Marfan Syndrome

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 Marfan Syndrome is an autosomal dominant multi-system genetic disorder

characterized by abnormal manifestations in the skeletal, cardiovascular, and
ocular systems.
 The typical facial features observed in Marfan syndrome include: an elongated
face, deep set eyes, flat cheek bones, a posteriorly positioned jaw, and down
slanting palpebral fissures. Abraham Lincoln had several of these features, but did
he have Marfan syndrome? Well, who knows.
 Increased linear growth of the long bones is a common finding and generally
results in a tall stature with long limbs. The torso length to leg length ratio is
often reduced, while the arm span to height ratio may be increased.
Thoracolumbar scoliosis, as seen in this image, is also commonly present.
 Increased joint laxity and arachnodactyly are common, and when both present
the combination can result in a of couple signs. The wrist sign is positive if the
distal phalanges of the thumb and fifth finger overlap when the wrist is grasped
with the opposite hand. And a positive thumb sign is present when the entire
distal phalanx of an adducted thumb is visible beyond the ulnar border of the
hand.
 Some other common skeletal manifestations include pectus excavatum, pectus
carinatum, hindfoot valgus, and pes planus.
 A variety of ocular manifestations can occur, such as sublaxation of the corneal
lens, myopia, cataracts, and glaucoma. Ectopio lentis, in which the lens is
typically displaced upwards and temporally, is a cardinal feature of Marfan
syndrome.
 Aortic dilation is a potentially life-threatening complication can occur. In this
echocardiography we can see that the aortic root is abnormally wide. Aortic
dissection is another serious complication. In this echocardiography we can see a
double lumen. Blood flow through during ventricular systole indicates that the
upper lumen is the true lumen.
 Two other cardiac manifestations that commonly occur in patients with Marfan
syndrome are mitral valve prolapse and a bicuspid aortic valve. As well, many
other abnormalities may be present, such as herniae and skin striae.
 Although it is an autosomal dominant condition, the phenotypic expression is
highly variable. Affected parents may not even be aware that they have it and
may negate a family history of the disease. De novo gene mutations also occur,
in which case no other family member will be affected.
 The diagnosis can be made if ≥2 of the following are present: family history,
ectopia lentis, aortic dilation/dissection, or a causal mutation in the FBN1 gene. It
is important to note that a minority of patients with Marfan syndrome do not have
a defined FBN1 gene mutation.
 If the patient only has the aortic criterion or a positive family history, then a
systemic score 7 or more in the REVISED GHENT CRITERIA is required.
 Transthoracic echocardiogram screening is recommended at 6 - 12 month
intervals.
 Consider B-blockers and advise patients to AVOID caffeine, stimulants, weight-
lifting, and high intensity/contact sports. The addition of an angiotensin receptor
blocker is also indicated for patients with an aortic aneurysm.
 Low to moderate-intensity exercise is beneficial and should be encouraged.

Homocystinuria
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  It is an autosomal recessive condition with high clinical variability. It can manifest
with intellectual disability, a variety of psychiatric and behavioral disorders,
skeletal and ocular abnormalities, vaso-occlusive disease, and other less common
physical anomalies.
 Affected babies are normal at birth, but may exhibit failure to thrive during
infancy and developmental delay during first years of life. The degree of
psychomotor delay that occurs is highly variable.*
 Subluxation of the ocular lens commonly occurs after the age of three. It is
associated with the development of severe myopia and iridodonesia, which is*a
quivering movement of the iris that can occur with head movement. Other less
common complications of ectopia lentis can occur later in life and include
astigmatism, glaucoma, staphyloma, cataracts, spontaneous retinal detachment,
and optic atrophy.
 These patients often have osteoporosis, which is associated with the development
of thoracic scoliosis. Dolichostenomelia is the abnormal lengthening of the long
bones, and it results in a tall stature with a lean physique. A variety of chest
abnormalities may be present, such as pectus excavatum/carinatum. Joints are
LIMITED in mobility.
 Thromboembolism can occur even in infancy, however the risk increases with
age. Clotting studies are NORMAL.
 High plasma/urine levels of homocysteine and methionine confirms the diagnosis.
False negative tests can occur in patients taking vitamins containing or foods
fortified with pyridoxine.
 It is treated with high doses of pyridoxine with folate and vitamin B12
replacement. Patients who do not respond to vitamin B6 therapy will require
methionine restriction and/or betaine supplementation.

Marfan Syndrome vs. Homocystinuria

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 Both Marfan syndrome and classical homocystinuria can manifest with a

marfanoid habitus and thus appear similar.
 Marfan syndrome is an autosomal dominant genetic disorder caused by an FBN1
mutation on chromosome 15. It may cause hyperextensible joints with an upward
dislocation of the ocular lense. Two potential cardiovascular complications include
aortic disease and valvular insufficiency. It is diagnosed with the revised Ghent
criteria. Management includes lifestyle modifications (e.g., caffeine restriction,
and avoidance of high-intensity physical activity) and consideration of b-blockers
and surgery for aortic disease.
 Classical homocystinuria is an autosomal recessive disorder, most commonly
caused by a CBS mutation on chromosome 21. It is manifest with rigid joints and
downward dislocation of the ocular lense. It can cause vaso-occlusive disease
(e.g., thromboembolism). High plasma/urine levels of homocysteine and
methionine confirms the diagnosis. It is primarily treated with high doses of
pyridoxine and folate and vitamin B12 replacement.