Marfan Syndrome


Article Author:
Irim Salik


Article Editor:
Prashanth Rawla


Editors In Chief:
Linda Lindsay


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
2/28/2019 8:10:39 PM

Introduction

One of the most common inherited disorders affecting connective tissue, Marfan syndrome (MFS) is an autosomal dominant condition with a reported incidence of 1 in 3000 to 5000 individuals.[1][2] There is a broad range of clinical severity associated with MFS, ranging from isolated features of MFS to neonatal presentation of severe and rapidly progressive disease involving multiple organ systems.[3] The syndrome is associated with classic ocular, cardiovascular, and musculoskeletal abnormalities, although involvement of the lung, skin, and central nervous system may also occur. Decreased life expectancy occurs primarily due to aortic complications. Outcome improves with early diagnosis, medical treatment to delay or prevent the progression of aortic dilatation, and timely elective surgery.

Etiology

Although MFS has autosomal dominant inheritance, rare case reports have described recessive fibrillin 1 gene (FBN1) mutations.[4]  While most individuals with MFS have an affected parent, 25% of patients develop the disease as a result of a de novo mutation involving the gene (FBN1) encoding the connective tissue protein fibrillin-1.[5][6] FBN1 is a large gene (65 exons) located at chromosome 15q-21.1 Fibrillin-1 is a matrix glycoprotein that is the main constituent of elastic fibers.[7][8] In less than 10% of patients with typical Marfan phenotype, no mutation in FBN1 is identifiable, likely due to complete allele deletion or altered regulation of the FBN1 gene. In patients with atypical presentations reminiscent of MFS, a mutation in a gene encoding for transforming growth factor-beta receptor (TGFBR) may be the cause. Some individuals with TGFBR1 or TGFBR2 mutations have clinical features consistent with MFS, while others have features of 1 of 2 other syndromes: Loeys-Dietz syndrome (LDS) or familial thoracic aortic aneurysm (FTAA) syndrome.[3]

Epidemiology

Approximately 1 in every 3000 to 5000 individuals is affected. The disease occurs worldwide, with no preference for race or gender. It exhibits complete penetrance with variable expression.[9] Twenty-five percent of cases present sporadically due to de novo mutations.[2] MFS is one of the most common of the single-gene malformation syndromes.

Pathophysiology

The pathophysiology of aortic dilatation in MFS is a complicated process. Fibrillin-1 is a regulator of TGF-beta bioavailability, which in turn leads to inflammation, fibrosis, and activation of specific matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9.[10] Cystic medial degeneration of the aorta occurs when an accumulation of mucopolysaccharide cysts lead to the loss of vascular smooth muscle cells. Aortic wall weakening is due to increased release of MMP, cytokines, chemokines, prostaglandin derivatives, and elastic degradation fragments. These factors, in conjunction with decreased collagen, reduce aortic structural integrity and lead to aneurysmal dilatation.[11] Reduced or altered forms of fibrillin-1 can stimulate the release of sequestered TGF-beta and increase its activity.[12]MFS is therefore caused by vascular remodeling due to a combination of structural microfibril changes, excess TGF-beta, and overexpression of MMP-2 and MMP-9.[11] The role of TGF-beta in the pathophysiology of MFS has been solidified by the use of the therapeutic angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs), both proven to decrease TGF-beta activity. Early studies in a mouse model of MFS have shown the utility of a TGF-beta-neutralizing antibody or the ARB losartan in the treatment of the disease.[13]Comparatively, mutant mice treated with propranolol only exhibited a moderate reduction in the rate of aortic root dilation. Human studies substantiated that ARB therapy resulted in a significant reduction in the rate of change in the aortic root diameter as compared with beta-blocker therapy alone.[14] Various conditions with pronounced clinical overlap with MFS are caused by primary mutations in genes encoding direct effectors and/or regulators of TGF-beta signaling, including Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS).

Histopathology

Histologic features of the medial layer of the aortic root in patients with Marfan syndrome (MFS) include cystic medial necrosis, fibrosis, and loss of smooth muscle cells.[15][16] Although cystic medial necrosis and the other histologic findings are not specific for MFS, greater elastin fragmentation has been shown in patients with aortic root aneurysms with MFS compared to those without a connective tissue diagnosis.[17]

History and Physical

History and physical for patients with MFS encompass various organ systems. Of primary concern is cardiac pathology. Aortic root disease, leading to aortic regurgitation, aneurysmal dilatation, and dissection, is the primary cause of morbidity and mortality in MFS, in up to 60% to 80% of patients. 

Revised Criteria for Patients with MFS

  • Aortic root dilatation
  • Family history of aortic root dilatation
  • FBN1 mutation previously associated with aortic root dilatation

Dilatation may also involve other segments of the thoracic aorta, the abdominal aorta, the root of the pulmonary artery or even the carotid and intracranial arteries, although this is much less frequent than observed in LDS.

As recommended in the 2010 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery (ACC/AHA/AATS) thoracic aorta guidelines, echocardiography is recommended at initial diagnosis and 6 months to assess the aortic root and ascending aorta in patients with Marfan syndrome.[18] A 6-month echocardiogram is performed to confirm the stability of the aortic dimension. Nomograms and Z-scores are used to identify aortic dilatation because normal range for aortic diameter varies with body size and age. Undiagnosed and untreated MFS is often associated with aortic dissection that begins above the coronary ostia and can extend the entire length of the aorta known as a type I dissection in the DeBakey classification. Based on a review from the International Registry of Aortic Dissection (IRAD),[19] MFS causes an aortic dissection in 50% of those under age 40, compared to only 2% of older patients with aortic dissection and, no patient over age 70.[20]

Aortic dissection and rupture are preventable in patients with MFS by replacement of the ascending aorta. Prophylactic surgery is recommended when the diameter of the ascending aorta at the level of the aortic sinuses reaches 5.0 cm. Patients with an aortic diameter of less than 2.75 cm/m2 are considered to be at low risk of dissection, those with 2.75 to 4.24 cm/m2  are at moderate risk, and those with greater than 4.25 cm/m2 are at high risk. A family history of dissection, increased rate of aortic dilation (greater than 2 mm per year), severe aortic valve regurgitation with left ventricular dilation, and relative feasibility of aortic valve-sparing surgery are also indicators for early surgical intervention.[21]

Mitral valve prolapse (MVP) is identified in 40% to 54% of patients with MFS.[22][23] Only 1 point in the systemic score is assigned for MVP since it is nonspecific.[24] The frequency of MVP in MFS increases with age and is more prevalent in women. Tricuspid valve prolapse may also occur. Patients with MFS and MVP have mild regurgitation (MR).[22] In these patients, worsening of MR is due to spontaneous rupture of the chordae tendineae or infective endocarditis. Heart failure caused by MVP and MR represents a major source of morbidity and mortality in young children with rapidly progressive MFS. Due to disrupted granular fibers from the proximal aorta to the base of the innominate artery, care should be taken without cross clamp placement for MFS patients with MVP.[25] The presence of aortic regurgitation should be taken into account when performing cardioplegia to ensure adequate myocardial protection. Freedom from moderate or greater mitral regurgitation at 5, 10, and 20 years has been shown to be about 95%, 89%, and 69%, respectively.[26] Patients with MFS may have cardiomyopathy with biventricular enlargement and mild systolic dysfunction.[27]Patients may exhibit proximal ascending aortic dilation, dilation of the proximal main pulmonary artery, thickening and prolapse of the atrioventricular valves and mitral annular calcification.

Patients with Marfan syndrome have excess linear growth of the long bones and joint laxity. Some have reduced joint mobility, particularly of the elbow and digits. Individuals with MFS are taller than the general population.[28] They have disproportionately long extremities in comparison to the length of the trunk, or dolichostenomelia.  Patients typically have arachnodactyly with a positive thumb sign where the entire distal phalanx protrudes beyond the ulnar border of a closed fist. Patients also exhibit a positive wrist sign where the top of the thumb covers the entire fingernail of the fifth finger when wrapped around the contralateral wrist. MFS commonly exhibit either pectus carinatum or pectus excavatum. Pes planus, or flatfoot deformity, caused by ligamentous laxity, leads to longer and narrower feet than the average person.[29]

Patient present with findings diagnostic for scoliosis, including a vertical difference of equal to 1.5 cm between the ribs of the left and right hemithorax, and a Cobb’s angle of at least 20 degrees. If scoliosis is absent, exaggerated kyphotic thoracolumbar spinal curvature can be taken into account to aid in the diagnosis of MFS. Radiographic findings of MFS scoliosis are indistinguishable from those of adolescent idiopathic scoliosis (AIS). Scoliosis associated with MFS is less responsive to a brace; therefore, a brace is only utilized in skeletally immature patients with scoliotic curves less than 25 degrees.[30] Surgery should be considered in patients with curves greater than 45 degrees, although it is associated with higher revision and complication rates as opposed to AIS.[31] In a retrospective, case-controlled study by Gjolaj et al.,[32] patients with MFS scoliosis had higher rates of cerebrospinal fluid leaks, an increased likelihood of complications related to implant placement, and more surgical revisions secondary to fixation failure and a spinal fracture. Studies have also reported higher blood loss and longer operative times than in patients with AIS.[33][34] Surgeons must also take the unique anatomic features of MFS patients into account, including narrow pedicles, wide transverse processes, and vertebral scalloping.[35]

An acetabular protrusion, or protrusio acetabuli, can be diagnosed by medial protrusion of the acetabulum equal to 3 mm beyond the ilio-ischial (Kohler) line. This reflects one of the main causes of osteoarthritis in patients with MFS. Degeneration of the hip joint is secondary to ligamentous laxity combined with this bony abnormality. Thakkar et al.[36] noted that hip dislocations are caused by impingement on the deeper acetabulum or ligamentous laxity, and implant failure may be secondary to osteoporosis or osteopenia. Annual ophthalmologic evaluation is recommended for all patients with MFS secondary to ectopia lentis which occurs in 50% to 80% of patients.[37] It is diagnosed by slit-lamp examination after maximal dilatation of the pupil; the lens is usually displaced upward and temporally. Other ocular findings in MFS include flat cornea, retinal detachment, glaucoma, and early cataract formation.[38]

Dural ectasia results from enlargement of the spinal canal secondary to vertebral bone enlargement most commonly in the lumbosacral region.[39] Dural ectasia is also seen in LDS and SGS, and the vascular form of Ehlers-Danlos syndrome. It is present in more than two-thirds of patients with MFS and commonly presents with pain.[40] Pain may be associated with periosteal pressure, erosion of lumbosacral elements, traction of the nerve roots, or sacral microfractures secondary to osteopenia. A mouse model of MFS revealed higher dural levels of TGF-ß caused by fibrillin-1 deficiency.[41]These changes increase the risk of surgical complications including spinal fracture and dural injury.

Patients with MFS develop lung bullae secondary to emphysematous pulmonary changes predominantly in the upper lobes, predisposing to spontaneous pneumothorax. Patients may exhibit skin striae, or striae atrophicae in MFS, owing to the disease as long as they are not associated with pronounced weight loss or pregnancy. Recurrent or incisional herniae and a high arched palate may occur but are not included in the systemic score since these features are considered nonspecific clinically.[42]

Evaluation

In 1996, criteria for the diagnosis of MFS were originally proposed, known as Ghent nosology. These criteria relied on major and minor clinical manifestations of the syndrome. Aortic root dilatation and ectopia lentis are cardinal features of the disease, and other systemic features involving the skeletal and cardiovascular organ systems, ocular and vertebral anomalies support the diagnosis. Major criteria included: ectopia lentis, aortic root dilatation involving the sinuses of Valsalva or aortic dissection, and lumbosacral dural ectasia by computed tomography or magnetic resonance imaging, family or genetic history, and four of eight typical skeletal manifestations. These criteria underwent revision in 2010 due to various limitations, including insufficient validation, limited applicability to children, and an inability to exclude syndromes such LDS and SGS. The 2010 revised Ghent nosology puts greater weight on aortic root dilatation/dissection and ectopia lentis as the cardinal clinical features of MFS and testing for mutations in FBN1.[42]

Systemic Score

The revised Ghent nosology includes the following scoring system for systemic features[42]

  • Wrist and thumb sign: 3 points
  • Wrist or thumb sign: 1 point
  • Pectus carinatum deformity: 2 points
  • Pectus excavatum or chest asymmetry: 1 point
  • Hindfoot deformity: 2 points
  • plain pes planus: 1 point
  • Pneumothorax: 2 points
  • Dural ectasia: 2 points
  • Protrusio acetabuli: 2 points
  • Reduced upper segment/lower segment ratio AND increased arm span/height AND no severe scoliosis: 1 point
  • Scoliosis or thoracolumbar kyphosis: 1 point
  • Reduced elbow extension (equal to 170 degrees with full extension): 1 point
  • At a minimum, 3 of the following 5 features: Dolichocephaly (reduced cephalic index or head width/length ratio), enophthalmos, down-slanting palpebral fissures, malar hypoplasia, retrognathia): 1 point
  • Skin striae: 1 point
  • Myopia greater than 3 diopters: 1 point
  • Mitral valve prolapse: 1 point
  • A systemic score equal to 7 indicates significant systemic involvement.

In patients with no family history of MFS, the presence of one of any of the following criteria is diagnostic for MFS:

  • Aortic criterion (aortic root dissection or diameter Z equal to 2) and ectopia lentis*
  • Aortic criterion (aortic root dissection or diameter Z equal to 2) and a causal FBN1 mutation
  • Aortic criterion (aortic diameter Z equal to 2 or aortic root dissection) and a systemic score equal to 7*
  • Ectopia lentis and an identified causal FBN1 mutation in an individual with an aortic aneurysm

In patients with a family history of MFS, the presence of one of any of the following criteria is diagnostic for MFS:

  • Ectopia lentis
  • Systemic score equal to  7 points*
  • Aortic criterion (aortic diameter Z equal to 3 below 20 years old, Z equal to 2 above 20 years, or aortic root dissection)*

For criteria with an asterisk (*), the diagnosis of MFS can be made only in the absence of discriminating features of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome and after TGFBR1/2, collagen biochemistry, or COL3A1 testing if indicated. Later data suggest that additional gene mutations should also be excluded, including those in SMAD3, TGFB2, and SKI.

The revised Ghent nosology recommends the following categories for individuals younger than 20 years old with features of MFS who do not meet diagnostic criteria for MFS[42]:

  • Nonspecific connective tissue disorder applies if the systemic score is less than 7 and/or aortic root measurements are borderline (Z less than 3) in the absence of an FBN1 mutation.
  • Potential MFS applies if an FBN1 mutation is identified in a sporadic or familial case but the aortic root Z-score is less than 3.

Treatment / Management

The use of beta-blockers, noninvasive monitoring, restriction of vigorous physical exercise, and elective repair of the aorta have a greatly improved prognosis. In 1968, Bentall and De Bono introduced the Bentall procedure as the standard surgical approach for patients with MFS. A Dacron conduit is attached to a mechanical aortic valve, which then replaces the dilated ascending aorta and aortic root.[43]  Both coronary arteries are then reimplanted. Multicenter studies documented an early mortality rate of 1.5% and a survival rate of 84% at five years, 75% at ten years, and 59% at 20 years. Rates of thromboembolism and endocarditis at 20 years have been 7% and 10%, respectively.[44] The mean age of surgery is 32 years old; mechanical aortic valves are the preferred device due to their longevity.

Patients require lifelong anticoagulation secondary to mechanical valve replacement. For patients in whom anticoagulation is not the recommendation, valve-sparing techniques have been adopted including the Yacoub technique and the valve reimplantation or David technique. With the Yacoub technique, the sinuses of Valsalva undergo resection and replacement with a vascular graft and coronary artery reimplantation; optimal patients have sinus and/or aortic dilation without annular dilation. The David technique involves reimplantation of the native aortic valve into a graft and is for patients with annular involvement.[45] Twenty-five percent of MFS patients undergoing valve-sparing procedures have aortic regurgitation at 10 years secondary to disease progression. Valve-sparing procedures have lower operative mortality as opposed to the Bentall procedure at 5 years, 89% vs. 96%, and reduced incidence of reoperation at five years, 92% vs. 84%.[46]

The 2010 ACC/AHA/AATS guidelines for the thoracic aortic disease include recommendations for MFS. Patients should have echocardiography performed at the time of diagnosis and 6 months later to determine aortic root and ascending aortic diameters, as well as their rate of growth.[18] To identify patients at risk for aortic dissection, regular monitoring of the aortic diameter is recommended with the use of computed tomography (CT), transthoracic echocardiography (TTE), and magnetic resonance imaging (MRI).[47] These imaging modalities provide information as to the classification, origin, and extent of dissection, potential areas of hemorrhage and other sequelae. Spiral CT angiography is the most frequently used modality worldwide for diagnosing TAAs and the degree of aneurysmal dilatation. CT limitations include aortic artifact secondary to cardiac motion and implanted devices. Iodinated contrast-induced nephropathy can also occur in selected patients, and the use of repeated episodes of ionizing radiation exposure should be weighed in pediatric patients who will require multiple scans in their lifetime. A Z-score, which designates a number of standard deviations from the mean for appropriate age and size matched the normal population, should be used to monitor aortic diameter via CT scan serially. MRI is an alternative to CT in stable patients with suspected thoracic aortic disease, providing information on aortic morphology, ventricular dimension and function, and valvular regurgitation. MRI also allows monitoring of systemic manifestations of MFS including dural ectasia, scoliosis, chest deformities, and protrusio acetabuli.

TTE is the primary modality in the diagnosis of MFS, although TEE is utilized in situations of suspected dissection to measure the maximal dimension of the aortic root with the parasternal long axis view. The leading-edge-to-leading-edge technique in diastole is implemented in adults, while the inner-edge-to-inner-edge technique in systole, is utilized amongst pediatric cardiologists. For MFS, aortic diameter at the sinuses of Valsalva is the key measurement since this is at greatest risk for aortic dissection, and monitoring is via echocardiography. A greater length of aortic dilation is associated with a worse prognosis.[48] Aortic root measurements should be parallel to the plane of the aortic valve and perpendicular to the axis of blood flow in end-diastole.

In a retrospective analysis of 140 MFS patients with FBN1 mutations who had undergone routine thoracoabdominal CT or MRI as part of their follow-up, about one third had incidental findings of peripheral vascular aneurysms, with 55% of these patients requiring intervention.[49] Another prospective series systematically examined the supra-aortic trunks, the arteries of the upper and lower extremities, the aortoiliac arteries, and the visceral branches of the abdominal aorta in 21 MFS patients. Ten (67%) had peripheral vascular arterial aneurysms, and 2 patients underwent semi-urgent repair.[50]

When ascending aortic dimensions are stable, and there is no identified aortic disease, cross-sectional imaging is repeated every three to five years and prior to elective operation, and annually if the aortic diameter is less than 45 mm. However, if the aortic diameter is 45 mm or is enlarging, more frequent imaging is suggested, up to twice annually, and may indicate the need for surgery. More frequent imaging is also prudent if the aortic diameter shows rapid change (equal to 0.5 cm per year) or if the heart or valve function is circumspect.[42] In the pediatric population with MFS, annual imaging the recommendation if aortic size is stable and not markedly enlarged. Since there are no validated age-specific aortic diameters that can be used to determine imaging intervals, aortic measurement comparisons should use body surface area. Individuals under 20 years of age with systemic findings suggestive of MFS, should have annual echocardiograms due to the potential risk of aortic disease.[42]

As noted in the 2010 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery (ACC/AHA/AATS) thoracic aorta guidelines, beta blockers are recommended in adults with MFS and aortic aneurysm to lower the rate of aortic dilatation.[18] Beta-blockers decrease myocardial contractility and pulse pressure and may improve the elastic properties of the aorta in patients with an aortic root diameter less than 40 mm.[51] Medication is recommended in patients with aortic root enlargement, a family history of aortic root enlargement, or a mutation previously associated with aortic disease. Dosing adjustments should be made to maintain the heart rate after submaximal exercise to less than 100 beats/minute in adults and less than 110 beats/minute in children.[42] Although propranolol was the first beta-blocker demonstrated to slow aortic dilation, longer acting agents such as atenolol and metoprolol are also options. Labetalol is used among pregnant women because atenolol may impair fetal growth.

Beta-blocker therapy is also recommended for children with MFS and aortic aneurysm, though data in children is inconclusive. In an observational study, 44 children and adolescents with MFS were followed for almost 4 years.[52] The 20 patients on beta-blocker therapy and the 6 patients taking a calcium channel blocker had a slower absolute aortic growth rate. In a retrospective study of 63 children in which compared beta-blocker therapy to no therapy,[53] there was no significant variation in the rate of change in aortic root measurements between the 2 groups at the study's end, and there were more side effects in treated patients.

While data are limited, the addition of an angiotensin II receptor blocker as tolerated to beta-blocker therapy may slow the rate of aortic root dilation in patients with MFS as evidenced in the 2010 ACC/AHA/AATS guidelines. Renin-angiotensin system blockers may alleviate the clinical manifestations of MFS by blocking TGF-beta signaling.[13] The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in MFS are attributed to central blood pressure control and the reduction of aortic wall stiffness.[54] In a 2005 nonrandomized study, MFS patients treated with ACE inhibition showed improved outcomes regarding aortic growth rate as compared to those treated with beta-adrenergic blocker therapy over three years.[14] Angiotensin II stimulates the proliferation of smooth muscle cells, increases fibrosis, attenuates the expression of MMP-2 and MMP-9, and reduces apoptosis through binding to the angiotensin type 1 (AT1)receptors in the aortic wall. Data from animal models suggest that AT1 receptor antagonists reduces TGF-beta levels and can prevent the pathogenesis of MFS. Chiu et al.,[55] have shown that losartan in combination with beta-blockade slows the progression of aortic root dilation more than beta-blockade alone in patients with MFS. Groenink et al.[56] provided additional evidence in the adult MFS population that losartan delays aortic root dilation of a native aortic root and decreases aortic arch dilation in a patient with prior aortic root replacement.

A randomized trial comparing losartan with atenolol in 608 children and adults with MFS and aortic Z-scores greater than 3.0 found no significant difference in the rate of aortic root dilation between the 2 treatment groups over 3 years.[57] A comparable and significant decline in aortic root dilation relative to body surface area occurred with both treatments. The 3-year rates of aortic root surgery, aortic dissection, and death were similar in the losartan and atenolol treatment groups. There is scant evidence regarding the efficacy of ACE inhibitor therapy in patients with MFS.[58] A small randomized trial comparing perindopril with placebo (in addition to standard beta-blocker therapy) was retracted.[59] Although no other drug therapy has been officially established,  statins may attenuate aortic root dilation in a mouse model of Marfan syndrome by reducing the activity of vascular smooth muscle cells in the Marfan aorta.[60]

Both 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. Patients with Marfan syndrome and other forms of thoracic aortic aneurysm taking calcium channel blockers have an increased risk of aortic dissection and the need for aortic surgery.[61] An American Heart Association expert panel recommends low to moderate intensity exercise (approximately 4 to 6 metabolic equivalents), for most patients with MFS, although those with aortic root and/or valve replacement may tolerate less.[62] MFS patients should avoid contact sports, exercise to exhaustion, and isometric activities that include the Valsalva maneuver.[42]

Elective replacement of aortic root disease in advance of critical enlargement has been shown to be integral as illustrated in a series of 675 patients with MFS from Johns Hopkins in which the 30-day mortality for elective, urgent (within 7 days of surgical consultation), or emergency repair (within 24 hours of consultation) was 1.5%, 2.6%, and 11.7%, respectively.[63] In another review, the actuarial survival at 5, 10, and 20 years of 231 patients who underwent elective aortic root replacement at Johns Hopkin's was 88%, 81%, and 75%, respectively.[64] The 2010 ACC/AHA/AATS guidelines recommend an elective operation for patients with MFS at an external diameter of equal to 50 mm to avoid acute dissection or rupture.[18] Indications for surgical repair at an external diameter less than 50 mm include rapid growth (greater than 5 mm per year), family history of an aortic dissection at a diameter less than 50 mm, or presence of progressive aortic valve regurgitation. The guidelines indicate if the maximal cross-sectional area (square centimeters) of the ascending aorta or root, divided by the patient's height in meters is greater than 10, surgical repair is appropriate.[65] In the pediatric population, dissection is rare; therefore surgical indications include aneurysms that show rapid enlargement (greater than 10 mm per year) and progressive aortic insufficiency.[66]

There is conflicting data on the safety profile of pregnant women with MFS. The 2010 thoracic aortic disease guidelines urge pregnancy avoidance if the aortic root diameter exceeds 40 mm and further recommend prophylactic aortic root replacement in women who will attempt pregnancy.  The European and Canadian guidelines report an aortic root diameter of 45 mm to be considered safe. In a 2012 study, there was a significantly higher rate of aortic growth documented during pregnancy than at baseline.[67] In previously pregnant women, adverse outcomes and elective aortic surgery during long-term follow-up were more common than in women who remained childless. In women devoid of cardiac complications with MFS, pregnancy is well tolerated up to an aortic root diameter of 45 mm, with proper clinical care. In the same vein, pregnancy should be strongly discouraged in women with a history of aortic dissection secondary to the high risk of aortic complications.[68]

Differential Diagnosis

  • Loeys-Dietz syndrome (LDS)
  • Shprintzen-Goldberg syndrome (SGS)
  • MASS phenotype*      
  • Mitral valve prolapse syndrome
  • Congenital contractural arachnodactyly (CCA)
  • Weill-Marchesani syndrome (WMS)   
  • Ectopia lentis syndrome (ELS)
  • Familial thoracic aortic aneurysm and dissection syndrome (FTAAD/FTAA)
  • FTAAD with bicuspid aortic valve 
  • FTAAD with patent ductus arteriosus
  • Homocystinuria
  • Arterial tortuosity syndrome (ATS)
  • Ehlers-Danlos syndrome (vascular type)         
  • Ehlers-Danlos syndrome (cardiac valvular subtype)    
  • Stickler syndrome (hereditary arthro-ophthalmopathy)
  • Klinefelter syndrome
  • Congenital bicuspid aortic valve disease with associated aortopathy    
  • Aortic coarctation with associated ascending aortic enlargement         
  • Congenital bicuspid aortic valve disease with associated aortopathy
  • Aortic coarctation with associated ascending aortic enlargement
  • Familial thoracic aortic aneurysm or aortopathy

Prognosis

The lifespan of untreated patients with the classic MFS was approximately 32 years in 1972 but has markedly increased to 72 years in 1993.[69][70] Beta-blockers, noninvasive aortic imaging, and elective aortic root repair have all contributed to an improvement in survival. Life expectancy is significantly lower in men than in women.

Complications

  • Aortic aneurysm and dissection
  • Mitral valve prolapse
  • Mitral regurgitation
  • Aortic regurgitation
  • Lens subluxation (ectopia lentis)
  • Cataract, glaucoma, and retinal detachment
  • Spontaneous pneumothorax
  • Inguinal hernias
  • Scoliosis

Consultations

Consultation with a cardiothoracic surgeon should be scheduled in patients whose aortic diameter is more than 4 cm. Genetic counselor consultation is also beneficial. MFS patients who are pregnant should consult a high-risk obstetrician. Ophthalmologic consultation is a strong consideration in patients who have a cataract, glaucoma, lens subluxation (ectopia lentis) and retinal detachment.

Deterrence and Patient Education

MFS may create a substantial mental and physical burden on the patient, with different areas of concern for each person. According to Rao et al.,[71] in the United States, the quality of life of patients with MFS is lower than that of control subjects without the disease. Pain is one of the most common concerns for patients with MFS. A recent systematic review of the literature estimated that the prevalence of pain in these patients is 47% to 92%.[72] Adults with MFS report limited physical capacity, reduced endurance, and ultimately, depression and anxiety. Through appropriate diagnosis and treatment, along with timely rehabilitation, patients are better able to lead productive lives. Optimal treatment of chronic pain in patients with MFS should be a focus of future research.

Pearls and Other Issues

  1. The basis of a diagnosis of MFS is upon the presence of characteristic manifestations, particularly aortic root dilatation/dissection and ectopia lentis, skeletal findings, mitral valve prolapse, dural ectasia, pneumothorax, and skin striae.
  2. Over 90% of patients with MFS have had FBN1 mutations identified.
  3. Application of diagnostic criteria to individuals younger than 20 years old can be challenging because not all clinical features may exhibit themselves.
  4. The aortic root Z-score is used to identify aortic dilatation in association with body size.
  5. First-degree relatives of patients with a gene mutation associated with aortic aneurysms and/or dissection (e.g., FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, MYH11) should undergo counseling, genetic testing and potentially aortic imaging.[42]

Enhancing Healthcare Team Outcomes

Management of MFS and its related complications involves a multidisciplinary effort by physicians including the patient's primary care physician/pediatrician and with appropriate referrals to a cardiologist, cardiothoracic surgeon, ophthalmologist, and orthopedics. Care coordination should take place between the different physicians as well as with the nurses taking care of these patients so that they can quickly report any potential complications. Pharmacists should be aware of medications that should require avoidance in patients with MFS. Physical therapists should be involved in guiding MFS patients on appropriate exercise activities which should not include high-intensity exercises.


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A 17-year-old is seen because his chest x-ray revealed an enlarged cardiac silhouette. The individual has no major complaints except that in the past he had some type of a tube placed in his chest. Examination reveals that he is tall, thin individual and auscultation reveals that he has a systolic click with a possible murmur. Which of the following genes is responsible for these findings?



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What cardiac disorder is most commonly seen in Marfanoid patients?



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A 17-year-old with an inherited disorder is a tall, thin male who had a pneumothorax 2 months ago. Auscultation reveals that the chest is clear, but he has a "clicking" sound in his heart. He most likely has which of the following conditions?



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Which group of drugs has been shown to be most beneficial in Marfan syndrome?



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What cardiovascular complication in patients with Marfan syndrome is the most likely cause of morbidity and mortality?



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Which is NOT a feature of Marfan syndrome?



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Which of the following heart defects is most likely in patients with Marfan syndrome?



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Patients with which condition might develop mucoid medial degeneration?



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In patients with Marfan syndrome, for which of the following cardiac conditions should be screened on a regular basis?



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A 12-year-old male is very tall, thin, and has mild scoliosis. Also noted is a high arched palate and joint hyperextensibility. He is a good student and must wear glasses as he had to have eye surgery for subluxation of the lenses. What is the most serious complication of this illness?



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A 21-year old tall male is in the clinic following a referral for pectus excavatum. The patient has extremely long arms with hypermobile joints. Last year he was diagnosed with mitral valve prolapse but has no symptoms. Which statement is false about patients who have this syndrome?



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A 21-year-old male presents to his primary care provider for a routine check-up. He has no complaints. He was referred to see a primary care doctor by his ophthalmologist after he was diagnosed with nearsightedness. On examination, he is 6 feet and 7 inches in tall, arms that are disproportionately long when compared to his lower extremities, has spider-like toes and fingers, feet are flat. He also has scoliosis. On listening to his chest at the apex area, he has a characteristic a mid-systolic click, followed by a late systolic murmur. What is the most characteristic finding of this murmur?



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Marfan Syndrome - References

References

Robinson PN,Arteaga-Solis E,Baldock C,Collod-Béroud G,Booms P,De Paepe A,Dietz HC,Guo G,Handford PA,Judge DP,Kielty CM,Loeys B,Milewicz DM,Ney A,Ramirez F,Reinhardt DP,Tiedemann K,Whiteman P,Godfrey M, The molecular genetics of Marfan syndrome and related disorders. Journal of medical genetics. 2006 Oct     [PubMed]
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Januzzi JL,Isselbacher EM,Fattori R,Cooper JV,Smith DE,Fang J,Eagle KA,Mehta RH,Nienaber CA,Pape LA, Characterizing the young patient with aortic dissection: results from the International Registry of Aortic Dissection (IRAD). Journal of the American College of Cardiology. 2004 Feb 18     [PubMed]
Hiratzka LF,Bakris GL,Beckman JA,Bersin RM,Carr VF,Casey DE Jr,Eagle KA,Hermann LK,Isselbacher EM,Kazerooni EA,Kouchoukos NT,Lytle BW,Milewicz DM,Reich DL,Sen S,Shinn JA,Svensson LG,Williams DM, 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation. 2010 Apr 6     [PubMed]
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Rybczynski M,Mir TS,Sheikhzadeh S,Bernhardt AM,Schad C,Treede H,Veldhoen S,Groene EF,Kühne K,Koschyk D,Robinson PN,Berger J,Reichenspurner H,Meinertz T,von Kodolitsch Y, Frequency and age-related course of mitral valve dysfunction in the Marfan syndrome. The American journal of cardiology. 2010 Oct 1     [PubMed]
Faivre L,Collod-Beroud G,Loeys BL,Child A,Binquet C,Gautier E,Callewaert B,Arbustini E,Mayer K,Arslan-Kirchner M,Kiotsekoglou A,Comeglio P,Marziliano N,Dietz HC,Halliday D,Beroud C,Bonithon-Kopp C,Claustres M,Muti C,Plauchu H,Robinson PN,Adès LC,Biggin A,Benetts B,Brett M,Holman KJ,De Backer J,Coucke P,Francke U,De Paepe A,Jondeau G,Boileau C, Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. American journal of human genetics. 2007 Sep     [PubMed]
Roman MJ,Devereux RB,Kramer-Fox R,Spitzer MC, Comparison of cardiovascular and skeletal features of primary mitral valve prolapse and Marfan syndrome. The American journal of cardiology. 1989 Feb 1     [PubMed]
Moon J,Shin MS,Lee HJ,Chung WJ,Park CH,Park KY, Newly developed aortic dissection after aorta cannulation during mitral valve surgery in a patient with marfan syndrome. Korean circulation journal. 2012 Jun     [PubMed]
David TE,Armstrong S,McCrindle BW,Manlhiot C, Late outcomes of mitral valve repair for mitral regurgitation due to degenerative disease. Circulation. 2013 Apr 9     [PubMed]
Alpendurada F,Wong J,Kiotsekoglou A,Banya W,Child A,Prasad SK,Pennell DJ,Mohiaddin RH, Evidence for Marfan cardiomyopathy. European journal of heart failure. 2010 Oct     [PubMed]
Erkula G,Jones KB,Sponseller PD,Dietz HC,Pyeritz RE, Growth and maturation in Marfan syndrome. American journal of medical genetics. 2002 Apr 22     [PubMed]
Lindsey JM,Michelson JD,MacWilliams BA,Sponseller PD,Miller NH, The foot in Marfan syndrome: clinical findings and weight-distribution patterns. Journal of pediatric orthopedics. 1998 Nov-Dec     [PubMed]
Shirley ED,Sponseller PD, Marfan syndrome. The Journal of the American Academy of Orthopaedic Surgeons. 2009 Sep     [PubMed]
Demetracopoulos CA,Sponseller PD, Spinal deformities in Marfan syndrome. The Orthopedic clinics of North America. 2007 Oct     [PubMed]
Gjolaj JP,Sponseller PD,Shah SA,Newton PO,Flynn JM,Neubauer PR,Marks MC,Bastrom TP, Spinal deformity correction in Marfan syndrome versus adolescent idiopathic scoliosis: learning from the differences. Spine. 2012 Aug 15     [PubMed]
Jones KB,Erkula G,Sponseller PD,Dormans JP, Spine deformity correction in Marfan syndrome. Spine. 2002 Sep 15     [PubMed]
Liang W,Yu B,Wang Y,Li Z,Qiu G,Shen J,Zhang J, Comparison of posterior correction results between Marfan syndrome scoliosis and adolescent idiopathic scoliosis-a retrospective case-series study. Journal of orthopaedic surgery and research. 2015 May 21     [PubMed]
Sponseller PD,Hobbs W,Riley LH 3rd,Pyeritz RE, The thoracolumbar spine in Marfan syndrome. The Journal of bone and joint surgery. American volume. 1995 Jun     [PubMed]
Thakkar SC,Foran JR,Mears SC,Sponseller PD, Protrusio acetabuli and total hip arthroplasty in patients with Marfan syndrome. The Journal of arthroplasty. 2012 May     [PubMed]
Tsipouras P,Del Mastro R,Sarfarazi M,Lee B,Vitale E,Child AH,Godfrey M,Devereux RB,Hewett D,Steinmann B, Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. The International Marfan Syndrome Collaborative Study. The New England journal of medicine. 1992 Apr 2     [PubMed]
Heur M,Costin B,Crowe S,Grimm RA,Moran R,Svensson LG,Traboulsi EI, The value of keratometry and central corneal thickness measurements in the clinical diagnosis of Marfan syndrome. American journal of ophthalmology. 2008 Jun     [PubMed]
Pyeritz RE,Fishman EK,Bernhardt BA,Siegelman SS, Dural ectasia is a common feature of the Marfan syndrome. American journal of human genetics. 1988 Nov     [PubMed]
Foran JR,Pyeritz RE,Dietz HC,Sponseller PD, Characterization of the symptoms associated with dural ectasia in the Marfan patient. American journal of medical genetics. Part A. 2005 Apr 1     [PubMed]
Jones KB,Myers L,Judge DP,Kirby PA,Dietz HC,Sponseller PD, Toward an understanding of dural ectasia: a light microscopy study in a murine model of Marfan syndrome. Spine. 2005 Feb 1     [PubMed]
Loeys BL,Dietz HC,Braverman AC,Callewaert BL,De Backer J,Devereux RB,Hilhorst-Hofstee Y,Jondeau G,Faivre L,Milewicz DM,Pyeritz RE,Sponseller PD,Wordsworth P,De Paepe AM, The revised Ghent nosology for the Marfan syndrome. Journal of medical genetics. 2010 Jul     [PubMed]
Cameron DE,Alejo DE,Patel ND,Nwakanma LU,Weiss ES,Vricella LA,Dietz HC,Spevak PJ,Williams JA,Bethea BT,Fitton TP,Gott VL, Aortic root replacement in 372 Marfan patients: evolution of operative repair over 30 years. The Annals of thoracic surgery. 2009 May     [PubMed]
Geisbuesch S,Schray D,Bischoff MS,Lin HM,Di Luozzo G,Griepp RB, Frequency of reoperations in patients with Marfan syndrome. The Annals of thoracic surgery. 2012 May     [PubMed]
David TE,Armstrong S,Manlhiot C,McCrindle BW,Feindel CM, Long-term results of aortic root repair using the reimplantation technique. The Journal of thoracic and cardiovascular surgery. 2013 Mar     [PubMed]
Patel ND,Weiss ES,Alejo DE,Nwakanma LU,Williams JA,Dietz HC,Spevak PJ,Gott VL,Vricella LA,Cameron DE, Aortic root operations for Marfan syndrome: a comparison of the Bentall and valve-sparing procedures. The Annals of thoracic surgery. 2008 Jun     [PubMed]
Alamri HS,Alotaiby M,Almoghairi A,El Oakley RM, Lessons from the SYNTAX trial. Journal of the Saudi Heart Association. 2010 Apr     [PubMed]
Roman MJ,Rosen SE,Kramer-Fox R,Devereux RB, Prognostic significance of the pattern of aortic root dilation in the Marfan syndrome. Journal of the American College of Cardiology. 1993 Nov 1     [PubMed]
Yetman AT,Roosevelt GE,Veit N,Everitt MD, Distal aortic and peripheral arterial aneurysms in patients with Marfan syndrome. Journal of the American College of Cardiology. 2011 Dec 6     [PubMed]
Gaertner S,Alembik Y,Cordeanu EM,Dollfus H,Lejay A,Chakfe N,Stephan D, Should we systematically screen for peripheral arterial aneurysms in all patients with Marfan syndrome? International journal of cardiology. 2014     [PubMed]
Groenink M,de Roos A,Mulder BJ,Spaan JA,van der Wall EE, Changes in aortic distensibility and pulse wave velocity assessed with magnetic resonance imaging following beta-blocker therapy in the Marfan syndrome. The American journal of cardiology. 1998 Jul 15     [PubMed]
Rossi-Foulkes R,Roman MJ,Rosen SE,Kramer-Fox R,Ehlers KH,O'Loughlin JE,Davis JG,Devereux RB, Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome. The American journal of cardiology. 1999 May 1     [PubMed]
Selamet Tierney ES,Feingold B,Printz BF,Park SC,Graham D,Kleinman CS,Mahnke CB,Timchak DM,Neches WH,Gersony WM, Beta-blocker therapy does not alter the rate of aortic root dilation in pediatric patients with Marfan syndrome. The Journal of pediatrics. 2007 Jan     [PubMed]
Yetman AT,Bornemeier RA,McCrindle BW, Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. The American journal of cardiology. 2005 May 1     [PubMed]
Chiu HH,Wu MH,Wang JK,Lu CW,Chiu SN,Chen CA,Lin MT,Hu FC, Losartan added to β-blockade therapy for aortic root dilation in Marfan syndrome: a randomized, open-label pilot study. Mayo Clinic proceedings. 2013 Mar     [PubMed]
Groenink M,den Hartog AW,Franken R,Radonic T,de Waard V,Timmermans J,Scholte AJ,van den Berg MP,Spijkerboer AM,Marquering HA,Zwinderman AH,Mulder BJ, Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. European heart journal. 2013 Dec     [PubMed]
Lacro RV,Dietz HC,Sleeper LA,Yetman AT,Bradley TJ,Colan SD,Pearson GD,Selamet Tierney ES,Levine JC,Atz AM,Benson DW,Braverman AC,Chen S,De Backer J,Gelb BD,Grossfeld PD,Klein GL,Lai WW,Liou A,Loeys BL,Markham LW,Olson AK,Paridon SM,Pemberton VL,Pierpont ME,Pyeritz RE,Radojewski E,Roman MJ,Sharkey AM,Stylianou MP,Wechsler SB,Young LT,Mahony L, Atenolol versus losartan in children and young adults with Marfan's syndrome. The New England journal of medicine. 2014 Nov 27     [PubMed]
Williams A,Kenny D,Wilson D,Fagenello G,Nelson M,Dunstan F,Cockcroft J,Stuart G,Fraser AG, Effects of atenolol, perindopril and verapamil on haemodynamic and vascular function in Marfan syndrome - a randomised, double-blind, crossover trial. European journal of clinical investigation. 2012 Aug     [PubMed]
Notice of Retraction: Ahimastos AA, et al. Effect of Perindopril on Large Artery Stiffness and Aortic Root Diameter in Patients With Marfan Syndrome: A Randomized Controlled Trial. JAMA. 2007;298(13):1539-1547. JAMA. 2015 Dec 22-29     [PubMed]
McLoughlin D,McGuinness J,Byrne J,Terzo E,Huuskonen V,McAllister H,Black A,Kearney S,Kay E,Hill AD,Dietz HC,Redmond JM, Pravastatin reduces Marfan aortic dilation. Circulation. 2011 Sep 13     [PubMed]
Doyle JJ,Doyle AJ,Wilson NK,Habashi JP,Bedja D,Whitworth RE,Lindsay ME,Schoenhoff F,Myers L,Huso N,Bachir S,Squires O,Rusholme B,Ehsan H,Huso D,Thomas CJ,Caulfield MJ,Van Eyk JE,Judge DP,Dietz HC, A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. eLife. 2015 Oct 27     [PubMed]
Maron BJ,Chaitman BR,Ackerman MJ,Bayés de Luna A,Corrado D,Crosson JE,Deal BJ,Driscoll DJ,Estes NA 3rd,Araújo CG,Liang DH,Mitten MJ,Myerburg RJ,Pelliccia A,Thompson PD,Towbin JA,Van Camp SP, Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. 2004 Jun 8     [PubMed]
Gott VL,Greene PS,Alejo DE,Cameron DE,Naftel DC,Miller DC,Gillinov AM,Laschinger JC,Pyeritz RE, Replacement of the aortic root in patients with Marfan's syndrome. The New England journal of medicine. 1999 Apr 29     [PubMed]
Gott VL, Antoine Marfan and his syndrome: one hundred years later. Maryland medical journal (Baltimore, Md. : 1985). 1998 Nov     [PubMed]
Svensson LG,Khitin L, Aortic cross-sectional area/height ratio timing of aortic surgery in asymptomatic patients with Marfan syndrome. The Journal of thoracic and cardiovascular surgery. 2002 Feb     [PubMed]
Zanotti G,Vricella L,Cameron D, Thoracic aortic aneurysm syndrome in children. Seminars in thoracic and cardiovascular surgery. Pediatric cardiac surgery annual. 2008     [PubMed]
Donnelly RT,Pinto NM,Kocolas I,Yetman AT, The immediate and long-term impact of pregnancy on aortic growth rate and mortality in women with Marfan syndrome. Journal of the American College of Cardiology. 2012 Jul 17     [PubMed]
Tang GH,Malekan R,Lansman SL,Spielvogel D, Aortic valve-sparing reimplantation and mitral repair in a pregnant, second trimester Marfan patient: surgical decision. The Annals of thoracic surgery. 2013 Feb     [PubMed]
Finkbohner R,Johnston D,Crawford ES,Coselli J,Milewicz DM, Marfan syndrome. Long-term survival and complications after aortic aneurysm repair. Circulation. 1995 Feb 1     [PubMed]
Silverman DI,Burton KJ,Gray J,Bosner MS,Kouchoukos NT,Roman MJ,Boxer M,Devereux RB,Tsipouras P, Life expectancy in the Marfan syndrome. The American journal of cardiology. 1995 Jan 15     [PubMed]
Rao SS,Venuti KD,Dietz HC 3rd,Sponseller PD, Quantifying Health Status and Function in Marfan Syndrome. Journal of surgical orthopaedic advances. 2016 Spring     [PubMed]
Velvin G,Bathen T,Rand-Hendriksen S,Geirdal AØ, Systematic review of chronic pain in persons with Marfan syndrome. Clinical genetics. 2016 Jun     [PubMed]

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