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Management of Marfan syndrome and related disorders

Management of Marfan syndrome and related disorders
Literature review current through: Aug 2023.
This topic last updated: Nov 30, 2022.

INTRODUCTION — Marfan syndrome (MFS, MIM #154700) is an autosomal dominant condition with a reported incidence of 1 in 3000 to 5000 individuals. There is a wide range of clinical severity associated with MFS. Although many clinicians view the disorder in terms of classic ocular, cardiovascular, and musculoskeletal abnormalities, these patients also demonstrate significant involvement of the lung, skin, and central nervous system.

The management and prognosis of MFS and related disorders will be reviewed here. The genetics, pathogenesis, clinical manifestations, and diagnosis of MFS and related disorders and issues related to MFS in pregnancy are discussed separately. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders" and "Heritable thoracic aortic diseases: Pregnancy and postpartum care".)

OVERVIEW — The prognosis of patients with MFS has improved with the use of medical therapy (beta blockers and angiotensin receptor blockers), routine and noninvasive monitoring of aortic size, elective surgical repair of the aorta, and restriction of vigorous physical exercise. The physiologic changes that occur during pregnancy are associated with an increased risk of aortic dilation and dissection and therefore require more intensive monitoring. (See "Heritable thoracic aortic diseases: Pregnancy and postpartum care".)

The 2022 American College of Cardiology/American Heart Association guidelines for aortic disease include recommendations for MFS, Loeys-Dietz Syndrome and other genetic syndromes affecting the aorta [1]. These guidelines are similar to the recommendations for MFS published in 2014 by a Task Force of the European Society of Cardiology [2].

AORTIC MONITORING — Monitoring of the thoracic aortic diameter is recommended to identify patients at high risk for aortic dissection.

How to measure — The aortic diameter measurement technique applied to follow a given patient should be noted and used consistently during serial follow-up with nomograms specific for that technique applied when determining deviation from the appropriate age- and size-matched normal population (generally expressed as a Z-score, which designates number of standard deviations from the mean). Since normal aortic dimensions vary with age and body surface area, these parameters should be taken into account (figure 1A-B). Measurement conventions for aortic diameter differ for echocardiography as compared with computed tomography (CT) or magnetic resonance imaging (MRI) and the measurement convention may also differ within modalities from one institution to another.

Multiple conventions are applied when measuring the maximal dimension of the aortic root and ascending aorta by echocardiography. Examples include the leading-edge-to-leading-edge technique in diastole (a common practice among adult cardiologists) or the inner-edge-to-inner-edge technique in systole (a common practice among pediatric cardiologists). Similar variability can be observed when applying CT or MRI measurements, depending upon whether or not contrast agents are utilized. In general, the external diameter is expected to be 2 to 4 mm larger than the internal diameter. There is also variation in practice with regard to whether the external or internal diameter is operative when considering thresholds for surgical repair. (See 'Indications in MFS' below.)

For MFS, aortic diameter at the sinuses of Valsalva is the key measurement since this is the segment that generally dilates initially and is at greatest risk for aortic dissection. This measurement can usually be monitored by echocardiography. Greater length of aortic dilation (ie, to the aortic arch versus limited to the sinuses of Valsalva) can be associated with a worse prognosis [3].

Monitoring MFS — As recommended in the 2022 American College of Cardiology/American Heart Association guidelines for aortic disease, patients with MFS should have transthoracic echocardiography (TTE) performed at the time of diagnosis and six months later to determine the aortic root and ascending aortic diameters and their rate of enlargement [1]. If the aortic root or ascending aorta are not adequately seen on TTE, CT or MRI is performed.

For patients with adequate aortic imaging by TTE, we suggest performing cross-sectional aortic imaging with CT or MRI at the time of initial evaluation to confirm that the aorta measurements determined by echocardiography are not underestimated, and also to identify aortic or vascular disease that is not appreciated by echocardiography. When ascending aorta dimensions measured by echocardiography and cross-sectional imaging correlate with each other and no additional aortic disease is identified, cross-sectional imaging is generally repeated every three to five years and prior to elective operation or planned pregnancy. This frequency should be increased if there is a personal or family history of disease in the descending thoracic or abdominal aorta in association with MFS.

In adults with MFS, if the aortic diameter is documented as stable over time, then annual imaging is recommended if the aortic dimension is less than 45 mm. If the aortic diameter is ≥45 mm or shows consistent growth over time, then more frequent imaging is suggested (eg, twice yearly) and surgery may be indicated (see 'Indications in MFS' below). More frequent imaging is also recommended if there are concerns regarding ventricular or valve function [4].

For children with MFS, annual imaging is recommended if the aortic dimension is documented as stable over time and not markedly enlarged. There are no validated age-specific absolute aortic diameters that can be used to determine when more frequent imaging should be performed or when prophylactic aortic surgery is indicated. It is recommended that aortic measurements be compared to the body surface area. Sonographic measurement of aortic diameter should be performed annually as long as the increase in aortic size remains proportional to the increase in body surface area. Twice-yearly measurements are recommended if aortic size (expressed as a percentage increase) diverges from the height when expressed in the same fashion.

Individuals under 20 years of age with systemic findings suggestive of MFS, but without cardiovascular involvement, should also have annual echocardiograms due to the potential risk of development of aortic disease [4]. Adults with repeatedly normal and stable aortic measurements without a definitive genetic predisposition for aortic enlargement but with a sense of predisposition based upon family history or borderline aortic measurements can be seen at two- to three-year intervals.

Since measurement techniques vary between imaging modalities, patient age, and institutional preference, it is important to try to use the same imaging modality at the same institution for a specific patient; this facilitates comparison of images and monitoring of aortic dimension over time.

Monitoring Loeys-Dietz and related syndromes — Complete aortic imaging should be performed at the time of diagnosis, and follow-up imaging of the thoracic aorta (generally by TTE) performed six months after, in patients with Loeys-Dietz syndrome [1] or a confirmed genetic mutation associated with aortic aneurysms and aortic dissections (eg, TGFBR1, TGFBR2, SMAD3, TGFB2, FBN1, ACTA2, or MYH11) to determine if aortic enlargement is occurring.

If the aortic dimension is stable and no other specific problem in another vascular segment has been identified, patients with Loeys-Dietz syndrome (potentially caused by mutations in TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3) should have serial MRI or CT angiography from the cerebrovascular circulation to the pelvis (with a maximal interval between studies of two years) since they commonly develop aneurysms that are amenable to prophylactic surgical management.

DRUG THERAPY — For adults with MFS and aortic aneurysm, we recommend a beta blocker or angiotensin II receptor blocker (ARB); we also suggest this therapy for children. For patients who tolerate beta blocker or ARB therapy, we suggest adding the other type of agent (beta blocker or ARB), as tolerated. For a patient with MFS and aortic aneurysm, it is reasonable to reduce blood pressure with beta blockers and/or ARB to the lowest level the patient can tolerate without adverse effects.

For adults and children with MFS without aortic aneurysm but with one or more risk factors for development of aortic aneurysm (such as demonstrated aortic root enlargement, a family history of aortic root enlargement, or a mutation previously observed to associate with aortic disease), we suggest a beta blocker or ARB.

Beta blocker

Beta blocker use — For a patient with MFS with an indication for beta blocker use, we generally use a long-acting agent (eg, atenolol or metoprolol extended release), as daily dosing may improve compliance.

We generally start with atenolol 0.5 mg/kg/day and increase the dose based upon heart rate response, with the goal of maintaining heart rate after submaximal exercise (eg, running up and down two flights of stairs) below 100 beats/minute in adults and below 110 beats/minute in children [4,5]. The atenolol dose rarely exceeds 2 mg/kg/day. We generally round the dose to the nearest 25 mg (ie, tablet size). The usual adult dose range for atenolol is 25 to 100 mg per day; maximum dose 200 mg/day.

Among pregnant women, labetalol or metoprolol are the preferred beta blockers since atenolol may impair fetal growth, as discussed separately. (See "Heritable thoracic aortic diseases: Pregnancy and postpartum care".)

Beta blocker outcomes — Prophylactic treatment with beta blockers has been adopted by many specialized care centers for adults with MFS since the mid-1990s, since publication of an open-label randomized trial comparing beta blocker therapy and no specific treatment in 70 adults with classic MFS [6]. The following observations were noted at approximately ten years:

Patients with MFS treated with propranolol (mean dose 212 mg/day) had a slower rate of aortic dilatation as reflected by a lower mean slope of the regression line for aortic root dimensions (0.023 versus 0.084 per year).

Survival for the propranolol group was higher during the middle years of the trial and slightly but not significantly better at the end of the trial. However, few patients reached a clinical end point (five in the treatment group and nine in the control group).

As there are limited data directly comparing beta blocker therapy versus control, an individual patient data meta-analysis estimated the effects of beta blocker versus control by comparing the effects of angiotensin II receptor blocker (ARB) versus control (mean age 28.6 years) with the effects of ARB versus beta blocker (mean age 13.9 years) on the annual rate of change of aortic root dimension Z score at the sinuses of Valsalva, adjusted for body surface area [7]. The indirectly calculated difference in the annual change in the aortic root Z score between beta blocker and control was -0.09 (95% CI -0.18 to 0.00). This indirect estimate of the effect of beta blockers is similar that seen in the small prior randomized trial directly comparing a beta blocker with no treatment [6,7].

Data supporting the use of beta blockers in children are less clear:

In an observational study, 44 children and adolescents with MFS were followed for almost four years [8]. The 20 patients who were taking a beta blocker and the six patients taking a calcium channel blocker had a slower absolute aortic growth rate (0.9 versus 1.8 mm/year in untreated patients) and aortic growth rate adjusted for age and body size. Protection was not complete since 5 of the 26 treated patients had a major cardiovascular complication requiring surgery over a four-year follow-up [8]. Of note, calcium channel blocker therapy is generally avoided in patients with MFS based on results of other studies. (See 'Drugs to avoid' below.)

A retrospective study of 63 children was conducted at two sites in which beta blocker therapy versus no therapy was assigned according to local practice [9]. There was no difference in the rate of change in aortic root measurements between the two groups during follow-up (mean of 79 months). Only three patients underwent aortic root replacement, one in the treatment group and two in the untreated group. There was a trend toward more side effects in treated patients.

Additional randomized trials are needed to determine the efficacy of beta blockers versus placebo in children with MFS.

Beta blockers decrease myocardial contractility, pulse pressure, and heart rate and may afford some protection from aortic root enlargement based on these hemodynamic effects. There is also limited evidence that beta blockers can improve the elastic properties of the aorta, particularly in patients with an aortic root diameter <40 mm [10,11].

Renin-angiotensin system antagonist — As described above, an ARB is an alternative or companion treatment to a beta blocker for patients with MFS with aortic aneurysm or a risk factor for development of aortic aneurysm.

Therapy targeting the renin-angiotensin system may attenuate the clinical manifestations of MFS by blocking TGF-beta signaling [12].

The role of therapy targeting the renin-angiotensin system has been evaluated by several studies [12-17] but there is limited evidence for impact on clinical endpoints:

ARB

Comparison with control – An individual patient data meta-analysis included four randomized trials with 676 total participants comparing ARB therapy with control [7]. During three-year median follow-up, the annual rate of change in the aortic root Z score was nearly halved with ARB therapy (mean annual increase 0.07 [ARB] versus 0.13 [control]; absolute difference -0.07, 95% CI -0.12 to -0.01). The mean age for patients in this analysis was 28.6 years.

Comparison with beta blocker therapy – The above-cited individual patient data meta-analysis included three trials with 766 total participants comparing ARB with beta blocker therapy [7]. During three-year median follow-up, the annual change in the aortic root Z score was similar in the two groups (annual increase -0.08 with ARB versus -0.11 with beta blocker; absolute difference 0.03, 95% CI -0.05 to 0.10). The mean age for patients in this analysis was 13.9 years.

The largest included trial was a randomized trial comparing losartan with atenolol in 608 children and young adults (mean age 11.5 years) with MFS and aortic Z-scores >3.0 found no significant difference in the rate of aortic root dilation between the two treatment groups over a three-year period [16]. A comparable and significant decline in aortic root diameter relative to body surface area was seen with both treatments. The three-year rates of aortic root surgery, aortic dissection, death, and a composite of these events were similar in the losartan and atenolol treatment groups, and the total numbers of events in both groups were small (19 versus 10 events). Importantly, this study compared an atypically high dose of atenolol (mean 2.7 mg/kg/day and up to 4 mg/kg/day) with a conventional dose of losartan (mean 1.3 mg/kg/day and up to 1.4 mg/kg/day).

Added to beta blocker therapy – Studies evaluating the effect of adding an ARB (to standard beta blocker therapy) have shown mixed results.

-Two randomized open-label trials in patients with MFS (one in 28 patients, predominantly children; the other in 233 adults) have reported reductions in aortic root dilation rate with the ARB losartan added to beta blocker therapy at three-year follow-up [14,15].

-In contrast, a double-blind randomized trial in 303 patients (mean age 29.9 years) found no significant difference between losartan and placebo on aortic root dilation rate at median 3.5-year follow-up [17]. Most patients in both treatment groups were also taking a beta blocker. One limitation of the study is inclusion of patients who would not meet current diagnostic criteria for Marfan syndrome (eg, revised Ghent nosology) since 22 percent of patients had no FBN1 mutation identified and many patients had no baseline aortic root dilation. In this light, it is notable that an individual patient data meta-analysis documented that the greatest effect of ARB treatment was observed in patients diagnosed with Marfan syndrome that had a definable FBN1 pathogenic variant [7].

Effect on clinical endpoints – In long-term (up to eight years) follow-up of patients with MFS treated with ARBs (with or without concomitant beta blockers), a study from the Netherlands documented a reduced rate of important clinical endpoints including surgery beyond the aortic root, mortality from aortic dissection, and all-cause mortality compared with affected individuals not receiving an ARB. There was a nonsignificant trend toward reduced incidence of aortic root surgery in those receiving an ARB [18].

ACE inhibitor – Scant evidence is available on the effect of ACE inhibitor therapy in patients with MFS [19,20]. A small randomized trial comparing perindopril with placebo (in addition to standard beta blocker therapy) was retracted [21].

Other drug therapy — The potential role of other drug therapy in MFS has not been established. Statins have been demonstrated to attenuate aortic root dilation in a mouse model of Marfan syndrome [22]. They appear to act through reducing the excessive protein manufactured by vascular smooth muscle cells, which occurs in the Marfan aorta. Human studies have not been reported.

Drugs to avoid — Patients with MFS should generally avoid use of calcium channel blockers if alternative medications are available for the control of blood pressure and/or heart rhythm. Although evidence is limited, preliminary animal and human data suggest that calcium channel blocker therapy may increase the risk of aortic complications. Marfan mice treated with calcium channel blockers demonstrated aneurysm expansion, rupture, and premature death. A study also reported that patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking calcium channel blockers display increased risk of aortic dissection and need for aortic surgery, compared with patients on other medical agents [23].

For patients with MFS (and other disorders with risk of arterial aneurysm, tear, or rupture), fluoroquinolone use should be avoided unless there is no alternative antibiotic that will be effective in the treatment of a serious infection [24]. Observational evidence suggests an associated between fluoroquinolone use and increased risk of aortic dissection or aortic aneurysm rupture.

RESTRICTION OF STRENUOUS ACTIVITY — An expert panel of the American Heart Association has made recommendations regarding permissible levels of physical activity for patients with genetic cardiovascular diseases, including MFS [25]. As a general principal, participation in recreational exercise, categorized as low to moderate intensity (approximately four to six metabolic equivalents), can be recommended for many patients with MFS, though these suggestions do not necessarily apply to patients who have had aortic root and/or valve replacement.

Recreational (noncompetitive) exercises that are of low and moderate intensity that are probably permissible include the following: bowling, golf, skating (but not ice hockey), snorkeling, brisk walking on ground or treadmill, stationary biking, modest hiking, and doubles tennis.

In general, patients with MFS are advised to avoid contact and competitive sports, exercise to exhaustion, and especially isometric activities which entail the Valsalva maneuver [4]. Activities that are not advised or strongly discouraged include [25]: isometric exercise (eg, weight lifting, sit-ups, pull-ups, push-ups), ice hockey, rock climbing, windsurfing, and surfing. Scuba diving should be avoided due to an increased risk of pneumothorax resulting from barotrauma [26].

Other activities that are thought to be of intermediate risk, and for which individual assessment is suggested, include the following [25]: basketball (both full and half-court), racquetball, squash, running, skiing (downhill and cross-country), singles tennis, touch (flag) football, soccer, baseball, softball, biking, lap swimming, motorcycling, and horseback riding.

Parents of children with MFS face difficult decisions regarding participation in physical education classes. Social pressure may necessitate inclusion of an affected child in a school-structured physical education program. Parents and school officials should agree upon permitted and excluded activities for the affected child. Physical education instructors must agree to abide by the activity restrictions and be able to monitor the child's participation to avoid excessive exertion. It is not considered acceptable for children with MFS to routinely simply observe exercise by their peers, as this practice is not benefiting the child and will promote stigmatization. If the school is unwilling or unable to offer a suitable and sustainable program, the student should be allowed to pursue an enriching activity in an alternative venue.

Recommendations in competitive athletes with MFS are presented separately. (See "Athletes: Overview of sudden cardiac death risk and sport participation", section on 'Marfan syndrome'.)

AORTIC ROOT REPLACEMENT

Elective replacement

Rationale — Elective replacement of aortic root disease before critical enlargement is preferable to emergency repair for marked dilatation or dissection. The importance of this approach was illustrated in a series of 675 patients with MFS from Johns Hopkins in which the 30-day mortality for elective repair, urgent repair (within seven days after a surgical consultation), or emergency repair (within 24 hours of consultation) was 1.5, 2.6, and 11.7 percent, respectively [27]. In this series, 46 percent of the adults with aortic dissection had an aortic root diameter of ≤65 mm at the time of operation; the authors suggested that prophylactic repair be performed when the aortic diameter is well below this size.

Thus, surgical intervention should be considered, regardless of the patient's symptoms, in patients with significant aortic root dilatation [28-30]. The goal is to improve survival. In a review of 231 patients who underwent elective aortic root replacement at Johns Hopkins, the actuarial survival at five, ten, and twenty years was 88, 81, and 75 percent, respectively [30].

Indications in MFS — The aortic root diameter at which elective surgery should be performed is uncertain. The 2022 American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend elective operation for patients with MFS at an external diameter of ≥50 mm to avoid acute dissection or rupture [1]. Indications for repair at an external diameter less than 50 mm (ie, aortic root diameter ≥45 mm) include rapid growth (≥3 mm/year), family history of aortic dissection, diffuse aortic root and ascending aortic dilation, or marked vertebral arterial tortuosity [1].

One limitation of recommendations based upon absolute aortic root diameters is that predicted aortic root diameter varies with body size [31] and age and may be smaller in women [32]. Smaller patients have dissection at a smaller aortic root size and 15 percent of patients with MFS have dissection at a diameter less than 50 mm [33]. Various strategies have been proposed to identify at risk patients with aortic size less than 50 mm [32-34].

The 2022 ACC/AHA aortic disease guidelines include the following recommendation for patients with MFS and other genetic aortic diseases [1]. If the maximal cross-sectional area in square centimeters of the ascending aorta or root divided by the patient's height in meters is >10, surgical repair is reasonable. This strategy was supported by a series of 103 patients with MFS who were managed using these criteria without development of aortic dissection [33].

The optimal timing of elective aortic repair in children is also uncertain and adjustment for body size is particularly relevant in this population. In children younger than 12 years of age, dissection is rare, irrespective of aortic dilation. In these young patients, surgical indications are aneurysms that satisfy the adult criterion for intervention, rapid enlargement (>10 mm/year), and progressive aortic insufficiency [35].

Indications in Loeys-Dietz syndrome — Patients with Loeys-Dietz syndrome tend to have severe vascular disease and nearly all have aortic root aneurysms that lead to aortic dissection. Since aortic dissection has been observed with aortic diameters <50 mm, repair is recommended at smaller diameters than recommended for MFS [1,36].

For adult patients with Loeys-Dietz syndrome or a confirmed TGFBR1 or TGFBR2 mutation and an aortic diameter of ≥4.2 cm by echocardiogram (internal diameter) or ≥4.4 to 4.6 cm by CT imaging and/or MRI (external diameter) it is reasonable to consider surgical repair of the aorta.

For young children with prominent craniofacial features of Loeys-Dietz syndrome, prophylactic surgery is indicated if the aortic valve annulus is at least 18 to 20 mm and the aortic diameter exceeds the 99th percentile for age.

Symptomatic aortic disease — Symptomatic expansion of a thoracic aortic aneurysm is generally an indication for prompt surgical intervention. An aortic dissection is an indication for emergency surgery when the ascending aorta is involved (type A) or for complications associated with type B dissections. These issues are discussed separately. (See "Management of thoracic aortic aneurysm in adults" and "Management of acute type B aortic dissection".)

Surgical technique — Two general approaches are used for aortic root replacement: a composite valve graft and valve-sparing aortic root replacement.

Composite valve graft — Total aortic root replacement with a composite valve graft consisting of the aortic root and a prosthetic (mechanical or bioprosthetic) aortic valve and reimplantation of the coronary arteries (Bentall procedure) (figure 2) was the surgical procedure of choice for older children and adults in the past [28,30]. It has been associated with 5-, 10-, and 20-year survivals of 88, 81, and 75 percent, respectively [30]. Mitral valve repair or replacement may be performed at the same procedure [28].

The ascending aorta is generally replaced from the valve to the mid-ascending aorta (figure 2). Some centers advocate aortic hemiarch replacement at the time of ascending aorta replacement for MFS patients. Data to support routine use of this procedure are lacking.

The importance of adequate hospital experience as well as early referral for optimizing composite valve graft outcomes was indicated by a study of 1962 composite valve grafts (percent MFS not known) in the United Kingdom Heart Valve Registry [37]. Hospital volume of ≤8 composite valve graft procedures per year and urgent or emergency surgery were among the risk factors for 30-day mortality.

Valve-sparing aortic root replacement — Surgical procedures that retain the patient's native aortic valve are attractive alternatives to composite grafts. Two such operations are referred to as remodeling and (David) reimplantation techniques (figure 3) [38-40]. The former attaches the aortic conduit to a cuff of native aorta just above the aortic valve, while the latter reimplants the native valve into the aortic graft and attaches the vascular graft to the left ventricular outflow tract.

While anticoagulation may be recommended for some time after surgery, life-long anticoagulation is not required for most patients who undergo a valve-sparing procedure (see 'Postoperative issues' below). Thus, valve-sparing surgery is a good option for women who desire to become pregnant and for other patients with relative contraindications to long-term anticoagulation. Structurally abnormal valves constitute a potential contraindication to valve-sparing surgery that requires individualized consideration.

Although these valve-sparing techniques are more complex than composite valve replacement, early outcomes are similar when performed by experienced surgeons. In a report from an international registry of 151 patients undergoing aortic root surgery, those undergoing valve-sparing procedures had longer cardiopulmonary bypass times than those undergoing valve replacement, but there were no in-hospital or 30-day deaths in either group and there were similar complication rates [41].

Limited data on long-term results of valve-sparing surgery are available. Patients who are considering such surgery should be advised that reoperation may be necessary. Reimplantation of the aortic valve appears to provide more stable valve function than the remodeling technique as illustrated by the following series [40]:

In the Johns Hopkins series of 372 patients with MFS undergoing aortic root replacement, five of 40 patients who underwent a remodeling valve-sparing procedure required late aortic valve replacement for aortic insufficiency [42]. In contrast, all 44 patients who underwent a reimplantation valve-sparing procedure had none or mild (1+) aortic regurgitation on follow-up.

In the Toronto series of 103 patients with MFS undergoing aortic valve sparing procedures, three of 26 patients who underwent the remodeling procedure required subsequent aortic valve replacement (two for aortic regurgitation and one for endocarditis) [43]. Of the 77 patients undergoing reimplantation, none required subsequent aortic valve replacement and only two had greater than mild aortic regurgitation.

Surgical guidelines — As recommended in the 2022 ACC/AHA guidelines, patients with Marfan, Loeys-Dietz or Ehlers Danlos syndromes (and others with dilated aortic root and sinuses of Valsalva) should undergo excision of the sinuses together with a modified David reimplantation operation if feasible, or, if not, root replacement with valved graft conduit [1].

Investigational approaches — We agree with the 2015 Professional Advisory Statement from the Marfan Foundation that there are insufficient data on alternative approaches that reinforce rather than replace an aortic aneurysm (eg, personalized external aortic root support [PEARS] procedure and "Florida sleeve" repair) to support a recommendation for clinical use at the present time [44]. Potential advantages include theoretically simpler technique and for PEARS, potential avoidance of use of cardiopulmonary bypass and minimizing the size of the surgical incision. However, data on these procedures are limited to small numbers of patients at a small number of centers with limited durations of follow-up [45-48]. An additional key consideration in the risk-benefit assessment of the PEARS procedure is that PEARS has been applied at an aortic dimension significantly lower than that at which aortic root replacement is generally considered for MFS.

Postoperative issues

Anticoagulation — Life-long anticoagulation is necessary for those receiving mechanical valves. In contrast, short-term anticoagulation is generally recommended in the postoperative period, for those receiving bioprosthetic valves, or valve-sparing surgery, regardless of type of repair. Most thromboembolic events occur within the first month after surgery. (See "Antithrombotic therapy for mechanical heart valves".)

Antibiotic prophylaxis — Antibiotic prophylaxis against infective endocarditis is suggested in association with dental procedures for patients who have had aortic valve replacement or prior endocarditis, consistent with the 2014 American Heart Association/American College Cardiology valve guidelines and the 2012 European Society of Cardiology valve guidelines [49,50]. The potential benefit and risk of antibiotic prophylaxis for patients with Marfan syndrome with aortic or mitral valve regurgitation without prior valve surgery remains controversial, warranting individualized consideration and counseling. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

Medical therapy — Preoperative medical therapy (including a beta blocker, angiotensin II receptor blocker, or both, as described above) should be resumed postoperatively and continued indefinitely due to the recognized vulnerability of the aorta remote from the site of aortic replacement. (See 'Drug therapy' above.)

Coronary ostial aneurysms — One complication of both composite and valve-sparing surgery is the development of coronary ostial aneurysms. These aneurysms develop at the site of native coronary artery reimplantation into the aortic graft as a result of stretch of the weakened wall of the coronary ostium; progressive dilatation is uncommon. In a report of 40 patients, ostial aneurysms were documented in 43 percent at a mean of five years after surgery; aneurysms were more common in those ≤35 years of age [51]. Time after operation did not influence the prevalence or size of coronary ostial aneurysms, suggesting that these are not progressive. Although these aneurysms can be recognized by transthoracic echocardiography, they are best visualized and monitored by CT or MRI.

Rarely, pseudoaneurysms occur at the site of coronary or distal aortic anastomosis; these usually require surgical repair.

Follow-up imaging — After initial surgical replacement of the ascending aorta, the arch and descending aorta are vulnerable to development of aneurysms and dissections, indicating that MFS is a disease involving the entire aorta. A significant number of patients require surgeries at other sites throughout the aorta [28]. Patients who have a dissection at the time of the first aortic surgery are more likely to require subsequent aortic surgery than those who undergo prophylactic composite graft repair or valve sparing procedure.

Periodic imaging of the entire aorta is suggested indefinitely following initial aortic repair for aortic dissection or after prophylactic repair. The 2022 ACC/AHA guidelines suggest imaging the aorta at one, six, and 12 months postdissection and then annually thereafter if stable [1]. Monitoring can be accomplished with MRI or CT angiography. Use of the same imaging modality at the same institution facilitates comparison of images over time. If a thoracic aortic aneurysm is relatively stable and moderate in size, MRI may be suggested over CT to minimize the patient's radiation exposure.

Suggested indications for elective prophylactic replacement/intervention of the aortic arch or descending aorta segment include [52]:

Rapid increase in size (eg, >5 mm/year or 5 percent for adults, or >10 mm/year for children)

Descending thoracic aortic diameter >55 to 60 mm

Affected segment diameter twofold greater than adjacent segment

Symptoms related to aortic dilation or malperfusion

TREATMENT FOR OTHER COMPLICATIONS OF MFS — Other complications that require attention include:

Ophthalmologic evaluation is suggested annually due to propensity to lens subluxation (ectopia lentis), cataract, glaucoma, and retinal detachment [4].

Eye care includes vision correction for myopia and photocoagulation for retinal tears and detachment. Early monitoring and aggressive refraction is recommended for children with MFS to prevent amblyopia [4]. (See "Refractive errors in children", section on 'Myopia' and "Amblyopia in children: Classification, screening, and evaluation".)

A dislocated lens should not be removed surgically unless more conservative means of correcting vision are ineffective. Indications for surgical lens extraction include lens opacity with poor visual function, refractive error not amenable to optical correction, impending complete luxation, and lens-induced glaucoma or uveitis [4].

Isolated mitral valve repair or replacement is recommended for severe mitral regurgitation with associated symptoms or progressive left ventricular dilatation or systolic dysfunction (see "Chronic primary mitral regurgitation: Indications for intervention"). Recommendations for concomitant mitral valve repair at the time of aorta replacement are being refined [53,54].

Scoliosis may be initially treated with bracing but surgical correction is usually considered when the curve exceeds 40 degrees. (See "Adolescent idiopathic scoliosis: Management and prognosis", section on 'Approach to surveillance and management'.)

Surgery may be necessary for severe pectus deformities. (See "Pectus carinatum and arcuatum" and "Pectus excavatum: Treatment".)

Surgery may be necessary for recurrent pneumothoraces. (See "Pneumothorax in adults: Epidemiology and etiology".)

The arthropathy associated with joint laxity may require orthopedic correction.

Pregnancy in women with MFS is discussed separately. (See "Heritable thoracic aortic diseases: Pregnancy and postpartum care".)

Screening of family members, genetic counseling, and prenatal genetic testing are discussed separately. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Screening relatives'.)

MANAGEMENT OF RELATED CONDITIONS — Periodic follow-up is indicated in patients with the MASS phenotype (mitral valve prolapse, mild aortic dilatation, striae atrophica, one or more skeletal features (picture 1)), mitral valve prolapse syndrome, or ectopia lentis syndrome (ELS), including regular cardiovascular imaging to monitor aortic size and mitral regurgitation and annual ophthalmological evaluation for patients with ELS. Patients with either MASS phenotype or ELS should be counseled regarding their potential development of aortic disease and the risk of more severe disease (including aortic aneurysm) in their offspring. Imaging frequency depends on aortic stability. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Disorders that may be genetically similar'.)

Careful cardiovascular and ophthalmologic follow-up is also indicated in individuals <20 years old diagnosed with potential MFS or nonspecific connective tissue disorder, since additional clinical features may emerge in such patients.

PROGNOSIS — The life span of untreated patients with the classic MFS was approximately 32 years in 1972. However, improved therapy has resulted in marked increases in life expectancy to 72 years in 1993 [28,55]. Beta blockers, noninvasive aortic imaging and elective aortic root repair have all contributed to this improvement in survival. For reasons that are not well understood, life expectancy is significantly lower in men than in women.

A family history of premature death or aortic surgery may identify patients at increased risk. In one study of 108 patients from 33 multigenerational families, those in the highest quartile for aortic size were more likely to have such a family history than those in the lowest quartile (>80 versus <10 percent) [56].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Aortic dissection and other acute aortic syndromes" and "Society guideline links: Marfan syndrome".)

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Basics topic (see "Patient education: Marfan syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

In children with Marfan syndrome (MFS), sonographic measurement of aortic diameter should be performed annually as long as the increase in aortic size remains proportional to the increase in body surface area. Twice-yearly measurements are recommended if aortic size indexed to body surface area exceeds the expected proportion. More frequent imaging is indicated once the absolute aortic dimension approaches a surgical threshold or to monitor progression of significant valve or ventricular dysfunction. (See 'Monitoring MFS' above.)

In adults with MFS, yearly sonographic measurement of aortic root diameter (after confirming that sonographic aortic measurement correlates with cross- sectional imaging measurement) is recommended as long as the diameter is <45 mm; more frequent monitoring is recommended if the aortic root diameter is ≥45 mm or if there are concerns regarding ventricular or valve function. (See 'Monitoring MFS' above.)

Patients with Loeys-Dietz syndrome and related disorders should have serial magnetic resonance imaging (MRI) from the cerebrovascular circulation to the pelvis. If the aortic and other vascular dimensions are stable after initial and first six-month follow-up, annual reassessment is generally recommended, since they commonly develop aneurysms that are amenable to prophylactic surgical management. (See 'Monitoring Loeys-Dietz and related syndromes' above.)

High-intensity exercise, exercise that involves bursts of activity (eg, sprinting), or activities likely to cause marked increases in blood pressure (eg, weight lifting or weight training) should be avoided for patients with MFS and related disorders. (See 'Restriction of strenuous activity' above.)

Low- and moderate-intensity noncompetitive recreational activities are often recommended for patients with MFS and related disorders. The participation of children in school-related physical education programs should be individualized.

For adults with MFS and aortic aneurysm, we recommend a beta blocker or angiotensin II receptor blocker (ARB) (Grade 1B); we also suggest this therapy for children (Grade 2C). For patients who tolerate beta blocker or ARB therapy, we suggest adding the other type of agent (beta blocker or ARB), as tolerated (Grade 2C). For a patient with MFS and aortic aneurysm, it is reasonable to reduce blood pressure with beta blockers and/or ARB to the lowest level the patient can tolerate without adverse effects. The beta blocker dose should be titrated to limit heart rate following submaximal exercise to less than 100 or 110 beats per minute for adults or children, respectively. (See 'Drug therapy' above.)

For adults and children with MFS without aortic aneurysm but with one or more risk factors for development of aortic aneurysm (demonstrated aortic root enlargement, a family history of aortic root enlargement, or a mutation with a known association with aortic disease), we suggest a beta blocker or ARB (Grade 2C). (See 'Drug therapy' above.)

For patients with MFS, elective aortic repair is associated with reduced mortality when compared with urgent or emergency repair. Elective surgical intervention should be considered when an adult has an aortic root diameter of ≥50 mm and a child has a disproportionately rapid increase in aortic diameter when compared with the rate of increase in body surface area even if the diameter is ≤50 mm. (See 'Indications in MFS' above.)

For adult patients with Loeys-Dietz syndrome or a confirmed TGFBR1 or TGFBR2 mutation and an aortic diameter of ≥4.2 cm by echocardiogram (internal diameter) or ≥4.4 to 4.6 cm by computed tomographic (CT) imaging and/or MRI (external diameter) it is reasonable to consider elective surgical repair of the aorta. (See 'Indications in Loeys-Dietz syndrome' above.)

For young children with prominent craniofacial features of Loeys-Dietz syndrome, prophylactic surgery is indicated if the aortic valve annulus is at least 18 to 20 mm and the aortic diameter exceeds the 99th percentile for age. (See 'Indications in Loeys-Dietz syndrome' above.)

For patients undergoing aortic root replacement, composite aortic root and valve replacement and valve-sparing surgical techniques are considerations, and the choice of operation is dependent upon patient specific considerations. (See 'Elective replacement' above.)

Life-long clinical and imaging follow-up is appropriate following operative intervention for patients with MFS and related conditions. (See 'Follow-up imaging' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Catherine M Otto, MD, for her contributions as Section Editor to previous versions of this topic review.

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Topic 8151 Version 27.0

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