Clinical Signs of Marfan Syndrome

Review of Clinical Signs
Series Editor: Bernard M. Karnath, MD
Clinical Signs of Marfan Syndrome
Umamahesh C. Rangasetty, MD
Bernard M. Karnath, MD
arfan syndrome is the most common inherited connective tissue disorder, with a reported incidence of 1 in 10,000 individuals
and equal distribution between the sexes.1 It
is caused by an autosomal dominant mutation in the
gene encoding fibrillin (FBN1, chromosome 15q15–
21.3),2 a glycoprotein that is an integral part of the connective tissue in the body (eg, ligaments, blood vessel,
eye lenses). Although the genetic and biochemical
bases of the condition have been identified, the disease
continues to be underdiagnosed.3,4 If unrecognized,
patients with Marfan syndrome may potentially develop
aortic rupture or sudden cardiac death5; therefore, it is
important to identify this potentially life-threatening
condition. This article reviews clinical signs associated
with Marfan syndrome and discusses the diagnostic criteria and differential diagnosis.
M
CLINICAL PRESENTATION
Most patients who have Marfan syndrome are usually diagnosed incidentally when they present for a routine physical examination for various reasons, such as a
pre-employment physical or screening examination
prior to participation in sports. Marfan syndrome primarily involves the skeletal, ocular, and cardiovascular
systems. Typically, patients with Marfan syndrome present with tall stature, ectopia lentis, aortic root dilatation, and a positive family history. Less frequently, the
diagnosis is made when a patient presents with complications of the syndrome, such as aortic dissection, or
with involvement of the pulmonary, skin/integument,
or nervous systems.5 Presentation of the disease varies
greatly, even among family members. Some persons
with Marfan syndrome experience only mild effects,
whereas others have severe problems. Uncommon presentations are summarized in Table 1. In most cases,
the disease worsens with age.
Skeletal Features
Skeletal manifestations are the cardinal signs of
Marfan syndrome and usually gain the attention of a
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SALIENT FEATURES OF
MARFAN SYNDROME
Skeletal
Disproportionately long limbs (span > height) and digits or reduced upper-to-lower segment ratio
Pectus excavatum or carinatum
Scoliosis
Highly arched palate with dental crowding
Ocular
Ectopia lentis (dislocation or subluxation of the lens)
Cardiovascular
Dilatation of the aortic root with regurgitation
Aortic aneurysm and/or dissection
Miscellaneous
Skin striae
Dural ectasia
physician. The most common features include tall
stature with the lower segment of the body greater than
the upper segment (Figure 1) and long, slender limbs,
or dolichostenomelia; thin body habitus with increased
arm span-to-height ratio; long, slender fingers, or
arachnodactyly (Figure 2); deformities of the chest,
such as pectus carinatum (Figure 3) or pectus excavatum; scoliosis; and highly arched palate with crowded
teeth and dental malocclusion (Figure 4). Other less
common manifestations include hypermobility of
joints, flat foot (pes planus), reduced extension of
elbows (< 170 degrees), and elongated face (dolichocephalia).
Dr. Rangasetty is a resident, and Dr. Karnath is an associate professor of
medicine, Division of General Medicine; both are at the University of
Texas Medical Branch at Galveston, Galveston, TX.
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Rangasetty & Karnath : Marfan Syndrome : pp. 33 – 38
Table 1. Uncommon Presentations of Marfan Syndrome
Present at birth, rapid aortic dilatation, deformities, and death
Dominant ectopia lentis with variable skeletal and negligible cardiac
involvement
Mitral valve prolapse without skeletal features
Dominant aortic aneurysm without skeletal and ocular features
Figure 2. Arachnodactyly: long and slender fingers (Reprinted with permission from Chua CN, Rauz S. Success in
MCQs for final FRCOphth/MRCOphth. Vol 2. London: BMJ
Publishing; 1998. Available at www.mrcophth.com/cataract/
ectopialentis.html. Accessed 3 Mar 2006.)
Figure 1. External phenotype of Marfan syndrome showing tall
stature, long arm span, and limbs disproportionately greater
than the body. (Reprinted from Braunwald. Heart disease: a
textbook of cardiovascular medicine, 6th ed. Philadelphia: WB
Saunders Company; 2001:2001, with permission from Elsevier.)
Cardiovascular Features
Cardiovascular manifestations are the most serious
complications and determine the prognosis and survival in Marfan syndrome. Abnormalities include aortic
root dilatation, aortic regurgitation, aortic dissection,
and aortic aneurysm, which most commonly involves
the ascending aorta but can involve the descending
aorta. The rate of aortic root dilatation is unpredictable and usually requires surgery when it measures
more than 50 mm. Mitral valve prolapse can also occur.
Although cardiovascular abnormalities typically appear
late, they can occur during childhood.4
34 Hospital Physician April 2006
Ocular Features
Ectopia lentis (subluxation of lens; Figure 5) is a
hallmark feature of Marfan syndrome and is present in
approximately 60% to 80% of patients.6 – 8 Ectopia
lentis is usually bilateral, symmetrical, and upward. The
diagnosis can be made by looking for iridodonesis
(tremor of iris), phacodonesis (abnormal movement
of lens), and a deep anterior chamber in the nondilated eye. The dislocation may be complete, with the lens
floating free within the vitreous cavity. Other nonspecific ocular features of Marfan syndrome include
myopia, elongated eye, flat cornea, and retinal detachment.
Miscellaneous Features
Striae may occur over the shoulders and buttocks.
Inguinal and incisional hernias are common.9 Pulmonary manifestations include spontaneous pneumothorax and apical blebs.10 Marked dilatation of the dural
sac may be seen frequently in computed tomography
or magnetic resonance imaging scans,11 but the condition is usually asymptomatic.
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Rangasetty & Karnath : Marfan Syndrome : pp. 33 – 38
Figure 3. Pectus carinatum.
DIAGNOSTIC EVALUATION
Marfan syndrome is a clinical diagnosis based on
the observation of specific physical signs and family history. However, diagnosing patients with this syndrome
is a challenge because of the increased prevalence of
marfanoid features in the general population, wide
variations in its clinical presentation even among the
family members, and features that overlap with other
connective tissue disorders (Table 2).3 Genetic testing
by itself cannot differentiate Marfan syndrome from
other genetic connective tissue disorders because the
many mutations in FBN1 have been linked to other
clinical entities.4 Diagnosis is further complicated by
age dependency of symptoms and signs, which leads to
a changing clinical picture and is the reason younger
patients with suspected Marfan syndrome who do not
fulfill the clinical diagnostic criteria should be offered
repeat clinical evaluations.4
Despite these challenges, the diagnosis can be established by a comprehensive clinical evaluation, and
diagnostic criteria have been established. The Ghent
criteria (Table 3) are based upon family/genetic history, involvement of organ systems (primarily skeletal,
cardiovascular, and ocular), and whether the clinical
sign is major or minor.12 Major criteria are specific for
Marfan syndrome and are rarely present in the general
population. According to these criteria, Marfan syndrome in a patient with unequivocal family history is
diagnosed when there is major involvement in 1 organ
system (skeletal, cardiovascular, or ocular) and involvement of a second organ system. If the patient has no
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Figure 4. Highly arched palate associated with Marfan’s syndrome. (Reprinted with permission from Chua CN, Rauz S. Success in MCQs for final FRCOphth/MRCOphth. Vol 2. London:
BMJ Publishing; 1998. Available at www.mrcophth.com/cataract/
ectopialentis.html. Accessed 3 Mar 2006.)
Table 2. Differential Diagnosis of Marfan Syndrome
Homocystinuria
Congenital contractural arachnodactyly
Familial aortic dissection
Familial arachnodactyly
Familial marfanlike (marfanoid) habitus
Familial thoracic aortic aneurysm/dissection
MASS (myopia, mitral valve prolapse, mild aortic dilatation, skin, and
skeletal) phenotype
Ehlers-Danlos syndrome
Shprintzen-Goldberg syndrome
XXY syndrome (Klinefelter’s syndrome)
Stickler’s syndrome (hereditary progressive arthro-ophthalmopathy)
Multiple endocrine neoplasia type IIB
Adapted from Child AH, Nuemann L, Robinson PN. Diagnosis and
treatment of Marfan syndrome—a summary. In: Robinson PN,
Godfrey M, editors. Marfan syndrome: a primer for clinicians and scientists. New York: Kluwer Academic/Plenum; 2004:19, with permission from Springer Science and Business Media.
first-degree relative who is unequivocally affected by
Marfan syndrome, the patient must have major criteria
in at least 2 different organ systems and involvement of
a third (skeletal, cardiovascular, and ocular) to be diagnosed with Marfan syndrome.
Because the diagnosis of Marfan syndrome is clinical,
patients should have their family history reviewed in
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Rangasetty & Karnath : Marfan Syndrome : pp. 33 – 38
Table 3. Ghent Criteria for Diagnosing Marfan Syndrome
System
Major
Minor
Family/genetic
history
Having a first-degree relative (parent, child, or sibling) who
meets these diagnostic criteria independently
Presence of a mutation in FBN1 known to cause the Marfan
syndrome
Presence of a haplotype around FBN1, inherited by descent,
known to be associated with unequivocally diagnosed Marfan
syndrome in the family
None
Skeletal
Presence of at least 4 of the following manifestations:
Pectus carinatum
Pectus excavatum requiring surgery
Reduced upper-to-lower segment ratio or arm span-to-height
ratio greater than 1.05
Wrist and thumb signs
Scoliosis > 20 degrees or spondylolisthesis
Reduced extensions at the elbows (< 170 degrees)
Medial displacement of the medial malleolus causing pes planus
Protrusio acetabulare of any degree (ascertained on radiographs)
Pectus excavatum of moderate severity
Joint hypermobility
Highly arched palate with crowding of teeth
Facial appearance (dolichocephaly, malar hypoplasia,
enophthalmos, retrognathia, down-slating palpebral
fissures)
Ocular
Ectopia lentis (dislocated lens)
Abnormally flat cornea (as measured by keratometry)
Increased axial length of globe (as measured by ultrasound)
Cardiovascular
Dilatation of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of Valsalva or dissection of the ascending aorta
Mitral valve prolapse with or without mitral valve regurgitation
Dilatation of the main pulmonary artery, in the absence
of valvular or peripheral pulmonic stenosis or any other
obvious cause in patients age < 40 years
Calcification of the mitral annulus in patients age < 40
years
Dilatation of dissection of the descending thoracic or
abdominal aorta in patients age < 50 years
Pulmonary
None
Spontaneous pneumothorax
Apical blebs (ascertained by chest radiography)
Skin and integument
None
Stretch marks not associated with marked weight changes,
pregnancy, or repetitive stress
Recurrent incisional hernias
Dura
Lumbosacral dural ectasia as demonstrated by computed
tomography or magnetic resonance imaging scans
None
NOTE: In the presence of family history, the diagnosis of Marfan syndrome is confirmed by the involvement of at least 2 systems (skeletal, cardiovascular, ocular) and the presence of at least 1 major criterion (eg, ascending aortic aneurysm, ectopia lentis). When family history is negative
or unknown, the patient must meet major criteria in 2 systems and have involvement of at least 1 other system (skeletal, cardiovascular, ocular).
Adapted from De Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet
1996;62:417–26. Reprinted with permission from Wiley-Liss, Inc., a subsuduary of John Wiley & Sons, Inc.
detail (eg, marfanoid habitus, family history of cardiac
disease, lens abnormalities) as well as receive a thorough
physical examination to assess for characteristic clinical
features, especially in the skeletal, cardiac, and ocular
systems. Skeletal examination should include anthropometric measurements of height, arm span-to-height
ratio, upper-to-lower segment ratio, and hand and foot
measurements. The upper segment of the body is measured from the top of the head to the top of the pubic
ramus, and the lower segment is measured from the top
36 Hospital Physician April 2006
of the pubic ramus to the floor. The ratio of upper body
to lower body in Marfan syndrome is usually less than
0.85. Patients should be examined for arachnodactyly;
positive wrist or Walker’s sign (the distal phalange of the
first and fifth fingers of the hand overlap when wrapped
around the opposite wrist; Figure 6); and positive thumb
or Steinberg sign (the thumb projects beyond the ulnar
border while completely opposed within the clenched
hand; Figure 7). When arachnodactyly is subtle clinically, a radiograph of the hand can be used to calculate the
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Rangasetty & Karnath : Marfan Syndrome : pp. 33 – 38
Figure 5. Ectopia lentis-supranasal subluxation of the lens.
(Reprinted with permission from Chua CN, Rauz S. Success
in MCQs for final FRCOphth/MRCOphth. Vol 2. London: BMJ
Publishing; 1998. Available at www.mrcophth.com/cataract/
ectopialentis.html. Accessed 3 Mar 2006.)
metacarpal index,13 which is determined by dividing the
length of each of the last 4 metacarpals by the width of
its midpoint and averaging the values. The metacarpal
index in Marfan syndrome patients is usually more than
8,5 whereas normal is 8 or less.
Eye examination with pupillary dilatation should be
performed to look for ectopia lentis (Figure 5). In
some cases, slit-lamp examination by the ophthalmologist may be required. The cardiac evaluation includes
auscultation and echocardiography. Computed tomography or magnetic resonance imaging may be required
to identify dural ectasia in the absence of specific clinical manifestations.7
Differential Diagnosis
Before the diagnosis of Marfan syndrome can be
made, other conditions with similar features (Table 2)
must be ruled out. Serum methionine levels should be
assessed to rule out homocystinuria in all suspected
cases because effective therapy is available.14 Homocystinuria is an autosomal recessive disorder characterized
by marfanoid habitus, arachnodactyly, pectus excavatum or carinatum, hypermobile joints, and ectopia
lentis. Approximately 60% of patients have mental
retardation, and these patients are at increased risk of
vascular thrombosis. Marfan syndrome must also be distinguished from congenital contractural arachnodactyly
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Figure 6. Positive (Walker) wrist sign.
Figure 7. Positive (Steinberg) thumb sign.
(Beals’ syndrome), which is an inherited disorder that
presents with joint contracture and arachnodactyly
but does not include lens or aortic abnormalities.
Shprintzen-Goldberg syndrome can be differentiated
from Marfan syndrome by the presence of exophthalmos, craniosynostosis, and mental retardation. Familial
ectopia lentis is not associated with other manifestations of Marfan syndrome, whereas patients with the
MASS phenotype never demonstrate progressive aortic
dilatation or lens dislocation. Other conditions associated with mitral valve prolapse, Klinefelter’s syndrome,
and multiple endocrine neoplasia IIB should also be
excluded.14
CONCLUSION
Marfan syndrome is the most common inherited
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Rangasetty & Karnath : Marfan Syndrome : pp. 33 – 38
connective tissue disorder and is characterized by diverse clinical manifestations. Genetic testing is nonspecific, and the diagnosis is based on clinical criteria.
When evaluating patients for Marfan syndrome, clinicians need to be aware that symptoms and signs are
age-dependent and manifestations of the syndrome
vary among patients. Additional information about
Marfan syndrome can be found at www.marfan.org and
HP
www.marfanworld.org.
REFERENCES
1. Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome
caused by a recurrent de novo missense mutation in the
fibrillin gene. Nature 1991;352:337–9.
2. Pyeritz RE. Disorders of fibrillins and microfibrilogenesis: marfan syndrome, MASS phenotype, contractural
arachnodactyly and related conditions. In: Rimoin DL,
Connor JM, Pyeritz RE, editors. Emery and Rimoin’s
principles and practice of medical genetics. 3rd ed. New
York: Churchill Livingstone; 1997:1027–66.
3. Pyeritz RE. The Marfan syndrome. Ann Rev Med 2000;
51:481–510.
4. Grimes SJ, Acheson LS, Matthews AL, Wiesner GL. Clinical consult: Marfan syndrome. Prim Care 2004;31:739–
42, xii.
5. Murdoch JL, Walker BA, Halpern BL, et al. Life expectancy and causes of death in the Marfan syndrome.
N Engl J Med 1972;286:804–8.
6. Maumenee IH. The eye in the Marfan syndrome. Trans
Am Ophthalmol Soc 1981;79:684–733.
7. Cross HE, Jensen AD. Occular manifestations in the Marfan syndrome and homocystinuria. Am J Ophthalmol
1973;75:405–20.
8. Fuchs J. Marfan syndrome and other systemic disorders
with congenital ectopia lentis. A Danish national survey.
Acta Paediatr 1997;86:947–52.
9. Grahame R, Pyeritz RE. The Marfan syndrome: joint
and skin manifestations are prevalent and correlated. Br
J Rheumatol 1995;34:126–31.
10. Hall JR, Pyeritz RE, Haller JA Jr. Pneumothorax in the
Marfan syndrome: prevalence and therapy. Ann Thorac
Surg 1984;37:500–4.
11. Ahn NU, Sponseller PD, Ahn UM, et al. Dural ectasia in
the Marfan syndrome: MR and CT findings and criteria.
Genet Med 2000;2:173–9.
12. De Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet
1996;62:417–26.
13. Eldridge R. The metacarpal index. A useful aid in the
diagnosis of the Marfan syndrome. Arch Intern Med 1964;
113:248–54.
14. Child AH, Nuemann L, Robinson PN. Diagnosis and treatment of Marfan syndrome—a summary. In: Robinson PN,
Godfrey M, editors. Marfan syndrome: a primer for clinicians and scientists. New York: Kluwer Academic/Plenum;
2004.
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38 Hospital Physician April 2006
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