Marfan syndrome | Journal of MEDICAL SCIENCES

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https://doi.org/10.53453/ms.2023.6.10

Marfan syndrome: current diagnostic and management strategy

Edvinas Ščefanavičius

, Aistė Šalkauskaitė-Rubliauskienė

Lithuanian University of Health Sciences Kauno klinikos, Department of Cardiology, Kaunas, Lithuania

Abstract

Background. Marfan syndrome (MFS) is a rare genetic disorder and affects connective tissue throughout the body,

leading to a variety of symptoms that can vary in severity, including skeletal, ocular, and cardiovascular systems, as

well as pulmonary, gastrointestinal, and other systems. The pathogenesis of Marfan syndrome is complex and involves

alterations in the structure and function of connective tissue throughout the body.

Aim. To review the genetic, clinical manifestations, and current therapeutic options of Marfan syndrome.

Methods. The literature used for this review was selected using “Google Scholar”, “Pubmed”, “UptoDate” databases.

The search was performed using the following keywords and their combinations: Marfan syndrome, Marfan syndrome

management, Marfan syndrome genetics, cardiovascular symptoms in patiens with Marfan syndrome.

Results. Marfan syndrome is a rare genetic disorder affecting approximately 1 in 5,000 individuals worldwide. The

disease is inherited in an autosomal dominant manner and caused by mutations in the gene encoding the protein

fibrillin-1. One important pathway of pathogenesis is the dysregulation of transforming growth factor-beta signaling,

which contributes to the development of connective tissue abnormalities. Another important pathway is oxidative

stress that can contribute to the dysregulation of TGF-β signaling, further exacerbating connective tissue

abnormalities. Genetic tests and the updated Ghent criteria are used to make the diagnosis. The cardiovascular risks

of aortic dilatation and dissection are linked to MFS. Therefore, controlling blood pressure with beta-blockers is the

primary objective of medical therapy. Patient should undergo surgery when aortic root maximal diameter is ≥ 50 mm

or ≥ 45 mm, when there are additional risk factors.

Conclusions. MFS is autosomal dominant connective tissue disorder, affecting mainly the cardiovascular system,

eyes, and skeleton. Early diagnosis, medical treatment to delay the progression of aortic dilatation or possibly halt the

pathologic process in the aortic wall, as well as timely elective surgery are the key measures to improve the outcome

of this disease as well as the quality of live for affected individuals. Ongoing research is needed to further understand

the underlying molecular mechanisms of Marfan syndrome and to develop more effective treatments for this complex

disorder.

Keywords: Marfan syndrome, Marfan syndrome management, Marfan syndrome genetics, cardiovascular symptoms

in patiens with Marfan syndrome, Marfan syndrome ESC.

Journal of Medical Sciences. 26 Jun, 2023 - Volume 11 | Issue 5. Electronic - ISSN: 2345-0592

Medical Sciences 2023 Vol. 11 (5), p. 79-85, https://doi.org/10.53453/ms.2023.6.10

1. Introduction

Marfan syndrome is a genetic disorder that affects the

connective tissue in the body. It is caused by mutations

in the fibrillin-1 gene and is inherited in an autosomal

dominant manner. Individuals with Marfan syndrome

may manifest a range of physical characteristics, such

as tall stature, long limbs, and a curved spine.

Additionally, Marfan syndrome can affect the heart,

eyes, and other organs, leading to serious health

complications if left untreated. Despite its prevalence

of 1 in 5,000 individuals, there is still much to be

understood about the underlying molecular

mechanisms and clinical management of this disorder.

In this paper, we aim to provide a comprehensive

overview of Marfan syndrome, including its genetic

basis, clinical manifestations, and current therapeutic

options.

2. Methods

The literature used for this review was selected using

“Google Scholar”, “Pubmed”, “UptoDate” databases.

The search was performed using the following

keywords and their combinations: Marfan syndrome,

Marfan syndrome management, Marfan syndrome

genetics, cardiovascular symptoms in patiens with

Marfan syndrome, Marfan syndrome ESC.

3. Results

3.1. Epidemiology

Marfan Syndrome (MFS) is a rare genetic disorder that

affects approximately 1 in 5,000 to 10,000 individuals

worldwide [1]. It is considered an autosomal dominant

condition, meaning that an affected individual has a

50 % chance of passing the disease-causing mutation

to each of their offspring. The incidence of MFS

appears to be similar across different ethnic and racial

groups [2].

While MFS is a rare disease, it is more common in

certain populations. For example, a study conducted in

Japan found a higher prevalence of MFS among

patients with aortic dissection compared to the general

population, with an estimated incidence of 1 in 3,792

individuals [3]. Additionally, a population-based

study in Denmark found an increased incidence of

MFS among individuals of Faroese descent [4]. These

findings suggest that there may be certain populations

at a higher risk for MFS, although further research is

needed to confirm these observations.

MFS can affect both males and females equally, and

symptoms typically appear during adolescence or

early adulthood [5]. However, the severity of MFS

symptoms can vary widely among affected

individuals, even within the same family. This

variability is partly due to differences in the location

and nature of the disease-causing mutation [6].

3.2. Pathogenesis

The pathogenesis of Marfan Syndrome is complex and

involves alterations in the structure and function of

connective tissue throughout the body [7]. MFS is

caused by mutations in the gene encoding the protein

fibrillin-1 (FBN1), which is an essential component of

the extracellular matrix (ECM) [8] and the gene is

found in the Chromosome 15. Fibrillin-1 is mainly

found in elastic fibers, which provide elasticity and

structural support to tissues such as the skin, lungs, and

blood vessels.

Mutations in FBN1 lead to the production of abnormal

fibrillin-1, which can result in the formation of an

abnormal ECM. This, in turn, leads to the

characteristic features of MFS, including skeletal

abnormalities, ocular complications, and

cardiovascular manifestations [6]. In addition to

FBN1, other genes have been implicated in the

Journal of Medical Sciences. 26 Jun, 2023 - Volume 11 | Issue 5. Electronic - ISSN: 2345-0592

pathogenesis of MFS, including TGFBR1, TGFBR2,

SMAD3, and COL3A1 [1].

The pathophysiology of MFS is complex and involves

multiple biological pathways. One important pathway

is the dysregulation of transforming growth factor-

beta (TGF-β) signaling, which plays a critical role in

the development and maintenance of connective

tissue. Mutations in FBN1 and other genes involved in

MFS can lead to excessive TGF-β signaling, which

contributes to the development of connective tissue

abnormalities [9].

Another important pathway in the pathogenesis of

MFS is oxidative stress. Studies have shown that

individuals with MFS have increased oxidative stress,

which can lead to tissue damage and dysfunction [10].

Oxidative stress can also contribute to the

dysregulation of TGF-β signaling, further

exacerbating connective tissue abnormalities.

The precise mechanisms by which abnormal ECM and

dysregulated TGF-β signaling lead to the

characteristic features of MFS are not fully

understood. However, it is thought that these

abnormalities lead to the progressive weakening of

connective tissue throughout the body, which can lead

to aortic aneurysms, dissections, and other

cardiovascular complications [5]. In addition,

abnormalities in connective tissue can lead to skeletal

abnormalities such as scoliosis, joint laxity, and bone

deformities [11].

3.3. Symptoms

Marfan syndrome affects connective tissue throughout

the body, therefore, leading to a variety of symptoms

that can vary in severity [9]. The symptoms incude

skeletal, ocular, and cardiovascular systems,

pulmonary, gastrointestinal and other systems.

3.3.1 Skeletal System. Skeletal features are often the

first to appear in patients with Marfan syndrome, and

can include a tall stature, long limbs, and a long,

narrow face [12]. Other skeletal abnormalities may

include scoliosis, pectus excavatum, and joint

hypermobility.

3.3.2 Ocular System. Ocular manifestations of

Marfan syndrome can include myopia, lens

dislocation, and retinal detachment [1]. Ectopia lentis,

or lens dislocation, is a hallmark feature of the disease,

occurring in up to 60 % of patients [1].

3.3.3. Cardiovascular System.Cardiovascular

manifestations of Marfan syndrome are the most

serious, and the major cause of morbidity and

mortality in affected patients [6]. The most common

cardiovascular manifestation is aortic root dilatation,

which occurs in over 90 % of patients with Marfan

syndrome [1]. This can lead to aortic dissection or

rupture, which is a life-threatening condition [13].

Other cardiovascular abnormalities that may occur in

patients with Marfan syndrome include mitral valve

prolapse, aortic regurgitation, and aortic

aneurysm [14].

3.3. 4 Pulmonary System. Marfan syndrome patients

may also experience respiratory symptoms, including

spontaneous pneumothorax. This is caused by the

weakening of lung tissue and can be a potentially life-

threatening complication.

3.3. 5 Gastrointestinal System. Gastrointestinal

symptoms may include hiatal hernia, which can cause

heartburn and difficulty swallowing [15].

3.3. 6 Other. Other less common symptoms of Marfan

syndrome include dural ectasia, which can cause back

pain and leg weakness [16], and skin manifestations

such as stretch marks and hernias [17].

3.4. Diagnosis

According to the ESC guidelines for the diagnosis and

management of Marfan syndrome, Marfan syndrome

should be diagnosed based on clinical criteria, genetic

Journal of Medical Sciences. 26 Jun, 2023 - Volume 11 | Issue 5. Electronic - ISSN: 2345-0592

testing, and imaging studies. The diagnosis should be

confirmed by a multidisciplinary team that includes

cardiologists, ophthalmologists, and geneticists.

Marfan syndrome is diagnosed using the Ghent

criteria. MFS is a multisystem disorder that typically

affects the cardiovascular system, skeletal system, and

eyes, but may also involve the central nervous system,

respiratory system, and skin. According to the 2010

revised Ghent nosology, the diagnosis of MFS can be

confirmed if there is isolated aortic root dilatation and

a pathogenic variant in the FBN1 gene is detected or if

isolated ectopia lentis is described in association with

the detection of a pathogenic variant in the FBN1 gene

in association with aortic root dilatation [18].

The main cardiovascular manifestation of MFS is

aortic root disease leading to aortic regurgitation,

aneurysmal dilatation, and dissection [19]. MFS is

found in 50 % of patients with aortic dissection

younger than 40 years of age and in only 2 % of the

elderly with aortic dissection [20]. Risk factors for

aortic dissection in MFS include upper aortic diameter

> 5 cm, rapid progression of dilation (> 0.5 cm per

year), family history of dissection, decreased

distensibility of the aorta, and moderate to severe

aortic regurgitation (31).

Echocardiography is recommended at initial diagnosis

and at six months for evaluation of the aortic root and

ascending aorta in patients with Marfan

syndrome [21]. Echocardiographic assessment of the

aortic root should include measurements at the

annulus, sinus, sinotubular junction, distal ascending,

arch, and descending thoracic aortic levels. Early and

severe disease often includes mitral valve prolapse and

regurgitation leading to dilatation, impaired left

ventricular function, and pulmonary

hypertension [18,35].

Cardiovascular magnetic resonance or computed

tomography angiography from the head to the pelvis

should be performed in every patient at baseline to

visualise the entire aorta and branching vessels [22].

Cardiac arrhythmias are common in patients with

Marfan syndrome. Holter monitoring should be

performed in symptomatic patients because

ventricular arrhythmias, conduction abnormalities,

and sudden cardiac death may occur [22]. Careful

antihypertensive drug treatment with the goal of a 24-

hour ambulatory systolic blood pressure < 130 mmHg

(110 mmHg in patients with aortic dissection) is

important.

3.5. Treatment

3.5.1 Medical therapy

Beta-blockers are recommended as initial medical

treatment for Marfan patients. The beneficial effects of

beta-blockers are the reduction of heart rate and left

ventricular ejection fraction and the risk of aortic

dissection [22,23]. For beta-blockers, dosing should be

titrated to maximum effect, usually to a resting heart

rate of < 60 bpm if blood pressure permits [23].

Moreover, studies have shown that the additional

administration of an angiotensin-2 receptor blocker

may reduce aortic root dilatation in patients with MFS.

Blockers of the renin-angiotensin system may

alleviate the clinical manifestations of MFS by

blocking TGF-beta signalling [19]. Other studies have

shown that angiotensin-converting enzyme inhibitors

(ACE) reduce aortic wall stiffness in MFS [23].

Patients with Marfan syndrome and other forms of

thoracic aortic aneurysms who take calcium channel

blockers are at increased risk for aortic dissection and

the need for aortic surgery [19,25].

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3.5.2 Surgical treatment

The 2020 ESC guidelines recommend that surgery is

indicated in patients with Marfan syndrome who have

aortic root disease with maximal aortic sinus diameter

50 mm. Indications for repair at an external diameter

less than 50 mm (aortic root diameter ≥45 mm) include

family history of dissection at a low diameter, desire

to become pregnant, systemic hypertension, rapid

growth (≥3 mm/year) [22].

Cardiac surgery replaces damaged part of aorta and

there are two general approaches used for aortic root

replacement: composite valve graft and valve-sparing

aortic root replacement.

Complete replacement of the aortic root 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) was the surgical procedure of choice for

older children and adults in the past. It should be noted

that mechanical heart valves require anticoagulation

and carry a high risk of thromboembolism and

endocarditis [26].

In patients with anatomically normal aortic valves,

valve-sparing aortic root replacement with a Dacron

prosthesis and reimplantation of the coronary arteries

into the prosthesis (David procedure) has been shown

to be an appropriate surgical procedure with good

results [4]. While anticoagulation may be

recommended for some time after surgery, lifelong

anticoagulation is not required. Therefore, valve-

sparing surgery is a good option for women who want

to become pregnant and for other patients in whom

long-term anticoagulation is contraindicated [26].

3.6. Genetics

Genetic testing is often used to confirm the diagnosis

of Marfan syndrome. If a Marfan mutation is found,

family members also should be tested. MFS is

inherited in an autosomal dominant manner.

Mutations of fibrillin-1 (FBN1) have been found in

> 90 % of cases of MFS. Fibrillin, together with

collagen and elastin, is the most important structural

component of extracellular connective tissue. FBN1 is

located on chromosome 15q21.1 and is comprised of

66 exons. The FBN1 mutation leads to increased

production of a protein called transforming growth

factor beta (TGF-β), which causes connective tissue

problems.

If the aortic root is dilated but FBN1 analysis is

negative, testing of TGFBR1 and TGFBR2 genes is

recommended.

Genetic variants in the TGFBR1 and TGFBR2 genes

have been associated with several inherited connective

tissue disorders, including thoracic aortic aneurysms

and dissections

TGFBR2 is located on chromosome 3p24.1 and

encodes the TGFBR2 protein, which forms a complex

with TGFBR1 and binds to TGF-β. This

receptor/ligand complex phosphorylates proteins that

regulate the transcription of genes related to cell

proliferation [2].

4. Conclusions

In conclusion, Marfan syndrome is a rare genetic

disorder that affects connective tissue throughout the

body, leading to a wide range of symptoms that can

vary in severity. Mutations in the FBN1 gene and

dysregulated TGF-β signaling contribute to the

pathogenesis of the disease, which can lead to

cardiovascular complications, skeletal abnormalities,

and ocular manifestations. Early diagnosis, medical

treatment to delay the progression of aortic dilatation

or possibly halt the pathologic process in the aortic

wall, as well as timely elective surgery are the key

Journal of Medical Sciences. 26 Jun, 2023 - Volume 11 | Issue 5. Electronic - ISSN: 2345-0592

measures to improve the outcome of this disease as

well as the quality of live for affected individuals.

Ongoing research is needed to further understand the

underlying molecular mechanisms of Marfan

syndrome and to develop more effective treatments for

this complex disorder.

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