Marfan syndrome (also called Marfan's syndrome) is a genetic disorder of the connective tissue. People with Marfan's tend to be unusually tall, with long limbs and long, thin fingers.
The syndrome is inherited as a dominant trait, carried by the gene FBN1, which encodes the connective protein fibrillin-1.[1][2] People have a pair of FBN1 genes. Because it is dominant, people who have inherited one affected FBN1 gene from either parent will have Marfan syndrome.
Marfan syndrome has a range of expressions, from mild to severe. The most serious complications are defects of the heart valves and aorta. It may also affect the lungs, the eyes, the dural sac surrounding the spinal cord, the skeleton and the hard palate.
In addition to being a connective protein that forms the structural
support for tissues outside the cell, the normal fibrillin-1 protein
binds to another protein, transforming growth factor beta (TGF-β).[2]
TGF-β has deleterious effects on vascular smooth muscle development and
the integrity of the extracellular matrix. Researchers now believe,
secondary to mutated fibrillin, excessive TGF-β at the lungs, heart
valves, and aorta weakens the tissues and causes the features of Marfan
syndrome.[3] Since angiotensin II receptor antagonists (ARBs) also reduce TGF-β, ARBs (losartan,
etc.) have been tested in a small sample of young, severely affected
Marfan syndrome patients. In some patients, the growth of the aorta was
indeed reduced.[4]
Marfan syndrome is named after Antoine Marfan,[5] the French pediatrician who first described the condition in 1896.[6][7] The gene linked to the disease was first identified by Francesco Ramirez in 1991.[8]
Signs and symptoms
The constellation of long limbs, dislocated lenses and the
aortic root
dilation are generally sufficient to make the diagnosis of Marfan
syndrome with reasonable confidence. More than 30 other clinical
features are variably associated with the syndrome, most involving the
skeleton,
skin, and
joints. Considerable clinical variability occurs within families carrying the identical mutation.
Skeletal system
Most of the readily visible signs are associated with the skeletal
system. Many individuals with Marfan syndrome grow to above-average
height. Some have long, slender limbs (
dolichostenomelia) with long fingers and toes (
arachnodactyly).
An individual's arms may be disproportionately long, with thin, weak
wrists. In addition to affecting height and limb proportions, Marfan
syndrome can produce other skeletal anomalies. Abnormal curvature of the
spine (
scoliosis), abnormal indentation (
pectus excavatum) or protrusion (
pectus carinatum) of the
sternum are not uncommon. Other signs include abnormal joint flexibility, a high
palate,
malocclusions,
flat feet,
hammer toes, stooped shoulders, and unexplained
stretch marks on the skin. It can also cause pain in the joints, bones and muscles in some patients. Some people with Marfan have
speech disorders resulting from symptomatic high palates and small jaws. Early
osteoarthritis may occur.
Eyes
Lens dislocation in Marfan's syndrome; the lens was kidney-shaped and was resting against the
ciliary body.
Marfan syndrome can also seriously affect the eyes and vision.
Nearsightedness and
astigmatism are common, but farsightedness can also result.
Subluxation (dislocation) of the crystalline
lens in one or both eyes (
ectopia lentis) (in 80% of patients) also occurs and may be detected by an
ophthalmologist or
optometrist using a
slit-lamp biomicroscope. In Marfan's the dislocation is typically superotemporal whereas in the similar condition
homocystinuria, the dislocation is inferonasal. Sometimes eye problems appear only after the weakening of connective tissue has caused
detachment of the retina.
[9] Early onset
glaucoma can be another related problem.
Cardiovascular system
The most serious signs and symptoms associated with Marfan syndrome
involve the cardiovascular system: undue fatigue, shortness of breath,
heart palpitations,
racing heartbeats, or
angina pectoris
with pain radiating to the back, shoulder, or arm. Cold arms, hands and
feet can also be linked to Marfan's syndrome because of inadequate
circulation. A
heart murmur, abnormal reading on an
ECG, or symptoms of angina can indicate further investigation. The signs of regurgitation from
prolapse of the mitral or aortic
valves
(which control the flow of blood through the heart) result from cystic
medial degeneration of the valves, which is commonly associated with
Marfan's syndrome (see
mitral valve prolapse,
aortic regurgitation). However, the major sign that would lead a doctor to consider an underlying condition is a
dilated aorta or an
aortic aneurysm. Sometimes, no heart problems are apparent until the weakening of the connective tissue (cystic medial degeneration) in the
ascending aorta causes an
aortic aneurysm or
aortic dissection,
a surgical emergency. An aortic dissection is most often fatal and
presents with pain radiating down the back, giving a tearing sensation.
Because underlying connective tissue abnormalities cause Marfan syndrome, there is an increased incidence of
dehiscence of prosthetic mitral valve.
[10] Care should be taken to attempt repair of damaged heart valves rather than replacement.
During pregnancy, even in the absence of preconception cardiovascular
abnormality, women with Marfan syndrome are at significant risk of
aortic dissection,
which is often fatal even when rapidly treated. Women with Marfan
syndrome, then, should receive a thorough assessment prior to
conception, and
echocardiography
should be performed every six to 10 weeks during pregnancy, to assess
the aortic root diameter. For most women, safe vaginal delivery is
possible.
[11]
Lungs
Marfan syndrome is a
risk factor for spontaneous
pneumothorax. In spontaneous unilateral pneumothorax, air escapes from a lung and occupies the
pleural
space between the chest wall and a lung. The lung becomes partially
compressed or collapsed. This can cause pain, shortness of breath,
cyanosis, and, if not treated, it can cause death. It has also been associated with
sleep apnea and
idiopathic obstructive lung disease.
Central nervous system
Dural ectasia, the weakening of the connective tissue of the dural sac encasing the
spinal cord,
though not life-threatening, can reduce the quality of life for an
individual. It can be present for a long time without producing any
noticeable symptoms. Symptoms that can occur are lower
back pain, leg pain,
abdominal pain, other neurological symptoms in the lower extremities, or
headaches.
Such symptoms usually diminish when the individual lies flat on his or
her back. These types of symptoms might lead a doctor to order an
X-ray of the
lower spine.
Dural ectasia is usually not visible on an X-ray in the early phases. A
worsening of symptoms and the lack of finding any other cause should
eventually lead a doctor to order an upright
MRI
of the lower spine. Dural ectasia that has progressed to the point of
causing these symptoms would appear in an upright MRI image as a dilated
pouch wearing away at the
lumbar vertebrae.
[9] Other spinal issues associated with Marfan syndrome include degenerative disk disease, spinal cysts and
dysautonomia.
Pathogenesis
Marfan syndrome is caused by mutations in the
FBN1 gene on
chromosome 15,
[12] which
encodes the
glycoprotein fibrillin-1,
a component of the extracellular matrix. Fibrillin-1 protein is
essential for the proper formation of the extracellular matrix,
including the biogenesis and maintenance of
elastic fibers.
The extracellular matrix is critical for both the structural integrity
of connective tissue, but also serves as a reservoir for growth factors.
[13] Elastin fibers are found throughout the body, but are particularly abundant in the
aorta,
ligaments and the
ciliary zonules of the eye; consequently, these areas are among the worst affected.
A
transgenic
mouse has been created carrying a single copy of a mutant fibrillin-1, a
mutation similar to that found in the human gene known to cause Marfan
syndrome. This mouse strain recapitulates many of the features of the
human disease and promises to provide insights into the
pathogenesis of the disease. Reducing the level of normal fibrillin 1 causes a Marfan-related disease in mice.
[14]
Transforming growth factor beta (
TGFβ)
plays an important role in Marfan syndrome. Fibrillin-1 directly binds a
latent form of TGFβ, keeping it sequestered and unable to exert its
biological activity. The simplest model of Marfan syndrome suggests
reduced levels of fibrillin-1 allow TGFβ levels to rise due to
inadequate sequestration. Although it is not proven how elevated TGFβ
levels are responsible for the specific pathology seen with the disease,
an inflammatory reaction releasing proteases that slowly degrade the
elastin fibers and other components of the extracellular matrix is known
to occur. The importance of the TGFβ pathway was confirmed with the
discovery of the similar
Loeys-Dietz syndrome involving the
TGFβR2 gene on
chromosome 3, a
receptor protein of TGFβ.
[15]
Marfan syndrome has often been confused with Loeys-Dietz syndrome,
because of the considerable clinical overlap between the two
pathologies.
[16]
