Marfan Syndrome

Marfan syndrome is a genetic condition with autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance. Marfan syndrome affects the elasticity of connective tissues throughout the body, most notably in the cardiovascular, ocular, and musculoskeletal systems. The skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, and central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System are also affected. Patients are usually tall with long limbs, fingers, and toes, and hypermobile joints. Associated conditions include aortic aneurysm Aneurysm An aneurysm is a bulging, weakened area of a blood vessel that causes an abnormal widening of its diameter > 1.5 times the size of the native vessel. Aneurysms occur more often in arteries than in veins and are at risk of dissection and rupture, which can be life-threatening. Extremity and Visceral Aneurysms or dissection, mitral valve prolapse Mitral valve prolapse Mitral valve prolapse (MVP) is the most common cardiac valvular defect, and is characterized by bulging of the mitral valve (MV) cusps into the left atrium (LA) during systole. Mitral valve prolapse is most commonly due to idiopathic myxomatous degeneration. Patients are typically asymptomatic. Mitral Valve Prolapse, and lens dislocation. Diagnosis is made clinically with set criteria, and genetic testing is done only when it may affect the management. Medical or surgical management is based on clinical manifestations. Cardiovascular involvement is followed closely, as it is the main cause of mortality.

Last update:

December 17, 2020
7:31 am

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Epidemiology and Genetics

Epidemiology

Incidence: 1 in 5,000 live births
Affects men and women in all ethnic and racial groups

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

Most commonly due to a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the FBN1 gene on chromosome 15
- Affects the connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue protein, fibrillin-1
  - Fibrillin-1 is the main component of microfibrils, which form elastic fibers in connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue.
  - Mutation in FBN1 gene → impaired fibrillin protein → defective microfibrils → ↓ elasticity in tissues
- Affects connective tissues throughout the body:
  - Organs
  - Blood vessels
  - Eyes
  - Skin
  - Skeletal components
Inheritance pattern: autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance
- 75% of patients have affected parents.
- 25% of cases are de novo mutations (idiopathic).
Penetrance: complete
Expressivity: variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables

Marfan syndrome in iranian family — Family members with Marfan’s syndrome
Image: “Family members with Marfan’s syndrome” by Birjand Atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis and Coronary Artery Research Centre, Birjand University of Medical Sciences, Birjand, Iran. License: CC BY 3.0

Clinical Presentation

Musculoskeletal

Tall stature with disproportionately long extremities:
- ↓ upper segment to lower segment ratio (US/LS)
- ↑ arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm span to height ratio
Long fingers and toes (arachnodactyly):
- Positive thumb sign (Steinberg’s sign): The distal phalanx of the adducted thumb extends beyond the ulnar border of a clenched fist palm.
- Positive wrist sign (Walker sign): The thumb and 5th finger of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand overlap with each other when wrapped around the contralateral wrist.
Joint laxity
Elbows may lack full extension mobility.
Vertebral column Vertebral column The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column abnormalities:
- Scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis
- Kyphosis
Chest abnormalities:
- Pectus excavatum (funnel chest)
  - Sternum protrudes inward.
  - Looks “caved in”
- Pectus carinatum (pigeon chest or sternal kyphosis): Sternum protrudes outward.
Hindfoot valgus:
- Heel points outward away from midline.
- Associated with pes planus (flat foot)
Protrusio acetabuli (acetabular protrusion)
High-arched palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate
Characteristic facial features:
- Dolichocephaly (↓ head width:length ratio)
- Enophthalmos (posterior displacement of the eyeball within the orbit Orbit The orbit is the cavity of the skull in which the eye and its appendages are situated. The orbit is composed of 7 bones and has a pyramidal shape, with its apex pointed posteromedially. The orbital contents comprise the eye, extraocular muscles, 5 cranial nerves, blood vessels, fat, the lacrimal apparatus, among others. The Orbit and Extraocular Muscles)
- Downslanting palpebral fissures (area between open eyelids)
- Malar hypoplasia (malar or zygomatic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones is small or absent)
- Retrognathia (lower jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint set back further than upper jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint)

Photograph showing arachnodactyly
Image: “Arachnodactyly” by Department of Pedodontics, SRM Dental College, SRM University, Chennai 600078, India. License: CC BY 3.0

Pectus excavatum — Photograph showing arachnodactyly
Image: “Arachnodactyly” by Department of Pedodontics, SRM Dental College, SRM University, Chennai 600078, India. License: CC BY 3.0

Cardiovascular

Aortic disease is the main cause of morbidity and mortality in Marfan syndrome (MFS) patients, and is due to degeneration of the media of the vessel walls.
- Dilation or aneurysm Aneurysm An aneurysm is a bulging, weakened area of a blood vessel that causes an abnormal widening of its diameter > 1.5 times the size of the native vessel. Aneurysms occur more often in arteries than in veins and are at risk of dissection and rupture, which can be life-threatening. Extremity and Visceral Aneurysms of the aorta
  - Present in 50% of children
  - Dilation may involve thoracic aorta, abdominal aorta, or root of pulmonary artery.
  - Dilation of the aortic root present in 60%–80% of adults with MFS
- Aortic regurgitation Aortic regurgitation Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation
  - Often occurs with aortic dilation
  - Valve leaflets prevented from closing properly
  - Diastolic heart murmur on exam
- Aortic dissection Aortic dissection Aortic dissection occurs due to shearing stress from pulsatile pressure causing a tear in the tunica intima of the aortic wall. This tear allows blood to flow into the media, creating a "false lumen." Aortic dissection is most commonly caused by uncontrolled hypertension. Aortic Dissection
  - Tear in the intima (innermost layer) of the aorta, allowing blood between the intima and media (middle layer)
  - Life-threatening condition
  - Presents with sudden, severe, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain that radiates to the back
  - MFS patients account for 50% of those with aortic dissection under 40 years of age.
  - ↑ risk of dissection during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care and postpartum
Mitral valve prolapse
- Valve leaflets bulge (prolapse) into left atrium during heart systole
- More frequently seen with ↑ age and in women
- Systolic heart murmur and midsystolic click on exam
- Can lead to mitral regurgitation Mitral regurgitation Mitral regurgitation (MR) is the backflow of blood from the left ventricle (LV) to the left atrium (LA) during systole. Mitral regurgitation may be acute (myocardial infarction) or chronic (myxomatous degeneration). Acute and decompensated chronic MR can lead to pulmonary venous congestion, resulting in symptoms of dyspnea, orthopnea, and fatigue. Mitral Regurgitation
Dilation of carotid and cranial arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries
- Much less common
- Berry (saccular) aneurysms are typically at the exit of the circle of Willis.
- Rupture of a cranial artery can cause subarachnoid hemorrhage Subarachnoid Hemorrhage Subarachnoid hemorrhage (SAH) is a type of cerebrovascular accident (stroke) resulting from intracranial hemorrhage into the subarachnoid space between the arachnoid and the pia mater layers of the meninges surrounding the brain. Most SAHs originate from a saccular aneurysm in the circle of Willis but may also occur as a result of trauma, uncontrolled hypertension, vasculitis, anticoagulant use, or stimulant use. Subarachnoid Hemorrhage (SAH).

Aortic dissection flap marfan syndrome — Gross pathology specimen of an aortic dissection flap and aortic wall
Image: “ Aortic dissection Aortic dissection Aortic dissection occurs due to shearing stress from pulsatile pressure causing a tear in the tunica intima of the aortic wall. This tear allows blood to flow into the media, creating a "false lumen." Aortic dissection is most commonly caused by uncontrolled hypertension. Aortic Dissection flap and aortic wall” by Department of Obstetrics and Gynaecology, Women’s and Children’s Hospital, Adelaide, SA 5006, Australia. License: CC BY 3.0

Ocular

Dislocation of the lens (ectopia lentis)
- Impaired supporting ciliary zonules fail to keep the lens in place.
- Upward and temporal displacement
- Occurs in 50%–80% of patients
- Iridodonesis can be seen on inspection (vibration of the iris with eye movement).
- Seen on slit lamp examination
Myopia (nearsightedness)
Retinal tears or detachment
- Often bilateral in MFS patients
- Associated with proliferative retinopathy
Glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
Early cataract formation

Other manifestations

Skin: striae atrophicae (stretch marks)
- Not associated with weight changes or pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
- Often in uncommon areas:
  - Upper arms
  - Axillary area
  - Mid and lower back
  - Thighs
Pulmonary: emphysematous changes in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs
- Lung bullae predominantly in the upper lobes
- ↑ risk for spontaneous pneumothorax Pneumothorax A pneumothorax is a life-threatening condition in which air collects in the pleural space, causing partial or full collapse of the lung. A pneumothorax can be traumatic or spontaneous. Patients present with a sudden onset of sharp chest pain, dyspnea, and diminished breath sounds on exam. Pneumothorax
Central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (CNS): lumbosacral dural ectasia
- Dilation of the dural sac surrounding the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord
- Symptoms:
  - Lower back pain Back pain Back pain is a common complaint among the general population and is mostly self-limiting. Back pain can be classified as acute, subacute, or chronic depending on the duration of symptoms. The wide variety of potential etiologies include degenerative, mechanical, malignant, infectious, rheumatologic, and extraspinal causes. Back Pain
  - Radicular pain
  - Paresthesias
  - Bowel and bladder dysfunction
  - Headaches

Diagnosis

Revised Ghent criteria
- Complex scoring system based on the presence of characteristic Marfan syndrome manifestations
- Requires varying combinations of:
  - Aortic root dilatation
  - Ectopia lentis
  - FBN1 gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
  - Systemic score > 7 (see table below)
- The presence, or absence, of a family history of MFS is factored in.
Genetic testing for the FBN1 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is done on a case-by-case basis if it will affect management.
Imaging is used to evaluate for complications of MFS.
- Radiographs → pneumothorax Pneumothorax A pneumothorax is a life-threatening condition in which air collects in the pleural space, causing partial or full collapse of the lung. A pneumothorax can be traumatic or spontaneous. Patients present with a sudden onset of sharp chest pain, dyspnea, and diminished breath sounds on exam. Pneumothorax, protrusio acetabuli, scoliosis
- Echocardiography (echo) → valvular and aortic root defects
- Computed tomography (CT) of chest, abdomen, and pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis with intravenous (IV) contrast → aortic dissection
- Magnetic resonance imaging (MRI) → dural ectasia, aortic dilation

**Table: Systemic score for the revised Ghent criteria (a score ≥ 7 indicates major systemic involvement)**
Wrist and thumb sign	3 points (both) 1 point (1)
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
↓ US/LS and ↑ arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm span/height and no severe scoliosis	1 point
Scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis or kyphosis	1 point
↓ elbow extension	1 point
Facial features (at least 3 of 5) Dolichocephaly Enophthalmos Downslanting palpebral fissures Malar hypoplasia Retrognathia	1 point
Skin striae	1 point
Myopia	1 point
Mitral valve prolapse	1 point

This table does not need to be memorized, but provides insight into the important clinical findings and the complexity of the diagnosis.

Marfan syndrome echocardiography — Transthoracic echocardiography showing an intimal tear in the dilated aortic root above the aortic valve level:
A: Linear intimal tear is seen just above the aortic valve in systole.
B: Linear intimal flap is visible in the dilated aortic root.
Image: “Fig2” by The Department of Interventional Cardiology, John Paul 2nd Hospital, Pradnicka 80, 31 202, Krakow, Poland. License: CC BY 4.0

Cardiovascular magnetic resonance marfan syndrome — Transthoracic echocardiography showing an intimal tear in the dilated aortic root above the aortic valve level:
A: Linear intimal tear is seen just above the aortic valve in systole.
B: Linear intimal flap is visible in the dilated aortic root.
Image: “Fig2” by The Department of Interventional Cardiology, John Paul 2nd Hospital, Pradnicka 80, 31 202, Krakow, Poland. License: CC BY 4.0

Management

The management of MFS is based on the clinical manifestations. A multidisciplinary team of cardiologists, ophthalmologists, orthopedists, and cardiovascular surgeons is needed.