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. 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

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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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

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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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

Figure 4. Highly arched palate associated with Marfans 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 (Klinefelters syndrome) Sticklers 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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Table 3. Ghent Criteria for Diagnosing Marfan Syndrome

System
Family/genetic history

Major
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 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) Ectopia lentis (dislocated lens)

Minor
None

Skeletal

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

Abnormally flat cornea (as measured by keratometry) Increased axial length of globe (as measured by ultrasound) 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 Spontaneous pneumothorax Apical blebs (ascertained by chest radiography) Stretch marks not associated with marked weight changes, pregnancy, or repetitive stress Recurrent incisional hernias None

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

Pulmonary Skin and integument Dura

None None

Lumbosacral dural ectasia as demonstrated by computed tomography or magnetic resonance imaging scans

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

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 Walkers 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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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.)

Figure 6. Positive (Walker) wrist sign.

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

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, Klinefelters syndrome, and multiple endocrine neoplasia IIB should also be excluded.14 CONCLUSION Marfan syndrome is the most common inherited

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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 Rimoins 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 syndromea 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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