Marfan Syndrome : Signs, Diagnosis, Management and Prognosis

Marfan Syndrome is an inherited, multisystem connective tissue disorder. The incidence is 1 in 10000 live births with no racial or gender preference. 25% of cases are found to be sporadic. Most inherited cases show Autosomal Dominant inheritance, with high penetrance but a variable expression. There is an old triad of Marfan Syndrome that was described some years back. Skeletal changes including long limbs and arachnodactyly, Aortic aneurysms, Reduced vision occurs due to Ectopia lentis.

Etiopathogenesis Of Marfan Syndrome

• The gene involved in more than 90% of cases is the FBN-1 gene on chromosome 15q21, comprising 65 exons. This FBN-1 gene codes for fibrillin 1 protein, an Extracellular matrix protein component. This Extracellular matrix protein is an essential component of microfibrils and elastic fiber of connective tissues. If it is absent, then the microfibril structure will be altered, and elastic fiber will get reduced, leading to the manifestation of Marfan syndrome. Nelson says more than 1000 types of mutations happen in Marfan syndrome. The majority of these mutations are missense-point mutations. 2/3rd of all mutations in Marfan syndrome are missense point  mutations, and 1/3rd of all mutations are premature termination of the peptide. It is also seen that early onset and severe Marfan Syndrome are seen when mutations involve exons 26-27 and 31-32. FBN-1 gene mutations are responsible for 90-95% of cases. However, 5-10% of cases of Marfan syndrome also arise in these patients. There is no FBN-1 gene mutation; instead, there have been other mutations, such as transforming growth factor-beta receptor mutation.

How Reduced Fibrillin 1 Cause Marfan Syndrome?

• It is reduced due to aberrant and high TGF-beta signaling production.
• Suppose there is a normal person in which TGF-beta is produced when needed. There are three forms of TGF-beta, such as TGF-beta 1, TGF-beta 2, and TGF-beta 3, all produced as inactive precursors. These are normally sequestered by fibrillin 1 in ECM. In a patient with Marfan syndrome, whenever there is a reduction in fibrillin 1, there will be fewer microfibrils to sequester the TGF-beta precursor, so there will be an inappropriate increase in the release of TGF-beta leading to increased signaling followed by the manifestation of Marfan syndrome.

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Clinical Manifestations

Skeletal System

• The most common manifestation is Dolichostenomelia which are abnormally long bones, especially in limbs compared to the trunk. This results in two problems- 1) The upper segment to lower segment ratio (US: LS) is below the -2 standard deviation of the mean for age and gender. 2)The ratio of arm span to height becomes elevated, which is more than 1.05 standard deviation.

Upper Segment: Lower Segment Ratio In Marfan Synrome

• Between the ages 0-5 years, it is less than 1. Between the ages 6-7 years, it is less than 0.95. Between the ages 8-9 years, US: LS is less than 0.9. Between the ages equal to or more than 10 years, it will be less than 0.85. Anterior chest deformities are of two types: Pectus carinatum (Pigeon-shaped chest) and  Pectus excavatum (Funnel shaped chest).

Spinal deformities most commonly found are thoracolumbar scoliosis, followed by kyphosis. Another manifestation is arachnodactyly which consists of abnormally thin, long spider-like fingers. Joint hypermobility and joint contractures are also found in these patients. Pes planus, or flat feet, are common in these individuals. In protrusion acetabuli, there is a protrusion of acetabulum into the pelvic bone. The contracture of fingers, also known as camptodactyly, and elbow contracture have also been found in patients.

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Signs Of Marfan Syndrome

The Walker Murdoch Sign

• It is also called the Wrist sign. In patients with Marfan syndrome, the thumb can touch or overlap the little finger.

The Steinberg Sign

• It is also called the Thumb sign. It is a visual sign that the thumb that other fingers should normally cover protrudes from the end due to Hyperextensibility or arachnodactyly.

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Cranio Facial Features

• These are not consistent and tend to show variability. These patients have a long, narrow skull known as dolichocephaly. They have deep-set eyes, which are said to be enophthalmos. There will be a recession of the mandible, also known as Retrognathia. They have small lower jaws known as micrognathia. Mid-face is flatter, known as malar hypoplasia. They have a high-arched palate with a downward-slanting palpebral fissure called the eyes' antimongoloid slant.

Cardiovascular System (CVS)

• Valvular Abnormalities- There are thickened atrioventricular valves and mitral valve prolapse. Mitral regurgitation, which can cause congestive cardiac failure and pulmonary hypertension leading to morbidity and mortality, is severe with the infancy onset of Marfan syndrome. Aortic root dilatation of aortic root aneurysm and aortic regurgitation is seen in later life. Arrhythmias- Supraventricular arrhythmias commonly accompany mitral regurgitation. Ventricular dysrhythmias and prolonged QTc intervals have also been proposed. Cardiomyopathy, specifically dilated cardiomyopathy, is seen due to valvular regurgitation. 
• Aortic Abnormalities and Complications- These are the most common life-threatening manifestations of Marfan syndrome. It comprises aortic aneurysm, aortic dissection, and aortic rupture(near aortic root / sinuses of Valsalva). Requires lifelong monitoring echocardiography. Dilatation of the main PA may also occur but is not associated with any serious clinical sequelae.

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Aortic Dissection In Marfan Syndrome

• The most important risk factors are maximal aortic root size and positive family history. The histology comprises cystic medial necrosis of the tunica media and disruption of elastic lamellae. It presents acutely as severe chest pain radiating to the back. It starts from the aortic root and remains confined to ascending aorta type 1 or may reach descending aorta type 2. It may cause acute CCF if the aortic valve is also involved. It may cause a stroke if carotids get involved. It may cause acute MI if coronary arteries get involved.

Ocular Features

• Ectopia lentis- It tends to happen in 69-70% of cases. Most cases are bilateral, upward, and outwards, called Superotemporal. Other ocular features include- Early and severe myopia, Flat cornea, The increased axial length of the globe, Hypoplastic iris, iliary muscles are hypoplastic due to reduced miosis, High risk of cataracts, glaucoma, and retinal detachment.

Other Systems

• It includes restrictive lung disease and spontaneous pneumothorax in about 15% of cases. Skin will show stretch marks or striae atrophicae in 1/3rd of cases. Inguinal and incisional hernias may also be found. There is little to absent subcutaneous fat. Later, adults tend to develop centripetal obesity.  Dural ectasia is also found in which the dural sac or root sleeves widen in 63-92% of MFS patients. It can cause lumbar back pain or be asymptomatic. If it is suspected, then it can be assessed by lumbosacral imaging with CT or MRI.

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Diagnosis Of Marfan Syndrome

Modified Ghent Criteria are used for diagnosis.

• Marfan syndrome can be diagnosed in any of the four scenarios without a positive family history. Aortic root Z score equal to or more than 2and Ectopia lentis. Aortic root Z score equal to or more than 2 and FNB-1 mutation. The aortic root Z score equals or exceeds 2, and the systemic score is more than 7. Ectopia lentis and FNB-1 mutation are known to cause aortic disease.
• In the presence of positive family history, Marfan syndrome can be diagnosed in the presence of If the patient is having Ectopia lentis. A systemic score equal to or more than 7. The aortic root Z score is greater than 2 if older than 20 years and greater than or equal to 3 if younger than 20.

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What Is Systemic Scoring?

• The wrist and thumb sign score equals 3; present singly, the score will be 1. The pectus carinatum is 2, and the score is 1 in the pectus excavatum of the asymmetric chest. The score of hindfoot deformity is 2; if it is pes planus, the score will be 1. For pneumothorax, the score is 2.  For Dural  Ectasia score is 2. For Protrusio Acetabuli score is 2. A score of reduced US or LS, increased arm or height, and no severe Scoliosis is 1. If Scoliosis or the thoracolumbar or kyphosis, then the score is 1. For reduced elbow extension, the score is 1. For facial features (3/5) (dolichocephaly , enophthalmos, retrognathia ,Mid-face hypoplsia  down slanting palpebral fissure) then the score will be 1. If skin striae, then the score is 1. In high myopia > 3 D, the score is 1. In case there is mitral valve prolapse, then it is 1.
• If the aortic root Z score is abnormal but less than 3, and systemic features are present, the systemic score will be less than 7. If there is no FBN-1 mutation, it is called non-specific Connective Tissue Disorder (CTD). If FBN-1 mutation is present, then it is said to be a potential MFS. Laboratory studies should document a negative urinary cyanide nitroprusside test for specific amino acid studies to exclude Cystathionine beta-synthase deficiency (homocystinuria).

Management Of Marfan Syndrome

Current Therapies

• Restriction of physical activity: Patients are allowed to moderate aerobic exercise. Patients should not do weightlifting, no strenuous activity, and no contact sports.
• Drugs: Beta-blockers are the drug of choice to prevent aortic root growth. Beta-blockers such as propranolol are very frequently used. They are found to have negative inotropic and negative chronotropic effects of decreasing hemodynamic stress. While giving beta blockers, targeting a heart rate of less than 100 per minute is necessary. IE prophylaxis is also needed.
• Aortic surgery: Elective surgery is better, and it is necessary to preserve native value.  It can be done in adults with an aortic root dimension over 50 mm. Surgery in adults can be done if the size of the aortic root increases by more than 5-10 mm/year. Surgery can also be done if there is a positive family history of aortic dissection. Indicators in children are less well-defined ( above indications and significant A.R).
• Mitral valve surgery: It is required in case there is severe mitral regurgitation or due to features of left ventricular dysfunction.

Emerging Therapies

• Angiotensin Receptors Blockers (ARBs)- Losartan has been extensively studied. Losartan is a selective ARB type 1 blocker that is much more effective.
• ACE Inhibitors - Among ACE inhibitors, Captopril or Enalapril can be considered.
• Extrinsic Signal Regulated Kinase (ERK) inhibitors- It includes Refamitinib or RDEA119. It is used to prevent aortic dilatation.

Marfan Syndrome In Pregnancy 

• There is a high risk of aortic dissection in pregnancy. The risk is lower if the aortic root diameter is less than 40 mm. Prophylactic aortic root replacement can minimize the risk of aortic dissection and death in women with MFS who wish to become pregnant. Still, this intervention would not modify the risk of more distal ascending or descending aortic dissection.

Management Of Scoliosis In Marfan Syndrome

• Scoliosis once begins. It usually becomes progressive. If it is over 20 degrees, mechanical bracing and physiotherapy can be done. If it is more than 45 degrees, surgery may be needed.

Prognosis In Marfan Syndrome 

• The most common cause of death is aortic complications. Aortic complications such as aortic aneurysm, aortic dissection, and aortic rupture are the most common cause of  most of the deaths happen in the 30s to 40s of age. Follow-up needs slit lamp examination and echocardiography. Genetic counseling is also needed.

Differential Diagnosis Of Marfan Syndrome 

Ectopia Lentis Syndrome

• Familial ectopia lentis- Homocystinuria- Cystathionine beta-synthase is deficient, which leads to elevated levels of homocysteine and methionine in the body. Also, there are ectopia lentis along with Marfanoid Habitus. There is a development delay and increased risk of thromboembolism and coronary artery disease (CAD).
• Weill Marchesani Syndrome- In Weill-Marchesani syndrome, there are three types of mutations: Type 1 ADAMTS 10 mutation, Type 2 FBN-1 mutation, and Type 3 LTBP2 mutation.  There are ectopia lentis along with myopia and microspherophakia. Additional findings have ruled out MFS, such as short stature and Brachydactyly. 

As Per Modified Ghent Criteria

• In the absence of a family history of Marfan syndrome- If the aortic root Z score is less than 2 And If a systemic score is more than or equal to 5 with at least 1 skeletal feature but no ectopia lentis, then there is a likely possibility of mass phenotype.

Aortic Aneurysm Syndrome

• Loeys - Dietz Syndrome- It is a syndrome in which skeletal and craniofacial features resemble Marfan syndrome. It comprises a classic triad of three things: Tortuous arteries and Aneurysm tendency, Hypertelorism, Bifid uvula, or Cleft palate. Aortic dissection occurs earlier age and with less dimensions, so it needs more aggressive therapy.

There are five types of LDS.

• Type 1, which includes TGFBR1 gene mutation. Type 2 will have a TGFBR2 gene mutation. Type 1 and type 2 have two subsets, including type 1 A, type 1 B, and type 2 A, type 2 B, which depend upon the presence or absence of craniofacial features. Type 3 is involved in SMAD3 gene mutation, which involves the early onset of OA and SVT. Type 4 consists of TGF-beta2 ligand mutation. Type 5, where TGF beta3 ligand will undergo mutation. Also, there is no arterial tortuosity and is less aortic dissection.
• Shprintzen-Goldberg Syndrome- There will be skeletal, cardiovascular, and craniofacial features similar to Marfan syndrome and LDS. Additional findings will include developmental delay and hypotonia. The mutated gene is the SKI gene, which encodes an intracellular repressor of TGF beta signaling. It shows less vascular involvement than either MFS or LDS. Familial Thoracic Aortic Aneurysm Syndrome- It is an autosomal dominant condition. They may have a high risk of aortic root aneurysm and dissection. Systemic manifestations of MFS are absent. It is managed similarly to MFS.

As Per The Modified Ghent Criteria

• In the absence of a family history of MFS- If mitral valve prolapse and aortic root Z score are less than 2 and the asymmetric score is less than 5 without ectopia lentis, then mitral valve prolapse syndrome is possible.

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