Clinical Signs of Marfan Syndrome - Hospital Clinical Signs of Marfan Syndrome Umamahesh C. Rangasetty, MD Bernard M. Karnath, MD SALIENT FEATURES OF MARFAN SYNDROME Skeletal ... or

arfan syndrome is the most common inherit-ed connective tissue disorder, with a re-ported incidence of 1 in 10,000 individualsand equal distribution between the sexes.1 It

is caused by an autosomal dominant mutation in thegene encoding fibrillin (FBN1, chromosome 15q15–21.3),2 a glycoprotein that is an integral part of the con-nective tissue in the body (eg, ligaments, blood vessel,eye lenses). Although the genetic and biochemicalbases of the condition have been identified, the diseasecontinues to be underdiagnosed.3,4 If unrecognized,patients with Marfan syndrome may potentially developaortic rupture or sudden cardiac death5; therefore, it isimportant to identify this potentially life-threateningcondition. This article reviews clinical signs associatedwith Marfan syndrome and discusses the diagnostic cri-teria and differential diagnosis.

CLINICAL PRESENTATION

Most patients who have Marfan syndrome are usual-ly diagnosed incidentally when they present for a rou-tine physical examination for various reasons, such as apre-employment physical or screening examinationprior to participation in sports. Marfan syndrome pri-marily involves the skeletal, ocular, and cardiovascularsystems. Typically, patients with Marfan syndrome pre-sent with tall stature, ectopia lentis, aortic root dilata-tion, and a positive family history. Less frequently, thediagnosis is made when a patient presents with compli-cations of the syndrome, such as aortic dissection, orwith involvement of the pulmonary, skin/integument,or nervous systems.5 Presentation of the disease variesgreatly, even among family members. Some personswith Marfan syndrome experience only mild effects,whereas others have severe problems. Uncommon pre-sentations are summarized in Table 1. In most cases,the disease worsens with age.

Skeletal Features

Skeletal manifestations are the cardinal signs ofMarfan syndrome and usually gain the attention of a

physician. The most common features include tallstature with the lower segment of the body greater thanthe upper segment (Figure 1) and long, slender limbs,or dolichostenomelia; thin body habitus with increasedarm span-to-height ratio; long, slender fingers, orarachnodactyly (Figure 2); deformities of the chest,such as pectus carinatum (Figure 3) or pectus excava-tum; scoliosis; and highly arched palate with crowdedteeth and dental malocclusion (Figure 4). Other lesscommon manifestations include hypermobility ofjoints, flat foot (pes planus), reduced extension ofelbows (< 170 degrees), and elongated face (dolicho-cephalia).

M

Dr. Rangasetty is a resident, and Dr. Karnath is an associate professor ofmedicine, Division of General Medicine; both are at the University ofTexas Medical Branch at Galveston, Galveston, TX.

www.turner-white.com Hospital Physician April 2006 33

R e v i e w o f C l i n i c a l S i g n s

Series Editor: Bernard M. Karnath, MD

Clinical Signs of Marfan Syndrome

Umamahesh C. Rangasetty, MDBernard M. Karnath, MD

SALIENT FEATURES OF MARFAN SYNDROME

SkeletalDisproportionately long limbs (span > height) and dig-

its or reduced upper-to-lower segment ratioPectus excavatum or carinatumScoliosisHighly arched palate with dental crowding

OcularEctopia lentis (dislocation or subluxation of the lens)

CardiovascularDilatation of the aortic root with regurgitationAortic aneurysm and/or dissection

MiscellaneousSkin striaeDural ectasia

Cardiovascular Features

Cardiovascular manifestations are the most seriouscomplications and determine the prognosis and sur-vival in Marfan syndrome. Abnormalities include aorticroot dilatation, aortic regurgitation, aortic dissection,and aortic aneurysm, which most commonly involvesthe ascending aorta but can involve the descendingaorta. The rate of aortic root dilatation is unpredict-able and usually requires surgery when it measuresmore than 50 mm. Mitral valve prolapse can also occur.Although cardiovascular abnormalities typically appearlate, they can occur during childhood.4

Ocular Features

Ectopia lentis (subluxation of lens; Figure 5) is ahallmark feature of Marfan syndrome and is present inapproximately 60% to 80% of patients.6 – 8 Ectopialentis is usually bilateral, symmetrical, and upward. Thediagnosis can be made by looking for iridodonesis(tremor of iris), phacodonesis (abnormal movementof lens), and a deep anterior chamber in the nondilat-ed eye. The dislocation may be complete, with the lensfloating free within the vitreous cavity. Other non-specific ocular features of Marfan syndrome includemyopia, elongated eye, flat cornea, and retinal detach-ment.

Miscellaneous Features

Striae may occur over the shoulders and buttocks.Inguinal and incisional hernias are common.9 Pulmo-nary manifestations include spontaneous pneumotho-rax and apical blebs.10 Marked dilatation of the duralsac may be seen frequently in computed tomographyor magnetic resonance imaging scans,11 but the condi-tion is usually asymptomatic.

34 Hospital Physician April 2006 www.turner-white.com

R a n g a s e t t y & K a r n a t h : M a r f a n S y n d r o m e : p p . 3 3 – 3 8

Figure 1. External phenotype of Marfan syndrome showing tallstature, long arm span, and limbs disproportionately greaterthan the body. (Reprinted from Braunwald. Heart disease: atextbook of cardiovascular medicine, 6th ed. Philadelphia: WBSaunders Company; 2001:2001, with permission from Elsevier.)

Figure 2. Arachnodactyly: long and slender fingers (Re-printed with permission from Chua CN, Rauz S. Success inMCQs for final FRCOphth/MRCOphth. Vol 2. London: BMJPublishing; 1998. Available at www.mrcophth.com/cataract/ectopialentis.html. Accessed 3 Mar 2006.)

Table 1. Uncommon Presentations of Marfan Syndrome

Present at birth, rapid aortic dilatation, deformities, and death

Dominant ectopia lentis with variable skeletal and negligible cardiacinvolvement

Mitral valve prolapse without skeletal features

Dominant aortic aneurysm without skeletal and ocular features

DIAGNOSTIC EVALUATION

Marfan syndrome is a clinical diagnosis based onthe observation of specific physical signs and family his-tory. However, diagnosing patients with this syndromeis a challenge because of the increased prevalence ofmarfanoid features in the general population, widevariations in its clinical presentation even among thefamily members, and features that overlap with otherconnective tissue disorders (Table 2).3 Genetic testingby itself cannot differentiate Marfan syndrome fromother genetic connective tissue disorders because themany mutations in FBN1 have been linked to otherclinical entities.4 Diagnosis is further complicated byage dependency of symptoms and signs, which leads toa changing clinical picture and is the reason youngerpatients with suspected Marfan syndrome who do notfulfill the clinical diagnostic criteria should be offeredrepeat clinical evaluations.4

Despite these challenges, the diagnosis can be estab-lished by a comprehensive clinical evaluation, anddiagnostic criteria have been established. The Ghentcriteria (Table 3) are based upon family/genetic histo-ry, involvement of organ systems (primarily skeletal,cardiovascular, and ocular), and whether the clinicalsign is major or minor.12 Major criteria are specific forMarfan syndrome and are rarely present in the generalpopulation. According to these criteria, Marfan syn-drome in a patient with unequivocal family history isdiagnosed when there is major involvement in 1 organsystem (skeletal, cardiovascular, or ocular) and involve-ment of a second organ system. If the patient has no

first-degree relative who is unequivocally affected byMarfan syndrome, the patient must have major criteriain at least 2 different organ systems and involvement ofa third (skeletal, cardiovascular, and ocular) to be diag-nosed with Marfan syndrome.

Because the diagnosis of Marfan syndrome is clinical,patients should have their family history reviewed in



Figure 3. Pectus carinatum.Figure 4. Highly arched palate associated with Marfan’s syn-drome. (Reprinted with permission from Chua CN, Rauz S. Suc-cess 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, andskeletal) 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 andtreatment of Marfan syndrome—a summary. In: Robinson PN,Godfrey M, editors. Marfan syndrome: a primer for clinicians and sci-entists. New York: Kluwer Academic/Plenum; 2004:19, with permis-sion from Springer Science and Business Media.

detail (eg, marfanoid habitus, family history of cardiacdisease, lens abnormalities) as well as receive a thoroughphysical examination to assess for characteristic clinicalfeatures, especially in the skeletal, cardiac, and ocularsystems. Skeletal examination should include anthropo-metric measurements of height, arm span-to-heightratio, upper-to-lower segment ratio, and hand and footmeasurements. The upper segment of the body is mea-sured from the top of the head to the top of the pubicramus, and the lower segment is measured from the top

of the pubic ramus to the floor. The ratio of upper bodyto lower body in Marfan syndrome is usually less than0.85. Patients should be examined for arachnodactyly;positive wrist or Walker’s sign (the distal phalange of thefirst and fifth fingers of the hand overlap when wrappedaround the opposite wrist; Figure 6); and positive thumbor Steinberg sign (the thumb projects beyond the ulnarborder while completely opposed within the clenchedhand; Figure 7). When arachnodactyly is subtle clinical-ly, a radiograph of the hand can be used to calculate the



Table 3. Ghent Criteria for Diagnosing Marfan Syndrome

System Major Minor

Family/genetic history

Skeletal

Ocular

Cardiovascular

Pulmonary

Skin and integu-ment

Dura

NOTE: In the presence of family history, the diagnosis of Marfan syndrome is confirmed by the involvement of at least 2 systems (skeletal, car-diovascular, ocular) and the presence of at least 1 major criterion (eg, ascending aortic aneurysm, ectopia lentis). When family history is negativeor 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 Genet1996;62:417–26. Reprinted with permission from Wiley-Liss, Inc., a subsuduary of John Wiley & Sons, Inc.

Having a first-degree relative (parent, child, or sibling) whomeets 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 Marfansyndrome in the family

Presence of at least 4 of the following manifestations: Pectus carinatumPectus 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 spondylolisthesisReduced extensions at the elbows (< 170 degrees)Medial displacement of the medial malleolus causing pes planus Protrusio acetabulare of any degree (ascertained on radio-

graphs)

Ectopia lentis (dislocated lens)

Dilatation of the ascending aorta with or without aortic regurgi-tation and involving at least the sinuses of Valsalva or dissec-tion of the ascending aorta

None

None

Lumbosacral dural ectasia as demonstrated by computedtomography or magnetic resonance imaging scans

None

Pectus excavatum of moderate severity Joint hypermobilityHighly arched palate with crowding of teethFacial appearance (dolichocephaly, malar hypoplasia,

enophthalmos, retrognathia, down-slating palpebral fissures)

Abnormally flat cornea (as measured by keratometry)Increased axial length of globe (as measured by ultra-

sound)

Mitral valve prolapse with or without mitral valve regur-gitation

Dilatation of the main pulmonary artery, in the absenceof valvular or peripheral pulmonic stenosis or any otherobvious cause in patients age < 40 years

Calcification of the mitral annulus in patients age < 40years

Dilatation of dissection of the descending thoracic orabdominal 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

metacarpal index,13 which is determined by dividing thelength of each of the last 4 metacarpals by the width ofits midpoint and averaging the values. The metacarpalindex in Marfan syndrome patients is usually more than8,5 whereas normal is 8 or less.

Eye examination with pupillary dilatation should beperformed to look for ectopia lentis (Figure 5). Insome cases, slit-lamp examination by the ophthalmolo-gist may be required. The cardiac evaluation includesauscultation and echocardiography. Computed tomog-raphy or magnetic resonance imaging may be requiredto identify dural ectasia in the absence of specific clini-cal manifestations.7

Differential Diagnosis

Before the diagnosis of Marfan syndrome can bemade, other conditions with similar features (Table 2)must be ruled out. Serum methionine levels should beassessed to rule out homocystinuria in all suspectedcases because effective therapy is available.14 Homocys-tinuria is an autosomal recessive disorder characterizedby marfanoid habitus, arachnodactyly, pectus excava-tum or carinatum, hypermobile joints, and ectopialentis. Approximately 60% of patients have mentalretardation, and these patients are at increased risk ofvascular thrombosis. Marfan syndrome must also be dis-tinguished from congenital contractural arachnodactyly

(Beals’ syndrome), which is an inherited disorder thatpresents with joint contracture and arachnodactyly but does not include lens or aortic abnormalities.Shprintzen-Goldberg syndrome can be differentiatedfrom Marfan syndrome by the presence of exophthal-mos, craniosynostosis, and mental retardation. Familialectopia lentis is not associated with other manifesta-tions of Marfan syndrome, whereas patients with theMASS phenotype never demonstrate progressive aorticdilatation or lens dislocation. Other conditions associ-ated with mitral valve prolapse, Klinefelter’s syndrome,and multiple endocrine neoplasia IIB should also beexcluded.14

CONCLUSION

Marfan syndrome is the most common inherited



Figure 6. Positive (Walker) wrist sign.

Figure 7. Positive (Steinberg) thumb sign.

Figure 5. Ectopia lentis-supranasal subluxation of the lens.(Reprinted with permission from Chua CN, Rauz S. Successin MCQs for final FRCOphth/MRCOphth. Vol 2. London: BMJPublishing; 1998. Available at www.mrcophth.com/cataract/ectopialentis.html. Accessed 3 Mar 2006.)

connective tissue disorder and is characterized by di-verse clinical manifestations. Genetic testing is nonspe-cific, and the diagnosis is based on clinical criteria.When evaluating patients for Marfan syndrome, clini-cians need to be aware that symptoms and signs areage-dependent and manifestations of the syndromevary among patients. Additional information aboutMarfan syndrome can be found at www.marfan.org andwww.marfanworld.org. HP

REFERENCES

1. Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndromecaused by a recurrent de novo missense mutation in thefibrillin gene. Nature 1991;352:337–9.

2. Pyeritz RE. Disorders of fibrillins and microfibrilogene-sis: marfan syndrome, MASS phenotype, contracturalarachnodactyly and related conditions. In: Rimoin DL,Connor JM, Pyeritz RE, editors. Emery and Rimoin’sprinciples and practice of medical genetics. 3rd ed. NewYork: 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. Clin-ical consult: Marfan syndrome. Prim Care 2004;31:739–42, xii.

5. Murdoch JL, Walker BA, Halpern BL, et al. Life ex-pectancy 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 Mar-

fan syndrome and homocystinuria. Am J Ophthalmol1973;75:405–20.

8. Fuchs J. Marfan syndrome and other systemic disorderswith congenital ectopia lentis. A Danish national survey.Acta Paediatr 1997;86:947–52.

9. Grahame R, Pyeritz RE. The Marfan syndrome: jointand skin manifestations are prevalent and correlated. BrJ Rheumatol 1995;34:126–31.

10. Hall JR, Pyeritz RE, Haller JA Jr. Pneumothorax in theMarfan syndrome: prevalence and therapy. Ann ThoracSurg 1984;37:500–4.

11. Ahn NU, Sponseller PD, Ahn UM, et al. Dural ectasia inthe 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 diag-nostic criteria for the Marfan syndrome. Am J Med Genet1996;62:417–26.

13. Eldridge R. The metacarpal index. A useful aid in thediagnosis of the Marfan syndrome. Arch Intern Med 1964;113:248–54.

14. Child AH, Nuemann L, Robinson PN. Diagnosis and treat-ment of Marfan syndrome—a summary. In: Robinson PN,Godfrey M, editors. Marfan syndrome: a primer for clini-cians and scientists. New York: Kluwer Academic/Plenum;2004.



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Clinical Signs of Marfan Syndrome - Hospital Clinical Signs of Marfan Syndrome Umamahesh C. Rangasetty, MD Bernard M. Karnath, MD SALIENT FEATURES OF MARFAN SYNDROME Skeletal ... or