Int J Adolesc Med Health 2014; 26(4): 469–488

Review Sze Choong Wong*, Michael Cheung and Margaret Zacharin

Aortic dilatation and dissection in Turner syndrome: What we know, what we are unclear about and what we should do in clinical practice? Abstract: Aortic dilatation and aortic dissection are increasingly recognised in patients with Turner syndrome (TS). Risk factors for aortic dissection include aortic dilatation, bicuspid aortic valves, coarctation of aorta and pregnancy. The risk of death due to aortic dissection in pregnancy in TS is 2%, which is approximately 100 times higher than the general population, as maternal mortality is extremely low. Ongoing cardiovascular monitoring is recommended, although there remain several unanswered questions in relation to cardiovascular imaging especially the choice of modality for detection of vascular, valvular abnormalities and measurements of aortic dimensions. Due to the relative short stature of patients with TS, aortic dimensions need to be defined by aortic measurements adjusted for body surface area, known as aortic sized index (ASI). The relationship of ASI and other risk factors with aortic dissection is only beginning to be clarified. Clinical management and monitoring of such patients should be delivered by a group of clinicians familiar with the issues unique to TS patients in a multidisciplinary fashion. All clinicians including the non-specialists need to have a low threshold of suspecting aortic dissection in these adolescents and young adults. This up to date review, including a summary of all 122 published cases of TS patients with aortic dissection,

*Corresponding author: Sze Choong Wong, Centre for Hormone Research, Murdoch Childrens Research Institute, Flemington Road, Parkville, Melbourne, VIC 3052, Australia, Phone: +613 93455951, E-mail: [email protected] Sze Choong Wong: Department of Endocrinology, The Royal Children’s Hospital, Melbourne, VIC, Australia Michael Cheung: Department of Cardiology, The Royal Children’s Hospital, Melbourne, VIC, Australia; Heart Research Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia; and Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia Margaret Zacharin: Department of Endocrinology, The Royal Children’s Hospital, Melbourne, VIC, Australia; Centre for Hormone Research, Murdoch Childrens Research Institute, Melbourne, VIC, Australia; and Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia

aims to provide a summary of recent publications on characteristics of aortic dissection and aortic dilatation in TS to highlight gaps in knowledge and propose possible clinical monitoring pathway of cardiovascular health in children and adults with TS. Cardiovascular assessment and risk counselling is especially crucial during the period of transition of adolescents with TS, although life long monitoring by expert cognizant to the issues specific in TS is essential. Keywords: aortic dilatation; aortic dissection; bicuspid aortic valve; cardiovascular; coarctation of aorta; congenital heart disease; echocardiogram; magnetic resonance imaging; mortality; pregnancy; screening; transition; Turner syndrome. DOI 10.1515/ijamh-2013-0336 Received November 3, 2013; accepted April 17, 2014; previously published online May 31, 2014

Introduction Turner syndrome (TS), a condition due to loss of or abnormality of the second X chromosome in at least one cell line in a phenotypic female, occurs in approximately 1 in every 2000 live female births (1). Whilst short stature and gonadal dysgenesis are common clinical features, a range of health problems exists in TS. It is increasingly recognised that TS is associated with a higher risk of aortic dilatation and aortic dissection, which can be fatal, if not recognised early (2). This review provides a summary of recent publications on characteristics of aortic dissection and aortic dilatation in TS to highlight gaps in knowledge and propose a possible clinical monitoring pathway of cardiovascular health. It also aims to raise awareness of the risk of aortic dissection in these groups of adolescents and young adults amongst clinicians of all background (paediatric and adult endocrinologists, paediatric and adult cardiologists, general paediatricians and adolescent physicians, adult physicians, emergency specialists and general practitioners).

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470      Wong et al.: Aortic dilatation and dissection in Turner syndrome The full Pubmed database was searched with no time restriction in August 2013 using the key words “Turner syndrome” as MeSH term, as well as “Turner syndrome”, “Turner’s syndrome”, “aortic dilatation”, “aortic dissection”. Relevant articles were obtained and reviewed. Publications included in this review were selected by the authors at their discretion.

Congenital heart desease in TS Congenital heart disease is a common feature of TS (3–5). Cytogenetic screening studies indicate that TS occurs in about 1 in 200 conceptions but approximately 90% do not survive delivery (1). Most die in the antenatal period due to left ventricular outflow tract pathology. For the 10% who survive, congenital cardiac abnormalities are described in approximately 30%–50% (6–9). Bicuspid aortic valve (BAV) is the commonest abnormality, reported in about 20%–30% (10–12) of these patients. A recent study also showed that other aortic valve abnormalities like partially fused aortic valves and unicuspid aortic valves are also seen and can be associated with aortic dilatation (13). Coarctation of the aorta (CoA) is present in about 4%–12% (7, 14), often presenting with neonatal collapse in the first week of life, or diagnosed later on in childhood due to hypertension or limb claudication. Other common anatomic anomalies include partial anomalous pulmonary venous drainage (9, 15), persistent left superior vena cava and elongation of the transverse arch (7). Elongation of the transverse arch (ETA), also known as pseudocoarctation, is often identified only using cardiac MRI, reported to be as high as 4% (7, 14). This is associated with kinking and elongation of the aorta at the isthmus and is not thought to be associated with haemodynamically significant obstruction, although such abnormalities have been seen in five published cases of aortic dissection in TS. The clinical significance of ETA as a risk factor for aortic dissection in TS is still unknown. Congenital heart disease is more common in individuals with webbed necks and those with monosomy X. Studies have confirmed the association of cystic hygroma, neck webbing, BAV and CoA in TS girls with 45XO karyotype. Previously, a mechanical theory of lymphatic compression on the aorta was postulated as aetiology for the cardiovascular abnormality in TS (8, 11). Haplo­insufficiency for a pseudoautosomal X chromosome gene FOXC2, involved in vascular morphogenesis has recently been reported to cause foetal lymphoedema and cardiovascular anomalies independently (16). A high prevalence of BAV and CoA have recently been linked to TS patients missing only the short arm of chromosome X, indicating that haploinsufficiency

for Xp genes contributes to abnormal aortic arch and valve pathology (17). Preliminary data shows that XIAP (X-linked inhibitor of apoptosis protein), located on the X chromosome is an important regulator of aortic endothelial cell survival in a bovine model, via enhanced nitric oxide production (18). The role of XIAP on cardiovascular abnormalities in TS needs further exploration.

Aortic dissection in TS Characteristics The estimated incidence of aortic dissection in TS is 36/100,000 patients per year from a Danish registry study, six times more common than seen in the healthy female population (19). To date, as far as we are aware, 122 cases of aortic dissection in TS have been reported (19–84) with a median age of dissection in TS in the third decade compared with the seventh decade in the general population (Tables 1–5). Of 122 published cases, 61 (50%) had no details of karyotype reported but 43 of 61 (70.5%) with karyotype reported were 45XO. Most reported aortic dissection in TS present with typical acute chest and gastrointestinal symptoms but also with change in phonation due to compression on recurrent laryngeal nerves for  > 24 hour. Eighty-seven of these cases have been comprehensively reviewed in a previous report in 2007 (68) and 20 were included in a recent case series identified from the International Turner Syndrome Aortic Dissection Registry (67). The majority of dissections in TS occur in the ascending aorta (2, 68). In our review of 122 published cases, 66 (54%) experienced dissection in the ascending aorta, 20 (16.4%) in descending aorta, 10 (8.2%) in ascending and descending aorta and the remainder at other sites (e.g., common carotid, abdominal in combination with either ascending or descending aorta) or sites not reported. In adults, it was previously thought 10% of TS with reported aortic dissection had no evidence of cardiovascular risk factors (including cardiovascular anomalies and hypertension) (68) which may be partly due to previous poor cardiovascular surveillance of adults with TS. In our review of the 122 cases published, 25 (20.5%) had no reported morphological cardiovascular abnormalities; two of whom were associated with pregnancy and two were   18 years (alive and no outcome details). Patient   Age  Karyotype no 45XO 45XO 45XO ND 45XO ND

  Outcome   BAV  CoA   Other CVS anomalies   Aortic dimensions

  Location of   Reference dissection

           

– – – – – Root 4.3 cm, root ASI 2.5   –   –   –

           

  Asc 4.8 cm, Asc ASI 3.1

  Proximal   Oza et al. (73) and distal

       

       

33  34  35  36  37  38 

19  19  19  19  20  21 

39  40  41 

23  ND 23  ND 25  ND

  Alive   Alive   Alive

  –   +   +

  +   –   –

42 

26  45XO

  Alive

  –

  +

43  44  45  46 

27  27  28  28 

       

       

       

47 

29  45XO

  Alive

  –

  –

 

48  49  50  51  52 

30  30  30  35  35 

ND ND 45XO 45XO/46XY ND

         

Alive Alive Alive Alive Alive

         

– – + – –

         

– – – – +

         

53  54  55  56 

36  36  36  37 

       

Alive Alive Alive Alive

       

+ + – +

       

– – + –

       

57  58  59  60 

45XO 45XO ND 45XO/46X+ mar 4 38  45XO 41  42  45XO 43  ND

       

Alive Alive Alive Alive

       

– + – +

       

– – – –

       

61 

44  ND

  Alive

  +

  –

– – – AI, single left carotid artery   –

62  63  64 

45  ND 45  ND 45  45XO

  Alive   Alive   Alive

  –   –   +

  +   +   –

  AS   –   PPAVR

65 

47  ND

  Alive

  +

  –

  ETA

66  67 

48  45XO 48  ND

  Alive   Alive

  +   –

  +   –

  AS, AI   AI

68  69  71 

48  ND   Alive 51  45XO/46X, r(x)  Alive 54  ND   Alive

  +   –   –

  –   –   –

  AS   –   PseudoCoA

  Asc 4.8 cm, Asc ASI 2.9   –   –   Asc 4.2 cm, Asc ASI 2.53   Asc 4.63 cm, Asc ASI 2.85   –   Asc 4.2 cm, Asc ASI 2.53   –   –   –

72 

64  45XO/46XY

  –

  –

  –

  –

ND ND 45XO ND

Alive Alive Alive Alive Alive Alive

Alive Alive Alive Alive

  Alive

           

+ + + + + +

– – – +

           

+ – + + + –

– – – –

           

AS, AI – AS, AI AS, AI AS –

  –   AI, MR   AI, single coronary artery   Incomplete, AV canal, AI, descending aortic aneurysm   –   AI   AS, AI   –

           

– – – Root 4.5 cm, root ASI 3.0; Asc 5.0 cm, Asc ASI 3.3 Mildly thickened aortic   Root 2.2 cm, root valve, mild mitral valve Z score –0.5 thickening –   – AI, PPAVR   – –   – –   – –   Root 1.8 cm, root ASI 1.1 AS   – –   – –   – –   –        

– – – –

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Proximal Proximal Proximal Proximal Proximal Proximal

  Distal   Proximal   Proximal

Distal Proximal Proximal Proximal

           

Imamura et al. (45) Gravholt et al. (18) Lin et al. (32) Youker et al. (58) Gravholt et al. (18) Carlson et al. (67)

  Kusaba et al. (30)   Vesin et al. (82)   Oohara et al. (53)

       

Bartlema et al. (40) Cecchi et al. (59) Goldberg et al. (47) Carlson et al. (67)

  Proximal

  Carlson et al. (68)

         

Proximal Proximal Proximal Distal Distal

         

Hirose et al. (23) Shiroma et al. (49) Subramaniam et al. (60) Gravholt et al. (18) Carlson et al. (68)

       

Proximal Proximal Distal Proximal

       

Apostopoulos et al. (50) Gravholt et al. (18) Di Eusanio et al. (77) Gravholt et al. (18)

       

Proximal   Proximal   Distal   Proximal &   distal   Proximal  

Meunier et al. (27) Carlson et al. (68) Akimoto et al. (55) Pollak et al. (63) Carlson et al. (69)

  Site of CoA   Martin et al. (83)   Distal   Badmanaban et al. (39)   Proximal   Kin et al. (74)   ND   Proximal   Proximal

  Matura et al. (69) and Bondy et al. (2)   Gopal et al. (20)   Maureira et al. (75)

  Proximal     Proximal     Proximal &   distal   Proximal &   distal

Carlson et al. (67) Gravholt et al. (18) Jeresaty et al. (65) Salgado et al. (56)

474      Wong et al.: Aortic dilatation and dissection in Turner syndrome (Table 4 Continued) Patient   Age  Karyotype no 73  64  45XO 74  ND   ND 75  ND   ND 76  27  ND 77  34  ND 78  46  45XO, 46X pseu idic (Y)

  Outcome   BAV  CoA   Other CVS anomalies   Aortic dimensions

  Location of   Reference dissection

           

           

Alive Alive Alive ND ND ND

           

– – – – – +

           

+ – – + – –

           

– – – – – AI, AS

           

– – ASI 2.6 AI – Asc 3.5 cm, Asc ASI 2.1

Distal Distal ND ND ND ND

           

Miller et al. (66) Clement et al. (28) Bondy et al. (2) Ohuchi et al. (46) Chlumsky et al. (26) Jagannam et al. (76)

BAV, bicuspid aortic vale; CoA, coarctation of aorta; CVS, cardiovascular; ASI, aortic sized index; cm, centimetres; ND, no details; AS, aortic stenosis; AI, aortic incompetence; MR, mitral regurgitation; PPAVR, partial anomalous pulmonary venous return; ETA, elongated transverse arch; AV, atrioventricular.

youngest published patient with TS and aortic dissection was aged 4 years (34). Twelve of the 18 (66.7%) resulted in death. Only two of those paediatric patients had details of aortic dimensions prior to dissection. As discussed later, the relationship between aortic dimensions and dissection in children and adolescents is unclear. Thus to summarise, our review of all published cases show that the clinical characteristics of patients with TS who experience an aortic dissection were similar to that of an earlier review published in 2007. However, we could not exclude duplication of published cases as we did not contact all the authors from publications spanning over 50 years. The majority of TS patients with aortic dissection have cardiovascular risk factors, underpinning the importance of careful and ongoing cardiovascular assessment and surveillance.

Risk factors A major risk factor for aortic dissection in TS is aortic dilatation (see below). Other possible risk factors include the following: Karyotype and other cardiovascular abnormalities TS with monosomy X (45XO) cell line is associated with higher incidence of CoA and BAV (86). Patients with 45XO karyotype also have a higher prevalence of aortic dilatation (87). It is unclear if the risk of aortic dissection is increased independent of other clinical risk factors in patients with monosomy X. BAV and CoA are commonly seen in patients with TS and aortic dissection (67, 68). Aortic dimensions are higher in TS patients with BAV (10). In the largest series of patients with TS and aortic dissection, 16 of 20 (80%) had BAV and four of 20 (20%) had CoA (67). It is known that dilatation of the ascending aorta can occur in karyotypically

normal patients with BAV. The postulated mechanisms are eccentric aortic flow pattern causing abnormal shear stress plus intrinsic vessel wall abnormality. Hypertension A recent report of ambulatory 24-h blood pressure monitoring in TS revealed approximately 60% of adults with TS to be hypertensive (10). There are few paediatric reports of blood pressure in TS. Aortic root dilatation has been closely linked with hypertension (88). There is no clear cut link between hypertension and aortic dissection in TS. In a literature survey of all published cases in 2007, only half of TS patients with dissection were hypertensive (68). As some of those patients may have received anti-hypertensive treatment, the contributing role of hypertension is unknown. Pregnancy Over recent years, increasing numbers of women with TS seek pregnancy via assisted reproductive technology (ART). Spontaneous pregnancies occur in about 2% of women with TS especially those with mosaic karyotype but also in 45XO and those women with Y material (89–91). Pregnancy is a high risk period for aortic dissection in TS (92–94). Increased stroke volume occurs due to reduction in systemic vascular resistance early in pregnancy, leading to approximately 50% increase in cardiac output by 8 weeks gestation. Stroke volume continues to increase throughout pregnancy. During labour and post partum, significant changes in cardiac output occur, amplifying haemodynamic stress. The estimated risk of death from aortic dissection during pregnancy in TS is 2% from a study from a USA national register 2010 (two deaths for every 100 TS women) (95) whereas only 0.02 dissection deaths occur for every 100 women in the general population. Risk of death during pregnancy due solely to aortic dissection is

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Age 

19  19  20  20  23 

24  24 

25  27  27  28  28  28  28 

29  29  29 

29  30  30  30 

34  34  34  34 

35  36  37  37  38  38  39  39  39 

Patient no 

78  79  80  81  82 

83  84 

85  86  87  88  89  90  91 

92  93  94 

95  96  97  98 

99  100  101  102 

103  104  105  106  107  108  109  110  111 

             

   

         

 

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45XO Mosaic 45XO ND 45XO 45XO 45XO 45XO 45XO

45XO ND ND ND

ND 45XO/46X+ring ND ND

                 

       

       

45XO/46X,r(x)   45XO   45XO  

45XO ND 45XO 45XO 45XO ND ND

ND 45XO/46XX

ND ND 45XO ND ND

Karyotype          

 

Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased Deceased

Deceased Deceased Deceased Deceased

Deceased Deceased Deceased Deceased

Deceased Deceased Deceased

                 

       

       

     

Deceased   Deceased (TS   diagnosed after death) Deceased   Deceased   Deceased   Deceased   Deceased   Deceased   Deceased  

Deceased Deceased Deceased Deceased Deceased

Outcome

+ – + + – – – – –

– + + +

+ – – +

– – +

– + + – + + +

+ –

– – – – +

                 

       

       

     

             

   

         

BAV 

– – – – – – – – –

– + – –

– – + –

– + –

+ – – – – + +

+ +

– + – – –

                 

       

       

     

             

   

         

CoA 

       

     

             

   

– –

AI

AI, AS – AI, AS VSD

                 

–   –   Hypoplastic aortic arch  –  

– –

–

– –

– – – – AS, AI – –

– –

AS   –   –   –   Interrupted aortic arch  

Other CVS anomalies  

Table 5 Summary of published cases of aortic dissection in TS  > 18 years (deceased).  

–   –   –   –   –   –   Root 3.6 cm, root ASI 2.5;   Asc 4.5 cm, Asc ASI 3.2 –   –   Root 2.2 cm, root ASI z   score –0.5 Root 2.2 cm, root ASI 1.7     –   Root 3.8 cm, root ASI 2.5;   Asc 4.5 cm, Asc ASI 3.2 –   –   –   Root 3.5 cm, root ASI 2.2;   Asc 5.1 cm, Asc ASI 3.2 –   –   –   Root 3.4 cm   AI, Aortic “dilatation”   Aortic “dilatation”   –   –   –  

–   –   –   –   Root 3.2 cm, root ASI 2.3;   Asc 4.1 cm, Asc ASI 2.9 Asc 3.6 cm, Asc ASI 3.0   –  

Aortic dimensions

Proximal Proximal Proximal & distal Proximal & distal Distal Distal ND Proximal & distal ND

Proximal Distal Proximal Proximal

Distal Distal

Proximal

ND Proximal Proximal

Proximal Proximal Distal Distal Proximal Proximal Proximal

Proximal Proximal

Proximal & distal Distal Proximal Proximal Proximal

                 

       

       

     

             

   

         

Location of dissection  

Kostich et al. (33) Kido et al. (54) Lie et al. (62) Carlson et al. (67) Price et al. (24) Price et al. (24) Price et al. (24) Price et al. (24) Sybert et al. (23)

Lippe et al. (34) Anabtawi et al. (61) Gravholt et al. (18) Carlson et al. (67)

Carlson et al. (67) Price et al. (22) Bordeleau et al. (37) Carlson et al. (67)

Price et al. (24) Gravholt et al. (18) Carlson et al. (67)

Alleman et al. (31) Edwards et al. (84) Gravholt et al. (18) Gravholt et al. (18) Lin et al. (32) Carlson et al. (67) Carlson et al. (67)

Carlson et al. (67) Mimasaka et al. (72)

Buheitel et al. (29) Fejzic et al. (36) Rubin et al. (21) Lippe et al. (34) Carlson et al. (67)

Reference

Wong et al.: Aortic dilatation and dissection in Turner syndrome      475

–

BAV: bicuspid aortic valves, CoA: coarctation of aorta, CVS: cardiovascular, ASI: aortic sized index, Asc: ascending, cm: centimetres, ND: no details, AS: aortic stenosis, AI: aortic incompetence, ETA: elongated transverse arch, VSD” ventricular septal defect.

    –   –   Deceased   61  122 

45XO

– –

            – – + – – +             Deceased Deceased Deceased Deceased Deceased Deceased             45  45  48  49  53  57  116  117  118  119  120  121 

ND 45XO/46X,r(x) 45XO ND 45XO ND

  –  

– ETA

ND

            Proximal ND ND Proximal & distal ND Proximal         –   Asc 4.78 cm, Asc ASI 3.06                          – – – – – –

– –

– Asc 3.7 cm, Asc ASI 2.6     – ETA     40  44  114  115 

ND ND

   

Deceased Deceased

   

– +

   

– –

   

   

Carlson et al. (67) Matura et al. (69) and Bondy et al. (2) Salgado et al. (56) Sybert et al. (23) Hochberg et al. (64) Hata et al. (42) Gravholt et al. (18) Matura et al. (69) and Bondy et al. (2) Gravholt et al. (18)

Slater et al. (51) Sybert et al. (23)    

ND Common carotid to diaphragm Proximal Proximal     – –     – –     – –     + –     Deceased Deceased     40  40  112  113 

ND 45XO

Age  Patient no 

(Table 5 Continued)

Karyotype

 

Outcome

 

BAV 

Aortic dimensions Other CVS anomalies   CoA 

 

Location of dissection  

Reference

476      Wong et al.: Aortic dilatation and dissection in Turner syndrome thus 100 times higher than the general population. Aortic dissection risk evaluation should now be mandatory for all patients with TS prior to consideration of pregnancy. However a recent study shows that fewer than 40% of women with TS undergoing oocyte donation for pregnancy had any form of cardiovascular screening (70).

Pathology of aortic dissection in TS Whilst the underlying aetiology of aortic dissection in TS is unclear, recent studies have demonstrated up regulation of TGFβ signalling, causing a generalised abnormality in vasculature in Marfan syndrome (MS) (96), a multisystem connective tissue disorder caused by fibrillin 1 gene mutation, leading to deficiency in fibrillin micro fibrils. Aortic dilatation and dissection frequently occurs in these patients. A preliminary study showed TGFβ1 levels to be 3.5 times higher in TS compared with healthy controls (97) In some cases where pathological reports are available for TS and aortic dissection, cystic medial necrosis and alteration in type 1: type III collagen is seen, similar to MS (98). Definitive studies clarifying the role of the TFGFβ signalling pathway in TS is needed, as there may be potential therapeutic options to prevent aortic dilatation (see below).

Aortic dilations and TS Most studies show that aortic dilatation is common in patients with TS. However, reports are inconsistent, hence variability in prevalence figures (10, 99). Several factors may influence this. These include the percentage of patients with monosomy X, age (children vs. adults), inclusion of patients with known cardiac disease, definition of aortic dilatation, control group or data used as control normative data, mode and site of assessment (Table 2). Recombinant human growth hormone (rhGH) is used in the majority of children with TS to improve growth rate and final height (100, 101). There are theoretical concerns that rhGH may lead to increase in aortic dimensions (102, 103) and therefore increase risk of aortic dissection. Reassuringly, published evidence suggests that rhGH does not increase aortic dimensions in TS (104, 105). Emerging research suggests the possibility of biomarkers, which may predict aortic dilatation in TS. N-terminal pro-brain natriuretic peptide is the precursor of brain natriuretic peptide (BNP), a cardiac hormone with natriuretic, diuretic and vasorelaxant properties and a role in

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Mortensen   et al. (118)

  BSA

  BSA

67  Mean   MRI 39 years (20–63)

  BSA

24  Mean   Echocardiogra,   Echo: Nil 43 years MRI MRI: BSA (25–63)

50  Mean   MRI 16.9 years (12–25)

Echocardiogram   BSA

MRI

Echocardiogram,   Echo-ht, BSA MRI MRI-nil

  Echocardiogram,   Nil MRI

  Echocardiogram,   BSA MRI

36  Mean   32.4 years (20.5–55) 26  Mean 35.3   years 407  Mean 6.4   years

  Nil

  Nil

  Method of size adjustment

 

 

 

 

 

 

 

  Outcome

Nil

Nil

Nil

Yes

Nil

Nil

Nil

Nil

  Z score reported

  Echo: 1/40 (2.5%)  > 90th centile normal   population echo data MRI: 5/40 (12.5%)  > 95th centile normal population CT data Echo-aortic root   Echo: aortic root 2.4 cm   MRI-ascending aorta MRI: ascending aorta 2.1 cm, descending aorta 1.5 cm, A: D  > 1.5 in 4/15 (27%0 Echo-aortic root   Echo: ↑ Ht and BSA adjusted aortic root   MRI-ascending, descending MRI: ↑ unadjusted ascending aorta, aorta ↔ descending aorta, ↔ A: D Ascending, descending aorta   ↑ ascending aorta,   ↔ descending aorta, ↑ A: D     Aortic annulus 0.63 SD (12%   ≥   +2SD) Aortic annulus, aortic Aortic root 0.99 SD (20%   ≥   + 2SD) root, sinotubular junction, Sinotubular junction 0.73 SD (18%   ≥   +2SD) ascending, descending, distal Ascending aorta 1.26 SD (30%   ≥   +2SD) transverse, aortic isthmus Distal transverse –1.18 SD Aortic isthmus –0.3 SD   Sinotubular junction,   ↔ sinotubular junction ↔ ascending aorta  ascending, proximal to  ↔ proximal to innominate artery  innominate artery, proximal  ↓ distal transverse arch  transverse arch, distal transverse arch, aortic isthmus, ↓ aortic isthmus  ↔ descending aorta descending aorta   Echo: sinotubular juncion   Echo: 8/97 (8.2%)  > 3.2 cm as previously MRI: sinotubular junction, defined as dilatation ascending (between sinotubular MRI: TS BSA adjusted dimensions vs controls junction and innominate artery), non adjusted dimensions ascending (proximal innominate  ↔ sinotubular jucntion  ↔ ascending aorta artery), proximal transverse  ↔ acsending proximal innomintae artery arch, distal transverse arch, aortic isthmus, descending  ↔ proximal transverse arch  ↓ distal transverse arch  ↓ aortic isthmus  ↔ descending aorta   ↑ percentage of aortic dilatation at all sites   Aortic sinus, sinotubular junction, mid ascending, distal except distal transverse (18.9–36.75) ascending, proximal arch, distal Aortic dilatation defined as  > +2SD of control arch, aortic isthmus, proximal BSA adjusted dimensions descending, distal descending

  Echo- aortic root RI- ascending aorta

  Site assessed

ND, No detail; MRI, magnetic resonance imaging; BSA, body surface area; CT, computer tomography; A:D ascending aorta, descending aorta ratio, SD, standard deviation.

80  Mean 38 years   (18–60)

57% 

Hjerrild   102  Mean 38 years   et al. (10) (18–62)

49% 

70% 

49.2% 

46.7%  Nil

44% 

 

 

 

 

  Nil

  Karyotype   No   Controls   Mode of (% 45XO) controls age assessment

3–34 years  ND

15  Mean 16.7 years (10–28) 128  Mean 29.2 years (18.7–55.5) 166  Mean 36.2 years 138  Mean 10.2 years (All   0.5 cm/year is an indication for consideration of prophylactic surgery due to very high risk of aortic dissection (113, 114). These parameters do not apply in TS, highlighted by a recent case of aortic dissection in TS with absolute aortic dimension of only 4 cm (75). Height adjusted aortic dimension Adjusting for height may be one way of reporting aortic dimensions in patients with TS. The upper limit of normal aortic root dimension of healthy controls was 3.4  cm in one study. 16% of patients with TS assessed using echocardiogram had height adjusted aortic root  > 3.4 in that study (112). No studies to date relate height adjusted aortic dimensions to aortic dissection. Ascending: descending aorta ratio The ascending aorta/descending aorta ratio of  > 1.5 has been suggested as another definition for aortic dilatation as it does not appear to be related to BSA or height (112) but may be impeded by the fact that patients with TS may have descending aorta abnormalities, making the ratio inherently flawed. The prevalence of aortic dilatation based on this parameter varies from 33% to 48% in published studies (10, 112). In addition, 38% of the group of healthy patients had A:D ratio of  > 1.5 in one study (10).

One study has assessed the predictive value of this ratio for aortic dissection and found it to be non-discriminatory for aortic dissection in TS (69). Body surface area adjusted aortic dimension Currently considered the most appropriate method of size adjustment, most published studies report BSA adjusted aortic dimensions in TS, commonly termed aortic sized index (ASI). Several methods of adjusting for BSA exist. Current published methods include: 1. Dividing absolute dimensions (cm) by BSA (m2) 2. Adjustment of TS aortic dimensions based on regression equations of aortic dimension vs. BSA of healthy controls, reported in cm/m2 or as Z score. Most studies reporting BSA adjusted aortic dimensions in TS demonstrate higher aortic dimensions and higher frequencies of aortic dilatation. Two studies, however, showed that aortic dimensions on MRI when adjusted for BSA were either similar or lower in TS compared with controls (10, 99). The frequency of CoA in current studies assessing aortic dimensions in TS varies (see Table 2. In patients with a history of CoA, aortic dimensions post area of stenosis may be lower.

What is the relationship of aortic dimensions and clinical outcome? BSA adjusted aortic dimensions and aortic dissection in adults with TS The cut-off of “aortic dilatation” placing an individual at high risk of aortic dissection in TS remains unclear. Four cases of aortic dissection (two leading to death) in a cohort of 158 TS women from the National Institute of Health (NIH), USA, has intensified discussions regarding identification and stratification of cardiovascular risks in TS (2,  69). All four women with aortic dissection had ASI  > 2.5 cm/m2. Absolute aortic dimensions were  > 3.5  cm. This led to the recommendation that TS patients with ASI  > 2.5 cm/m2 and/or absolute aortic dimensions  > 3.5 cm are at very high risk of aortic dissection. Patients with ASI  > 2.0 cm/m2 are considered at high risk. The relationship of ASI and acute dissection was confirmed in a recent report from the International Turner Syndrome Aortic Dissection Registry of 20 TS patients. It is also now apparent that TS patients dissect even when there is moderate aortic dilatation (67). Ongoing studies relating ASI to aortic dissection are still required as it is clear that whilst aortic dilatation in TS is common, aortic dissection is still uncommon. In a

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Wong et al.: Aortic dilatation and dissection in Turner syndrome      479

study in TS patients with no history of aortic dissection using MRI, mean BSA adjusted dimensions at ST junction and ascending aorta was 2.62 cm/m2 and 2.82 cm/m2 (10). The NIH group of TS and controls only included adults (69). For other reasons to be discussed in the next section, those cut offs may not apply for children and adolescents. BSA adjusted aortic dimension and aortic dissection in younger TS patients Whilst it has been suggested that patients with TS with ASI  > 2.5 cm/m2 are at very high risk for aortic dissection, it is unclear if this cut off is predictive at different ages and BSA. A study using contrast MRI in 53 healthy children highlights the close relationship between aortic dimensions (measured at aortic sinus, sinotubular junction, ascending aorta, transverse, isthmus and descending aorta) and BSA (115). Examining these data, ASI is greater in smaller children with lower BSA. The 95th centile ASI for children with BSA of 0.5 m2 is approximately 3.0–4.0 cm/m2 whilst the 95th centile ASI for children with BSA of 1.8 m2 is approximately 1.8–1.2 cm/m2. The authors of that study have generated equations from their data to allow calculation of z scores of aortic dimensions based on BSA. The predictive value of z-scores of aortic dimensions and acute dissection in TS, especially in children, requires further exploration. We suggest that the recommendation of ASI  > 2.0 and 2.5 cm/m2, respectively, representing high and very high risk for aortic dissection, may not be appropriate in younger children and patients with lower BSA. Using thresholds of ASI of 2.0 cm/m2 and 2.5 cm/m2 may overestimate the percentage of younger patients with “abnormal” aortic dimensions. Conversely, an absolute aortic dimension of  > 3.5 cm may be too high a threshold for children and adolescents and therefore fail to identify patients with increased aortic dimensions. Clinicians monitoring aortic dimensions in TS patients   0.5 cm increase in aortic dimensions per year.

There is limited data on longitudinal changes in aortic dimensions in TS. Discrepancies between reports may reflect modality of assessment. An early study reported no change in aortic dimensions measured at aortic root, ST junction and ascending aorta using echocardiogram in 78 patients with TS (mean 22 years) over a median follow-up period of 37  months (117). A more recent study assessed 80 patients with TS (mean 38 years) using MRI and found statistically significant increases in aortic dimensions at aortic sinus, sinotubular junction and mid ascending aorta over a 2.5 year follow-up period. The highest mean rate of change per year was at the aortic sinus (0.38 mm/year) (118). This was confirmed in 102 TS patients with follow up MRI up to almost 5 years. Other than increase in aortic sinus, sinotubular junction and mid ascending aorta, there was also a trend towards increase at distal ascending aorta and proximal aortic arch (119). It is also unclear if the reported rate of increase in aortic diameter is clinically significant, although current published data suggest that the annual rate of aortic root in healthy females is 0.07 mm/year (120). Despite documented gradual increase in aortic dimensions in a 16-yearold girl over 6 years, acute increase was associated with aortic dissection (71). In the largest series of published TS patients with aortic dissection, five of 20 patients had serial echocardiogram for aortic dimensions. None of these had evidence of excessive increase in aortic dimensions prior to dissection (67). Therefore, the question of whether increase in aortic dimensions predicts dissection in TS is unclear. A mathematical model to predict aortic dilatation for patients with TS based on numerous risk factors including age, blood pressure, BSA, cardiac abnormalities and use of anti-hypertensive has been proposed (119), and this may aid in the identification of TS patients with greater than expected increase in aortic dimensions. This mathematical model allows for data for an individual TS patient in the clinic to be compared with a large group of TS patients and therefore avoid stigmatisation, inappropriate risk counselling and treatment, which may be harmful. It however now needs to be validated against the clinical outcome of aortic dissection.

Which modality should we use for cardiovascular imaging? Cardiac imaging modalities in TS need to detect vascular abnormalities (e.g., CoA), valvular abnormalities (e.g., BAV) and to accurately measure aortic dimensions. There is emerging evidence that MRI may be superior for assessment in TS. MRI may not be widely available, may

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480      Wong et al.: Aortic dilatation and dissection in Turner syndrome be limited by costs in certain settings and a few patients (112) may be unable to tolerate the investigation. In younger children, a general anaesthetic is often required for MRI. Echocardiogram is widely available but attaining adequate views in patients with TS with a broad chest, especially adults with a thicker chest wall can be difficult. Inaccuracies in attaining correct aortic measurements with echocardiogram may occur if the ultrasound beam is not perfectly perpendicular to the major axis of the vessel, with resultant falsely high aortic dimensions acquired. In children, echocardiography remains the modality of choice in most situations. Which modality is better for detecting CoA? Current studies suggest that MRI may be superior for detecting CoA, especially in adults. Two previous studies show that 6.7% (121) and 7.5% (110) of patients with CoA were only identified using MRI, not identified on echocardiogram. In a study of 128 women with TS, median age 29.2  years (18.7–55.5), only two patients had CoA identified on echocardiogram but 40 had CoA identified on MRI: 120 underwent echocardiogram and 115 underwent MRI in that study (112). These reports underline the importance of MRI in excluding CoA beyond infancy or at any point when the patient is hypertensive, even with a normal echocardiogram. MRI may also be better at detecting pseudocoarctation of aorta, seen as elongation of the transverse arch (7, 14). Which modality is better for detecting BAV? Transthoracic echocardiography is thought to be the imaging modality of choice for assessment of valve anatomy and function. It is well recognised that ultrasound windows may be limited in older patients with TS. In this situation, either trans-oesophageal echocardiography or cardiac MRI should be considered. In a study of 253 patients with TS (62% 45X0, age range 7–67 years), eight of 15? were found to have BAV on MRI when aortic valves were not well visualised on echocardiogram (11). In an older smaller study, BAV was detected in seven patients (17.5%) solely on echocardiogram. (110) BAV was not found on MRI in any patients in that study. A recent study using MRI in 208 adults with TS was able to demonstrate a spectrum of aortic valve abnormalities including BAV (23%), partially fused aortic valves (12%) and unicuspid aortic valves (1%). (122) Currently there is no direct comparative study of echocardiogram and MRI for detection of BAV in TS in the paediatric population. Adult studies of non TS patients report accuracies of 54%–93% of echocardiogram for reporting BAV when using anatomic correlation from surgical or pathology

interpretation of valve leaflets as gold standards(123–125). In a group of adults with aortic valve disease who underwent echocardiogram and MRI pre-operatively, the sensitivity and specificity for diagnosing BAV with echocardiogram was 86% and 96%, respectively, compared with a sensitivity and specificity of 96% and 97%, respectively, using MRI (126). Detection of BAV with raphe, representing approximately 50% of cases, may be better with echocardiogram compared with MRI (127). If views are adequate, we suggest that echocardiogram may be the modality of choice for detection of BAV in the younger children. However, MRI may be needed for detection of aortic valve abnormalities in adolescents and adults. Which modality is better for measuring aortic dimensions? Accurate aortic dimension is important. In some instances echocardiogram maybe limited as views of the aorta beyond the transverse arch may be limited. A comparative study shows that the relationship between aortic measurements on echocardiogram and MRI in TS is good at the level of aortic root and ascending aorta with correlation coefficients of 0.81 and 0.85, respectively. At other sites, the correlation coefficient is lower. At aortic arch and descending aorta, the concordance correlation coefficient is as low as 0.21 and 0.30, respectively. Echocardiogram overestimates aortic arch and aortic root dimensions by  > 1 mm in 68.4% and 25.5%, respectively, but echocardiogram underestimates sinotubular junction, descending and ascending aorta dimensions in 75.6%, 67.4% and 47.5%, respectively (128). We suggest that echocardiogram may be appropriate for assessment of aortic dimensions if adequate views are obtained, especially in limited resource settings. If uncertainties or concern regarding echocardiograph measurements exist, we recommend the use of an additional imaging modality.

Which sites do we measure? Prevalence of “aortic dilatation” varies depending on site of measurement (Table 6). Echocardiograph studies suggest that aortic dilatation is more prevalent when measured at aortic root and ascending aorta (111). MRI studies suggest that dilatation at aortic sinus and sinotubular junction are more commonly observed. Descending aorta dimensions are more difficult to measure on echocardiogram. The relationship between aortic dissection at descending aorta and aortic dimensions at various sites in TS is unclear. Generalised aortic dilatation occurs

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Wong et al.: Aortic dilatation and dissection in Turner syndrome      481

in patients with TS. However, it is unknown if there is a greater degree of aortic dilatation in descending aorta compared to other sites in those TS patients with descending aorta dissection. Minimum measurements of aortic dimensions should be done at aortic root and ascending aorta on echocardiogram. Aortic dimensions on MRI should be measured at least at the following sites: 1. Ascending aorta, given that the only currently available evidence relating ASI to aortic dissections was measured at that site 2. Aortic sinus, given that the greatest degree of change occurs at that site 3. Descending aorta In our institution, aortic dimensions on MRI are measured at the following sites: annulus, root, sinus, sinotubular junction, transverse arch, proximal and distal aorta. ASI is calculated at ascending aorta or at the site with the largest dimension.

How should we monitor patients clinically? There is currently limited robust evidence base to guide cardiovascular monitoring and management in TS. Recent 2010 consensus guidelines for diagnosis and management of patients with thoracic aortic disease recommends that TS patients should have ongoing reevaluation of the aorta every 5–10 years even without any risk factors for aortic dissection, prior to pregnancy or transition to adult clinics (129). The consensus however, did not address the modality of imaging and frequency of re-evaluation in those with risk factors. A proposed monitoring pathway of cardiovascular health in patients with TS from late adolescence is shown in Figure 1. We wish to highlight the limitation of absolute ASI as a measurement of aortic dilatation in younger adolescents and children (  2 cm/m2) especially if there is underlying BAV or other cardiovascular anomalies or increase of absolute aortic dimensions of  > 0.4 mm/year, MRI should be repeated sooner (see Figure 1). –– MRI and echocardiogram should be repeated together again prior to consideration of pregnancy or as soon as pregnancy is known, if spontaneous? (70, 130). Echocardiogram should be repeated during

pregnancy and approximately 2 weeks after delivery. We recommend repeat MRI in the third trimester especially in patients with moderately “raised” ASI or those with BAV and/or previous CoA. –– A low threshold for ambulatory blood pressure monitoring should be undertaken to diagnose hypertension (131–133) and appropriate treatment commenced. –– Given that conduction and repolarisation abnormalities are relatively common (134, 135), ECG should be performed at initial cardiac assessment prior to transition to adult care, prior to pregnancy or at the first instance pregnancy is known. It is unclear if all patients with TS should have ongoing clinical follow-up with a cardiologist especially if risk factors are less, such as structurally normal aortic valve, mosaic karyotype, ASI   2.5 cm/m2. A recent statement from the American Society for Reproductive Medicine (ASRM) states that any significant cardiac abnormality and/or ASI  > 2 cm/m2 represents an absolute contra-indication for pregnancy in TS (136). The ASRM consensus does not specify what constitutes significant cardiac abnormality. Given that some studies suggest that a large proportion of women with TS may have ASI  > 2 cm/m2 whereas aortic dissection is still a relatively uncommon occurrence in TS, it is possible those recommendations

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Wong et al.: Aortic dilatation and dissection in Turner syndrome      483

may exclude a large group of TS women from the possibility of pregnancy. However, consequences of aortic dissection in pregnancy could be catastrophic. The French College of Obstetricians and Gynaecologists has recommended the following as contraindications for pregnancy in TS: history of aortic surgery, previous aortic dissection, aortic dilatation (ASI  > 2.5 cm/m or absolute dimension  > 3.5 cm), CoA and uncontrolled hypertension despite treatment (137). In our clinical practice, we consider TS patients with ASI  > 2.5 cm/m2 or those with ASI  > 2.0 cm/ m2 and BAV, CoA or uncontrolled hypertension as very high risk for aortic dissection during pregnancy and carefully counsel them about those risks, including risk of death. Written information regarding such risks may need to be provided for the adolescent and family at the time of transition. Anti-hypertensive and other pharmacological agents Aggressive treatment of hypertension in TS with beta blockers and angiotensin converting enzyme inhibitor are recommended even though there is currently no available evidence to support their efficacies in terms of reducing aortic dimension and risk of aortic dilatation. In MS, drug therapies that are either used clinically or are being explored in patients in MS to reduce ongoing aortic dilatation and risk of dissection include: β blockers; angiotensin converting enzyme inhibitors; angiotensin II receptor 1 blocker and statins (138, 139). Angiotensin II and its two receptors have been shown to play a crucial role in the cystic medial necrosis seen in MS. Angiotensin converting enzyme inhibitors and angiotensin YY type 1 receptor blocker may stabilise the aortic wall by down regulation of angiotensin II, reducing TGFβ and MMP expression (140). Animal and human studies (141, 142) have shown its role in lowering the incidence of aortic dilatation in MS. Surgical intervention The possibility of surgical resection or stenting (143) in older TS patients with short segment CoA have been suggested which may alleviate hypertension, although this may not be routine clinical practice. Those patients with clinically significant CoA should have either transcathether or open surgical therapy. Some experts recommend that TS patients with ASI  > 2.5 cm/m2 should undergo prophylactic aortic surgery (67), although it is unclear if this prevents aortic dissection, given that in TS a generalised vasculopathy exists. Significant dilated segments of aorta may require surgical plication or using endovascular stent graft surgically placed or conduit grafts.

Unresolved questions and future research It is clear that aortic dissection is a major cause of mortality in patients with TS but there are numerous unresolved questions requiring future research: Predictive value of aortic dimensions and aortic dilatation Further studies are required to clarify the predictive value of size corrected aortic dimensions and clinical dissection, in particular the relationship between different methods of quantifying aortic dimensions (BSA ASI, BSA ASI z score, height adjusted ASI). The clinical significance of aortic growth and potential contribution of other clinical risk factors (e.g., hypertension, BAV, CoA, karyotype) should also be examined. The predictive value of size adjusted aortic dimensions for aortic dissection in younger patients and those with lower BSA needs clarification. Frequency of monitoring and modality for optimal imaging in TS patients Clarification of the contribution of risk factors to aortic dilatation and aortic dissection in TS will inform potential risk stratification and therefore frequency of cardiovascular screening. There may be a possible role of dual imaging with echocardiogram and MRI. Timing of these investigations need to be addressed. The need for cardiovascular imaging in younger children and interpretation of aortic dimensions require further studies.

Pathophysiology of aortic dissection and the possible involvement of the TGF system This is important and should be clarified before studies using angiotensin converting enzyme or angiotensin II type 1-receptor blockers are conducted, to ensure a robust scientific rationale in TS. Efficacy and safety of anti-hypertensive for aortic dilatation risk reduction Current recommendations suggest that a lower blood pressure threshold for commencing anti hypertensives should be undertaken in TS, to avoid excessive load to the aorta. There are numerous unanswered questions including the threshold of blood pressure for commencing therapy, target blood pressure levels to aim for with treatment.

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484      Wong et al.: Aortic dilatation and dissection in Turner syndrome Efficacy and safety of prophylactic aortic surgery in adult patients with TS Currently little evidence exists regarding safety and efficacy of prophylactic aortic surgery in adults with TS to prevent aortic dissection. Importantly, aortic dimensions and other risk factors when considering surgery are still unknown.

Conclusion Women and girls with TS have a significantly higher risk for aortic dissection than the general population. Careful follow-up of these patients with cardiovascular surveillance in adulthood and during pregnancy is crucial, although there are numerous unresolved controversies. Future studies are now needed to aid in stratifying cardiovascular risks in TS. Until further evidence is available, all patients with TS should be considered at risk for aortic dissection and clinical surveillance is recommended. Clinical monitoring of cardiovascular risk factors should be dependent on local resources and expertise, with guidance from expert consensus. Care, however, should only be provided by clinicians familiar with the issues unique to patients with TS given that numerous issues pertaining to cardiovascular, gynaecology and fertility and endocrine aspects may be intricately related (132, 144). We believe that comprehensive cardiovascular assessment should be performed in adolescents with TS prior to transition to clarify risk and for adequate risk counselling. This should not be left to the adult managing clinicians, given the possibility of lost to follow up following transition to adult care. Acknowledgements: The Murdoch Childrens Research Institute is supported by the Victorian Government’s Operational Infrastructure Support Program. The Heart Research Group is supported by RCH 1000, The Royal Children’s Hospital Foundation. Conflict of interest statement: All the authors have no conflicts of interest to declare in relation to this clinical review.

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