SAMIKSHA HEART AND DIABETIC CARE
''CONNECTIVE TISSUE DISORDERS''
''Marfan Syndrome''
Marfan syndrome is a systemic connective tissue disorder
with a frequency of 2 to 3 in 10, 000. The disorder is characterized
by manifestations involving the cardiovascular, skeletal,
and ocular systems. Current diagnostic criteria are based
on involvement of above organ systems and family history.
Cardiovascular manifestations include mitral valve prolapse,
progressive aortic root enlargement, and ascending aortic aneurisms,
possibly leading to aortic regurgitation, dissection, or
rupture. Some characteristic skeletal manifestations of this
syndrome include disproportional increase of linear bone
growth resulting in malformations of the digits (arachnodactyly),
craniofacial abnormalities, pectus excavatum/carinatum,
and scoliosis. A common ocular involvement is severe myopia
and lens dislocation in one or both eyes (ectopia lentis).
Marfan syndrome is an autosomal dominant disorder caused
by fibrillin-1 gene mutations encoding for the extracellular
matrix protein fibrillin (Fbn-1). Fibrillin is an integral component
of both elastic and nonelastic connective tissue. The
mechanism of fibrillin mutation in Marfan syndrome remains
unclear. However, animal models of Fbn-1 have demonstrated
a role of TGF-beta signaling. In some patients with
phenotypes similar to Marfan syndrome but without fibrillin-
1 gene mutations, TGF-beta receptor mutations have
been identified, suggesting a significant role of TGF-beta
pathway in the pathogenesis of Marfan syndrome features.
Aortic root involvement remains the leading cause of death
in patients with Marfan syndrome. Echocardiography is
recommended to routinely screen and to follow aortic root
dilation. In addition, all first-degree relatives of the family
should have screening echocardiography. Patients should
be advised against strenuous exercises. Medical therapy for
Marfan syndrome includes beta-blockers to reduce myocardial
contractility and pulse pressure. Animal models of
Marfan syndrome have demonstrated a possible benefit of
losartan in preventing progression of the disease by inhibiting
the TGF-beta pathway, and this therapy is the subject
of an active clinical trial. Elective aortic root replacement
remains the therapy of choice once the aortic root becomes
significantly enlarged. Marfan patients who become pregnant
need to be counseled not only about the 50% chance
of transmitting the disease but also the substantially increased
risk of aortic rupture/dissection during and after
pregnancy. Important components of Marfan syndrome
counseling are consideration of contraception and pregnancy
management.
Loeys-Dietz Syndrome
Recently, an aortic aneurysm syndrome has been identified
with TGF-beta receptor mutations. Loeys-Dietz syndrome
is an autosomal dominant condition with a characteristic
triad of arterial tortuosity/aneurysm, hypertelorism, and
bifid uvula or cleft palate. There is significant overlap with
Marfan syndrome, and the management is similar in terms
of cardiovascular manifestation. Early, elective, surgical intervention
should be considered in patients with significant
aneurysmal dilation of the aorta. Some clinicians have argued
for much earlier surgical intervention for the dilated
aorta in this condition, compared with Marfan syndrome,
since there appears to be a much greater risk of rupture and
dissection at earlier ages and smaller aortic sizes. Pregnancy
counseling is also an integral part of therapy.
Ehlers-Danlos Syndrome
Ehlers-Danlos syndrome is a group of disorders that affect
connective tissue development due to defects in collagen
and connective tissue biosynthesis. Prevalence of the disease
is about 1 in 400, 000 people in the United States.
Cardiac manifestations include spontaneous rupture of medium
to large sized arteries including the aorta. Frequently,
extracardiac presentations include hyperextensible skin and
hypermobile joints.
To date, 11 types of the disorder have been recognized, but collagen
defects have been described in only 6 types. Although
all types of Ehlers-Danlos syndrome affect the joints and the
skin, clinical features vary by type. Different features characterize
each type of the syndrome. Type IV carries the poorest
prognosis, especially due to spontaneous ruptures of arteries
and organs. Extreme caution needs to be taken if surgical
intervention is needed due to weakened connective tissue
structures. Many genes, including ADAMTS2, COL1A1,
COL1A2, COL3A1, COL5A1, COL5A2, PLOD1, and
TNXB, have been implicated in the pathogenesis of Ehlers-
Danlos syndrome, but the predominant cardiovascular concern
exists in the Type IV vascular form of Ehlers-Danlos
associated with mutations in the COL3A1 gene
and aortic dilation/aneurysms. Other less commonly associated
anomalies include ventricular septal defect, patent
ductus arteriosus, bicuspid pulmonic valve, and Ebstein’s
anomaly. Bicuspid aortic valve has been shown to demonstrate
familial clustering. However, identifying culprit genes
have been difficult due to variable penetrance and the common
nature of the disorder.
