V. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain. 2012;135:2506–14. [PMC free article: PMC3407424] [PubMed: 22831780]
  • Nicod P, Bloor C, Godfrey M, Hollister D, Pyeritz RE, Dittrich H, Polikar R, Peterson KL. Familial aortic dissecting aneurysm. J.Am.Coll.Cardiol. 1989;13:811–19. [PubMed: 2647812]
  • Pannu H, Fadulu VT, Chang J, Lafont A, Hasham SN, Sparks E, Giampietro PF, Zaleski C, Estrera AL, Safi HJ, Shete S, Willing MC, Raman CS, Milewicz DM. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation. 2005;112:513–20. [PubMed: 16027248]
  • Pannu H, Tran-Fadulu V, Papke CL, Scherer S, Liu Y, Presley C, Guo D, Estrera AL, Safi HJ, Brasier AR, Vick GW, Marian AJ, Raman CS, Buja LM, Milewicz DM. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet. 2007;16:2453–62. [PMC free article: PMC2905218] [PubMed: 17666408]
  • Pape LA, Tsai TT, Isselbacher EM, Oh JK, O'gara PT, Evangelista A, Fattori R, Meinhardt G, Trimarchi S, Bossone E, Suzuki T, Cooper JV, Froehlich JB, Nienaber CA, Eagle KA, et al. Aortic diameter >or = 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation. 2007;116:1120–7. [PubMed: 17709637]
  • Regalado ES, Guo DC, Estrera AL, Buja LM, Milewicz DM. Acute aortic dissections with pregnancy in women with ACTA2 mutations. Am J Med Genet A. 2014;164A:106–12. [PMC free article: PMC4012224] [PubMed: 24243736]
  • Regalado ES, Guo DC, Prakash S, Bensend TA, Flynn K, Estrera A, Safi H, Liang D, Hyland J, Child A, Arno G, Boileau C, Jondeau G, Braverman A, Moran R, Morisaki T, Morisaki H, Pyeritz R, Coselli J, LeMaire S, Milewicz DM, et al. Aortic disease presentation and outcome associated with ACTA2 mutations. Circ Cardiovasc Genet. 2015;8:457–64. [PMC free article: PMC4601641] [PubMed: 25759435]
  • Regalado ES, Guo DC, Santos-Cortez RL, Hostetler E, Bensend TA, Pannu H, Estrera A, Safi H, Mitchell AL, Evans JP, Leal SM, Bamshad M, Shendure J, Nickerson DA, Milewicz DM, et al. Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections. Clin Genet. 2016;89:719–23. [PMC free article: PMC4873375] [PubMed: 26621581]
  • Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, Clarke L, Bernier F, Santos-Cortez RL, Leal SM, Bertoli-Avella AM, Shendure J, Rieder MJ, Nickerson DA, Milewicz DM, et al. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res. 2011;109:680–6. [PMC free article: PMC4115811] [PubMed: 21778426]
  • Renard M, Callewaert B, Baetens M, Campens L, MacDermot K, Fryns JP, Bonduelle M, Dietz HC, Gaspar IM, Cavaco D, Stattin EL, Schrander-Stumpel C, Coucke P, Loeys B, De PA, De BJ. Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFbeta signaling in FTAAD. Int J Cardiol. 2013;165:314–21. [PMC free article: PMC3253210] [PubMed: 21937134]
  • Richer J, Milewicz DM, Gow R, de Nanassy J, Maharajh G, Miller E, Oppenheimer L, Weiler G, O'Connor M. R179H mutation in ACTA2 expanding the phenotype to include prune-belly sequence and skin manifestations. Am J Med Genet A. 2012;158A:664–8. [PubMed: 22302747]
  • Rienhoff HY Jr, Yeo CY, Morissette R, Khrebtukova I, Melnick J, Luo S, Leng N, Kim YJ, Schroth G, Westwick J, Vogel H, McDonnell N, Hall JG, Whitman M. A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome. Am J Med Genet A. 2013;161A:2040–6. [PMC free article: PMC3885154] [PubMed: 23824657]
  • Rodríguez-Palomares JF, Teixidó-Tura G, Galuppo V, Cuéllar H, Laynez A, Gutiérrez L, González-Alujas MT, García-Dorado D, Evangelista A. Multimodality Assessment of Ascending Aortic Diameters: Comparison of Different Measurement Methods. J Am Soc Echocardiogr. 2016;29:819–826.e4. [PubMed: 27288090]
  • Rylski B, Blanke P, Beyersdorf F, Desai ND, Milewski RK, Siepe M, Kari FA, Czerny M, Carrel T, Schlensak C, Krüger T, Mack MJ, Brinkman WT, Mohr FW, Etz CD, Luehr M, Bavaria JE. How does the ascending aorta geometry change when it dissects? J Am Coll Cardiol. 2014;63:1311–9. [PubMed: 24509277]
  • Semina EV, Brownell I, Mintz-Hittner HA, Murray JC, Jamrich M. Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum Mol Genet. 2001;10:231–6. [PubMed: 11159941]
  • Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta- adrenergic blockade in Marfan's syndrome. N Engl J Med. 1994;330:1335–41. [PubMed: 8152445]
  • Stheneur C, Collod-Béroud G, Faivre L, Buyck JF, Gouya L, Le Parc JM, Moura B, Muti C, Grandchamp B, Sultan G, Claustres M, Aegerter P, Chevallier B, Jondeau G, Boileau C. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009;17:1121–8. [PMC free article: PMC2986588] [PubMed: 19293843]
  • Tran-Fadulu V, Chen JH, Lemuth D, Neichoy BT, Yuan J, Gomes N, Sparks E, Kramer LA, Guo D, Pannu H, Braverman AC, Shete S, Milewicz DM. Familial thoracic aortic aneurysms and dissections: three families with early-onset ascending and descending aortic dissections in women. Am J Med Genet A. 2006;140:1196–202. [PubMed: 16646045]
  • Tran-Fadulu V, Pannu H, Kim DH, Vick GW 3rd, Lonsford CM, Lafont AL, Boccalandro C, Smart S, Peterson KL, Hain JZ, Willing MC, Coselli JS, LeMaire SA, Ahn C, Byers PH, Milewicz DM. Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J Med Genet. 2009;46:607–13. [PubMed: 19542084]
  • Valleix S, Niel F, Nedelec B, Algros MP, Schwartz C, Delbosc B, Delpech M, Kantelip B. Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans. Am J Hum Genet. 2006;79:358–64. [PMC free article: PMC1559477] [PubMed: 16826526]
  • van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, Hoedemaekers YM, Willemsen R, Severijnen LA, Venselaar H, Vriend G, Pattynama PM, Collée M, Majoor-Krakauer D, Poldermans D, Frohn-Mulder IM, Micha D, Timmermans J, Hilhorst-Hofstee Y, Bierma-Zeinstra SM, Willems PJ, Kros JM, Oei EH, Oostra BA, Wessels MW, Bertoli-Avella AM. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011;43:121–6. [PubMed: 21217753]
  • van der Linde D, van de Laar IM, Bertoli-Avella AM, Oldenburg RA, Bekkers JA, Mattace-Raso FU, van den Meiracker AH, Moelker A, van Kooten F, Frohn-Mulder IM, Timmermans J, Moltzer E, Cobben JM, van Laer L, Loeys B, De Backer J, Coucke PJ, De Paepe A, Hilhorst-Hofstee Y, Wessels MW, Roos-Hesselink JW. Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants. J Am Coll Cardiol. 2012;60:397–403. [PubMed: 22633655]
  • Vaughan CJ, Casey M, He J, Veugelers M, Henderson K, Guo D, Campagna R, Roman MJ, Milewicz DM, Devereux RB, Basson CT. Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder. Circulation. 2001;103:2469–75. [PubMed: 11369687]
  • Villamizar C, Regalado ES, Fadulu VT, Hasham SN, Gupta P, Willing MC, Kuang SQ, Guo D, Muilenburg A, Yee RW, Fan Y, Towbin J, Coselli JS, LeMaire SA, Milewicz DM. Paucity of skeletal manifestations in hispanic families with FBN1 mutations. Eur J Med Genet. 2010;53:80–4. [PMC free article: PMC4354948] [PubMed: 19941982]
  • Wang L, Guo DC, Cao J, Gong L, Kamm KE, Regalado E, Li L, Shete S, He WQ, Zhu MS, Offermanns S, Gilchrist D, Elefteriades J, Stull JT, Milewicz DM. Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet. 2010;87:701–7. [PMC free article: PMC2978973] [PubMed: 21055718]
  • Williams JA, Loeys BL, Nwakanma LU, Dietz HC, Spevak PJ, Patel ND, François K, DeBacker J, Gott VL, Vricella LA, Cameron DE. Early surgical experience with Loeys-Dietz: a new syndrome of aggressive thoracic aortic aneurysm disease. Ann Thorac Surg. 2007;83:S757–63. [PubMed: 17257922]
  • Zhu L, Vranckx R, Van Kien PK, Lalande A, Boisset N, Mathieu F, Wegman M, Glancy L, Gasc JM, Brunotte F, Bruneval P, Wolf JE, Michel JB, Jeunemaitre X. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006;38:343–9. [PubMed: 16444274]

Chapter Notes

Author History

Dianna M Milewicz, MD, PhD (2003-present)
Ellen Regalado, MS, CGC (2011-present)
Van Tran-Fadulu, MS, CGC; University of Texas Medical School (2003-2011)

Revision History

  • 14 December (aa) Revision: three genes added (BGN, FOXE3, LOX)
  • 29 December 2016 (dm) Revision: MYH11 added to Table 2
  • 1 December 2016 (bp) Comprehensive update posted live; scope changed to overview
  • 12 January 2012 (cd) Revision: MYLK and SMAD3 mutations found to cause TAAD (testing available); multi-gene testing panels now listed in GeneTests™ Laboratory Directory
  • 11 January 2011 (me) Comprehensive update posted live
  • 13 January 2009 (cd) Revision: clinical testing available for mutations in ACTA2 and MYH1
  • 6 January 2009 (cd) Revision: ACTA2 mutations responsible for 14% of inherited TAAD; TGFBR1 mutations also responsible for some cases of inherited TAAD
  • 10 May 2006 (me) Comprehensive update posted live
  • 28 April 2005 (me) Comprehensive update posted live
  • 13 February 2003 (me) Review posted live
  • 11 July 2002 (dm) Original submission
Copyright © 1993-2018, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2018 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1120PMID: 20301299

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Related information

  • MedGen
    Related information in MedGen
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...