ARTICLE IN PRESS

Current Orthopaedics (2006) 20, 418423

Available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/cuor

SYNDROMES

Marfan syndrome
Andrew R.T. McBridea, Martin Garganb,
a

Department of Trauma & Orthopaedic Surgery, Weston General Hospital, Grange Road, Weston-super-Mare BS23 4TQ, UK
Department of Trauma & Orthopaedic Surgery, Bristol Royal Hospital for Sick Children, Bristol BS2 8HW, UK

KEYWORDS
Marfan syndrome;
Connective tissue disease

Summary
Marfan syndrome is an inherited connective tissue disorder with multi-organ system
involvement caused by mutations in the gene encoding the glycoprotein brillin-1 (FBN1).
The condition presents to the orthopaedic surgeon with an array of musculoskeletal
problems. This article will review the pathogenesis, diagnosis, clinical manifestations and
treatment options.
& 2006 Elsevier Ltd. All rights reserved.

Introduction

Antoine Bernard-Jean Marfan

Marfan syndrome is an autosomal dominant inherited

disorder of connective tissue. Clinical manifestations are
varied in range and severity and involve many organs. The
majority of anomalies are found in the cardiovascular,
respiratory, ocular and skeletal systems. Advances in the
medical and surgical treatment of life threatening cardiovascular complications of the condition now enable more
individuals to expect an improved life expectancy.1 However
this longevity is associated with an increased frequency of
musculoskeletal problems.
Specic musculoskeletal anomalies may be found in the
spine, hip, knee, hand, and foot. Generalised joint laxity
and an increased incidence of joint dislocation also feature.
Arthralgia is a common complaint in all age groups.

Antoine Bernard-Jean Marfan was born in Castlenaudary,

Southern France in 1858. He completed his medical training
in Paris in 1886. A career in paediatrics followed, culminating
in a professorship at the University of Paris School of Medicine.
In 1896, Marfan presented the case of a 5-year-old girl to the
Socie
te Medicale des Ho
pitaux de Paris. He described her
disproportionately long limbs and her ngers as pattes
daraignee (spider ngers). He called her condition dolichostenome
lie (slender limbs). Retrospective analysis has
shown this was probably a case of Beals syndrome. However
Marfans description of over one hundred similar cases led to
the discovery of the disorder named after him.2

Corresponding author. Tel.: +44 117 928 2121;

fax: +44 117 928 2659.
E-mail addresses: Andrew.McBride@Bristol.ac.uk
(A.R.T. McBride), martin.gargan@ubht.swest.nhs.uk (M. Gargan).

0268-0890/$ - see front matter & 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cuor.2006.09.007

Epidemiology and genetics

The incidence of the disorder is approximately 1 in 5000,
sporadic mutations making up a quarter of all cases. No
particular racial or geographical factors are recognised
features.2
The condition is inherited in an autosomal dominant
pattern with a high degree of penetrance but variable

ARTICLE IN PRESS
Marfan syndrome

Table 1

419

Revised (Ghent) diagnostic criteria.5

Major criteria
Skeletal system
 pectus carinatum
 pectus excavatum requiring surgery
 reduced upper to lower segment ratio or arm span to height ratio
41.05
 positive wrist and thumb signs
 scoliosis of 4201 or spondylolisthesis
 reduced extension of the elbows (o1701)
 medial displacement of the medial malleolus causing pes planus
 protrusio acetabuli of any degree

Minor criteria






pectus excavatum of moderate severity

joint hypermobility
high arched palate
facial appearance (dolichocephaly, malar
hypoplasia, enophthalmos, retrognathia,
down-slanting palpebral ssures)

At least two components of the major criteria or one major criterion and two minor criteria must be present for the skeletal
system to be considered in the diagnosis.
Ocular system
 ectopia lentis

 abnormally at cornea (as measured by

keratometry)

 increased axial length of globe (as measured

by ultrasound)

 hypoplastic iris or hypoplastic ciliary muscle

causing decreased miosis
At least two minor criteria must be present for the ocular system to be considered in the diagnosis.
Cardiovascular system
 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, below the age of 40 years
 calcication of the mitral annulus below the
age of 40 years; or
 dilatation or dissection of the descending
thoracic or abdominal aorta below the age
of 50 years

One major criterion or one minor criterion must be present for the cardiovascular system to be considered in the diagnosis.
Pulmonary system
 none

 spontaneous pneumothorax; or
 apical blebs (ascertained by chest
radiography)

One minor criterion must be present for the pulmonary system to be considered in the diagnosis.
Skin and integument
 none

 striae atrophicae (stretch marks) not

associated with marked weight changes,
pregnancy or repetitive stress, or
 recurrent or incisional herniae

One minor criterion must be present for the skin and integument to be considered in the diagnosis.
Dura
 lumbosacral dural ectasia (CT or MRI)

 none

The major criterion must be present for dura to be considered in the diagnosis.

ARTICLE IN PRESS
420

A.R.T. McBride, M. Gargan

Table 1 (continued )
Major criteria

Minor criteria

Family/genetic history
 having a parent, child or sibling who meets these criteria
independently
 presence of a mutation in FBN1 known to cause the Marfan syndrome;
or
 presence of a haplotype around FBN1, inherited by descent, known to
be associated with unequivocally diagnosed Marfan syndrome in the
family

 none

One major criterion must be present for the family/genetic history to be considered in the diagnosis.

Figure 1 Arachnodactyly.

phenotypical expression. Mutations in the gene encoding the

glycoprotein brillin-1 (FBN1) situated on chromosome
15q21 cause Marfan syndrome.3 Despite the discovery and
genetic mapping of the FBN1 gene, its large size and a lack
of mutational hot spots have prevented the development of
a single and therefore clinically useful genetic test.1
FBN1 is an important component of extracellular microbrils. The exact role of microbrils is unclear but they are
found in a wide range of connective tissues and are vital for
normal elastogenesis, elasticity and homoeostasis of elastic
bres.
The molecular pathogenesis of Marfan syndrome has yet
to be accurately dened. Mutated FBN1 proteins may
interfere with the correct assembly of mature microbrils
or the defective proteins may increase their susceptibility to
proteolysis.4

unfortunately late diagnosis is not uncommon. Due to the

lack of a molecular diagnostic test, diagnosis depends upon
the revised (Ghent) clinical criteria5 (Table 1).
The large variation in phenotypical expression of clinical
features can make diagnosis difcult. Large variation can
even be encountered between affected individuals of the
same family. Overlap of clinical features with other Marfanlike disorders also requires care when diagnosing a new case
of Marfan syndrome. The differential diagnosis includes
homocystinuria, Beals syndrome (congenital contractual
arachnodactyly), EhlersDanlos syndrome, Stickler syndrome (hereditary arthro-ophthalmopathy), Klinefelter syndrome, familial mitral valve prolapse syndrome, multiple
endocrine adenomatosis and X-linked mental retardation
with marfanoid habitus.

Skeletal features
Clinical diagnosis
The progressive and potentially fatal clinical features of
Marfan syndrome make early diagnosis very important;

The typical body habitus in the Marfan syndrome comprises

tall stature, with disproportionately long, slender limbs
compared with the trunk (dolichostenomelia). At birth the

ARTICLE IN PRESS
Marfan syndrome

421

Figure 2 Thumb sign.

Figure 4

Figure 3

Wrist sign.

Figure 5

Scoliosis.

Dural ectasia (MRI scan).

ARTICLE IN PRESS
422

A.R.T. McBride, M. Gargan

Marfan infant is longer than the normal infant; this

difference remains through childhood into adult life. Growth
rates compared to a normal population are increased in
childhood. The puberty-associated growth spurt and skeletal
maturation occur early.6
The upper body to lower body segment ratio is reduced
(o0.85), this may be exaggerated by spinal deformity.
Arachnodactyly is a non-specic feature (Fig. 1). However,
the thumb sign (positive if the thumb nail, when the thumb
is maximally opposed within a clenched st, projects beyond
the ulnar border of the hand) (Fig. 2), or the wrist sign
(overlap of the thumb on the terminal phalanx of the little
nger when held around the contralateral wrist) (Fig. 3),
feature as major skeletal criteria in the revised (Ghent)
diagnostic system. Pectus excavatum (depression) or carinatum (protrusion) deformities of the anterior chest wall
due to longitudinal overgrowth of the ribs occur, often
progressing and evolving with age. The facial skeleton is
affected, including a high-arched palate, a narrow jaw
(resulting in crowded dentition) and retrognathia leading to
malocclusion and obstructive sleep apnoea.
Abnormal FBN1 may affect calcium binding in bone;
however the investigations of lowered bone mineral density
by DEXA analysis have been inconclusive so far. Whether or
not the improving life expectancy of the Marfan population
will render individuals more susceptible to later onset
osteoporosis remains to be seen.7

infancy tends to progress relentlessly. Around half of

individuals will have a kyphosis of more than 501.8
The prevalence of a lumbosacral spondylolisthesis is only
slightly higher in the young Marfan population (6%)
compared to the general population (3%). However the
degree of forward slip, when it is seen, is probably much
greater (30%) than in the normal population (15%).8
The frequency of back pain in the Marfan population is
greater than in an age-matched normal population (age
range 3545 years: 53% vs. 13%, p 0.001). Functional
impairment due to pain is also signicantly greater
(p 0.001).8
Atlantoaxial rotatory instability has also been reported.9
Dural ectasia, a dilatation of the dural sac or nerve root
sleeve, occurs in up to 90% of individuals, usually at the L5-S1
level (Fig. 5). The severity can be graded 13 with most
patients having a grade 2 (moderate) dilatation.10 Dural
ectasia occurs as a result of the gradual pulsatile effect of
CSF in combination with gravity upon the abnormally
composed dura mater of the dural sac. The expansion of
the dural sac can cause erosion and scalloping of the
vertebral bodies and the development of a meningocele.
Mild cases are usually asymptomatic, but moderate and
severe cases can be associated with, the symptoms of
headache, low back pain, radicular pain radiating into the
buttocks and legs and rarely urinary symptoms or motor
weakness.11

The lower limb

Specic orthopaedic problems

Spine
Spinal deformity is one of the most common skeletal
manifestations encountered. Between 50% and 60% of
individuals have a scoliosis at one or more vertebral levels8
(Fig. 4). The prevalence between the sexes is equal.
Approximately one-fth of these will have a severe
deformity. Deformity usually worsens during the rapid
growth of early adolescence so that scoliosis detected in

Figure 6

Developmental dysplasia of the hip is probably increased but

does not represent a common clinical problem.12 Protrusio
acetabuli is common affecting up to 77% of individuals.13
Genu valgum can occur late in childhood.
The foot is long and narrow with arachnodactyly. Joint
laxity in the foot leads to a number of problems. Severe
deformities left untreated can lead to signicant discomfort
and gait disturbances. Pes planus (with or without calcaneoplano valgus) affects 25% of individuals (Fig. 6), hallux
valgus is also common.14

Pes planus.

ARTICLE IN PRESS
Marfan syndrome

Other joint problems

Joint laxity is frequently encountered, with hyperextensible
ngers, wrists, elbows and knees. Some individuals have joint
contractures, usually affecting the ngers and elbow. These
can co-exist with lax joints in a proportion of patients.
Recurrent dislocations can occur, most commonly affecting the
rst metacarpophalangeal joints and patellae. Ligamentous
sprains are commonly encountered. Arthalgia is a common
complaint in all age groups and the older Marfan patient
commonly has arthritis in those previously lax joints.15

423

 If a mutation known to cause Marfan syndrome in others

is detected, a major criterion in an organ system and
involvement of another system must be present.
For a relative of an index case:

 Presence of a major criterion from the family/genetic

history and from one organ system with involvement of a
second.

Orthopaedic management
References
A multi-disciplinary team approach is advised. Close cooperation with a geneticist, paediatrician and cardiologist is
required because of the life threatening complications that
can occur.
Early diagnosis and treatment of deformity can slow
progression and improve function. Spinal complications may
require early surgical intervention including fusion and instrumentation in childhood or adolescence depending on the
severity of deformity, symptoms and age of the patient. Bracing
is generally unsuccessful because of the severity or rigidity of
curves or the poor maintenance of correction obtained.16
Protrusio acetabuli in childhood should be closely followed with serial radiographs. Early surgical intervention is
recommended with closure of the triradiate cartilage in
patients with signicant radiographic progression before
waiting for the onset of pain or stiffness.13
Foot problems are common but can usually be treated with
orthotics, a triple fusion maybe rarely be required for the pes
planovalgus foot to improve pain relief, stability and function.
Severe genu valgum in late childhood can be treated with
hemiepiphyseal stapling.

Pre-operative considerations
Cardiovascular assessment is mandatory before embarking
on any major orthopaedic surgery because of the threat to
life from mitral valve prolapse and aortic dilatation. Blood
pressure is usually maintained below normal with antihypertensive agents. Antibiotic prophylaxis is indicated
before the majority of surgical procedures. Anti-coagulation
for prosthetic heart valves may have to be negotiated.
Individuals are at risk from spontaneous pneumothoraces,
usually arising from an apical bulla, which may complicate
an already compromised pulmonary reserve from spinal or
chest wall deformity.
Spinal surgery requires careful planning and the judicious
use of pre-operative CT and MRI scans to assess pedicle
adequacy and the presence of dural ectasia. Large blood
losses should be anticipated and staged procedures considered when possible.17
Requirements for diagnosis of Marfan syndrome
For an index case:

 If the family/genetic history is not contributory, at least

two different organ systems and involvement of a third
system must be present.

1. Silverman DI, Burton KJ, Gray J, Bosner MS, Kouchoukos NT,

Roman MJ, et al. Life expectancy in the Marfan syndrome. Am J
Cardiol 1995;75:15760.
2. Ho NCY, Tran JR, Bektas A. Marfans syndrome. Lancet 2005
[published online August 2, 2005].
3. Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corsen
GM, et al. Marfan syndrome caused by a recurrent de novo
missense mutation in the brillin gene. Nature 1991;352:
3379.
4. Robinson PN, Booms P. The molecular pathogenesis of the
Marfan syndrome. Cell Mol Life Sci 2001;58:1698707.
5. De Paepe A, Devereux RB, Dietz HC, Hennekam RCM, Pyeritz RE.
Revised diagnostic criteria for the Marfan syndrome. Am J Hum
Genet 1996;62:41726.
6. Erkula G, Jones KB, Sponseller PD, Dietz HC, Pyeritz RE. Growth
and maturation in Marfan syndrome. Am J Med Genet
2002;109:10015.
7. Giampietro PF, Peterson M, Schneider R, Davis JG, Raggio C,
Myers E, et al. Assessment of bone mineral density in adults and
children with Marfan syndrome. Osteoporos Int 2003;14:
55963.
8. Sponseller PD, Hobbs W, Riley LH, Pyeritz RE. The thoracolumbar spine in Marfan syndrome. J Bone Jt Surg 1995;77A:
86776.
9. Herzaka A, Sponseller PD, Pyeritz RE. Atlantoaxial rotatory
subluxation in patients with Marfan syndrome. Spine 2000;25:
5246.
10. Fattori R, Nienaber CA, Descovich B, Ambrosetto P, Reggiani LB,
Pepe G, et al. Importance of dural ectasia in
phenotypic assessment of Marfans syndrome. Lancet 1999;354:
9103.
11. Foran JRH, Pyeritz RE, Dietz HC, Sponseller PD. Characterization of the symptoms associated with dural ectasia in the
Marfan patient. Am J Med Genet 2005;134A:5865.
12. Sponseller PD, Tomek IM, Pyeritz RE. Developmental dysplasia
of the hip in the Marfan syndrome. Br J Paediatr Orthoped
1997;6:2559.
13. van de Velde S, Fillman R, Yandow S. Protrusio acetabuli in
Marfan syndrome. Indication for surgery in skeletally immature
Marfan patients. J Pediatr Orthoped 2005;25:6036.
14. Lindsey JM, Michelson JD, MacWilliams BA. The foot in Marfan
syndrome. Clinical ndings and weight-distribution patterns.
J Paediatr Orthoped 1998;18:7559.
15. Grahame R, Pyeritz RE. Marfan syndrome: joint and skin
manifestations are prevalent and correlated. Br J Rheumatol
1995;34:12631.
16. Robins PR, Moe JH, Winter RB. Scoliosis in Marfans syndrome.
J Bone Jt Surg 1975;57A:35868.
17. Jones KB, Erkula G, Sponseller PD, Dormans JP. Spine deformity
correction in Marfan syndrome. Spine 2002;27:200312.