Review Article

Marfan Syndrome: A Clinical

Update

Abstract
Adam D. Bitterman, DO Marfan syndrome is a connective tissue disorder that can affect many
Paul D. Sponseller, MD, MBA organ systems. Affected patients present with orthopaedic
manifestations of the syndrome during all phases of life. Pain caused
by musculoskeletal abnormalities often requires definitive
orthopaedic treatment. Orthopaedic surgeons must understand the
phenotypes of Marfan syndrome so they can recognize when
screening is warranted and can appropriately address the skeletal
manifestations. Through medical advancements, patients with Marfan
syndrome are living longer and more active lives. Knowledge of the
latest diagnostic criteria for the disorder, as well as of advances in
understanding the skeletal phenotype, clinical trials of medication
therapy, and lifestyle considerations is important for orthopaedic
surgeons who treat these patients because these clinicians often are
the first to suspect Marfan syndrome and recommend screening.

M arfan syndrome (MFS) is an

autosomal dominant disorder
best known for its associated cardio-
tion, and strict blood pressure con-
trol have improved overall survival.2
The initial suspicion of the role of
From the Department of Orthopaedic
Surgery, Hofstra Northwell School vascular abnormalities. It is now transforming growth factor-beta
of Medicine, Hempstead, NY understood to affect many other sys- (TGF-b) in MFS is now con-
(Dr. Bitterman) and the Department of firmed.3 Studies of mice showed that
tems, including the ophthalmologic
Orthopaedic Surgery, The Johns
Hopkins University, Baltimore, MD and pulmonary systems. Musculo- fibrillin-1 deficiency leads to an
(Dr. Sponseller). skeletal symptoms include general- increase in TGF-b, and the excessive
Dr. Sponseller or an immediate family ized ligamentous laxity, scoliosis, signaling and activation of TGF-b
member has received royalties from chest deformity, protrusio acetabuli, are theorized to cause the various
DePuy Synthes and Globus Medical; foot deformities, hypermobility, manifestations of MFS.4,5
serves as a paid consultant to and has
received research or institutional dural ectasia, and low bone mineral Advanced medical and surgical
support from DePuy Synthes; and density. therapies for aortic dilatation allow
serves as a board member, owner, The protein encoding fibrillin-1, patients with MFS to live longer.
officer, or committee member of the Life expectancy has increased from
known as the FBN1 gene, is located
Scoliosis Research Society. Neither
Dr. Bitterman nor any immediate on chromosome 15.1 Fibrillin-1 is 47 years to 75 years.6 Furthermore,
family member has received anything the main component of elastic aortic measurement surveillance
of value from or has stock or stock matrix microfibrils, which have a through echocardiography has al-
options held in a commercial company
or institution related directly or role in the connective tissue of the lowed cardiologists to better tailor
indirectly to the subject of this article. cardiovascular and musculoskeletal treatment with angiotensin-receptor
J Am Acad Orthop Surg 2017;25: systems. Although cardiovascular blockers and b-blockers. Surgical
603-609 manifestations are the main cause of interventions continue to evolve and
DOI: 10.5435/JAAOS-D-16-00143 death in patients with MFS, medical include valve-sparing and composite
therapies combined with early sur- graft replacement techniques. Car-
Copyright 2017 by the American
Academy of Orthopaedic Surgeons. gical management, serial cardiac diac surgeons are seeing musculo-
imaging, refined exercise participa- skeletal manifestations of the disease,

September 2017, Vol 25, No 9 603

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Marfan Syndrome: A Clinical Update

Table 1
Revised Ghent Criteria for Diagnosing Marfan Syndrome and Related Conditions
Criteria Diagnosis

Family history of Marfan syndrome absent

AO (Z-score $2) and ectopia lentisa Marfan syndrome
AO (Z-score $2) and FBN1 gene mutation Marfan syndrome
AO (Z-score $2) and systemic scoreb .7a Marfan syndrome
Ectopia lentis and FBN1 gene mutation with known AOc Marfan syndrome
Ectopia lentis with or without systemic score $7b and FBN1 gene mutation Ectopia lentis syndrome
unknown with AOd or no FBN1 gene mutation
AO (Z-score ,2) and systemic scoreb $5, with at least 1 skeletal feature, MASS
without ectopia lentis
Mitral valve prolapse, AO (Z-score ,2), and systemic scoreb ,5, without Mitral valve prolapse syndrome
ectopia lentis
Family history of Marfan syndrome present
Ectopia lentis Marfan syndrome
Systemic score $7a Marfan syndrome
AO (Z-score $2) in patients aged $20 years, (Z-score $3) in patients Marfan syndrome
aged ,20 yearsa

AO = aortic diameter at the sinuses of Valsalva with indicated Z-score or aortic root dissection; FBN1 = fibrillin-1 gene; MASS = mitral valve prolapse,
aorta root diameter at the upper limit of normal, striae, and skeletal features similar to Marfan syndrome
a
Without discriminating features of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, or vascular form of Ehlers-Danlos syndrome and after
collagen biochemistry and TGFBR1 and 2 and COL3A1 gene testing, if indicated
b
As described in Table 2
c
FBN1 gene mutation that has been identified in a patient with aortic aneurysm
d
FBN1 gene mutation that has not been associated with aortic root aneurysm/dissection
Adapted with permission from Loeys B, Dietz H, Braverman A, et al: The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47
(7):476-485.

which require the attention of better identify MFS and related have been removed from the diag-
orthopaedic surgeons. disorders. nostic evaluation. Counseling and
In the revised nosology, several follow-up recommendations for
major changes were made to the those diagnosed with MFS are also
Diagnosis diagnostic criteria for MFS.7 More provided in the revised nosology.
diagnostic weight is given to the The revised classification includes a
The diagnosis for MFS has evolved presence of aortic root enlargement systemic scoring system that empha-
recently, because various clinical and ectopia lentis, the cardinal fea- sizes various clinical features of the
expressions of the disease have tures of MFS (Table 1). Aortic root disease (Table 2). MFS can be diag-
been identified.7 The main clinical measurements have been standard- nosed or excluded using this scoring
attributes of MFS are long bone ized through the use of the Z-score, system in conjunction with the
overgrowth, dislocated lenses of the which accounts for body surface presence or absence of a family his-
eye, and aortic root aneurysm. In area, as well as the aortic root tory of the disorder. The scoring
1991, Dietz et al8 reported that a measurement (ie, aortic root diame- system also accounts for the fact that
mutation of the FBN1 gene resulted ter measurement at the sinus of phenotypic features evolve over time
in MFS, and in 1996, the Ghent Valsalva), seen on echocardiogra- and may not all be present at birth or
nosology criteria were established.9 phy. Genetic testing is emphasized, in young children, enabling pro-
These diagnostic criteria stress the particularly testing for a mutation of viders to identify patients who war-
importance of a positive genetic FBN1, which has a detection rate of rant follow-up.7
finding and help differentiate MFS 97%.10,11 Clinical testing to identify Radiography, family history, and
from other disorders with similar possible alternative diagnoses that genetic testing are used in the diag-
symptoms. More than a decade later, overlap with MFS is recommended, nosis of MFS. It is important for
an expert panel reconvened in Brussels, and certain MFS clinical findings orthopaedic surgeons to recognize
Belgium, to modify the nosology to have been deemed less important or the signs of MFS; however, a

604 Journal of the American Academy of Orthopaedic Surgeons

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 Adam D. Bitterman, DO, and Paul D. Sponseller, MD, MBA

diagnosis should come from a genet- Table 2

icist. Genetic specialists are aware of
Systemic Scoring System for the Diagnosis of Marfan Syndrome
the indications for and implications
of genetic testing and of the differen- Maximum Possible
Feature (Points) Score
tial diagnoses. The cost of testing
typically is covered by insurance. Chest deformity 2
Prompt diagnosis and treatment are Pectus carinatum deformity (2)
essential to optimize outcomes. Pectus excavatum (1)
Chest asymmetry (1)
Dural ectasia (2) 2
Clinical Manifestations
Facial featuresa (1) 1
Foot deformity 2
Cardiovascular
Hindfoot deformity (2)
The cardiovascular manifestations of Plain pes planus (1)
MFS are well established. The main Mitral valve prolapse, all types (1) 1
cause of death in patients with MFS is Myopia .3 diopters (1) 1
aortic root dissection. Other manifes- Pneumothorax (2) 2
tations include mitral valve prolapse,
Protrusio acetabuli (2) 2
pulmonary artery enlargement, and
Reduced elbow extension (1) 1
left ventricular dilatation.
Reduced US/LS ratiob, increased arm/height, 1
Serial clinical examinations and and no severe scoliosis (1)
echocardiography help the clinician to Skin striae (1) 1
identify patients at risk of increased left Spine deformity 1
ventricular dilatation. Management of Scoliosis (1)
cardiovascular manifestations typi-
Thoracolumbar kyphosis (1)
cally begins with b-blocker medica-
Wrist and thumb deformities 3
tion, although several alternative
Wrist sign (1)
medications have been investigated. In
Thumb sign (1)
a recent randomized, double-blind
Wrist and thumb signs (3)
trial, patients aged 6 months to
25 years were studied to determine Maximum total score 20
whether angiotensin II type 1 receptor LS = lower segment, US = upper segment
blockade was as effective as b-blockers, a
Presence of three of the following features: dolichocephaly, enophthalmos,
the current standard of care.12 downslanting palpebral fissures, malar hypoplasia, retrognathia
b
US length is the total arm span from each finger. LS is measured from the top of the symphysis
Research suggests that angiotensin II pubis to the floor.
type 1 receptor blockade has attenu- Adapted with permission from Loeys B, Dietz H, Braverman A, et al: The revised Ghent nosology
for the Marfan syndrome. J Med Genet 2010;47(7):476-485.
ated TGF-b signaling in other diseases
by lowering the expression of the
ligand,5,13 receptors,14 or activators.15 manifestations associated with MFS. or posteriorly (pectus carinatum
This study found that both agents Ocular conditions may be the initial or pectus excavatum, respectively;
were effective, with no substantial presenting symptoms in patients in Figure 1). Abnormally long fingers,
difference in aortic root dilatation whom cardiovascular symptoms also known as arachnodactyly, fre-
(based on the Z-score) between the have not yet developed and should quently are seen. A positive wrist sign
b-blocker group and the angiotensin prompt a more advanced diagnostic occurs when the contralateral thumb
II type 1 receptor blockade group.12 workup. overlaps the entire nail of the little
finger when grasping the opposite
Ocular Musculoskeletal wrist. A positive thumb sign occurs
Annual ophthalmic examinations are The main orthopaedic feature of MFS when the entire distal phalanx of the
encouraged for patients with MFS. is overgrowth of the long bones.16 clenched thumb protrudes beyond
Superiorly dislocated lenses, myopia, This overgrowth produces a tall the ulnar border of the hand. The
glaucoma, cataracts, and retinal stature and may affect the ribs, wrist sign and thumb sign represent
detachment are some of the ocular displacing the sternum anteriorly aspects of arachnodactyly (Figure 2).

September 2017, Vol 25, No 9 605

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Marfan Syndrome: A Clinical Update

Figure 1 Figure 2 of MFS and is present in more than

two thirds of patients with MFS.23
A study using a mouse model of
MFS showed higher levels of TGF-b
within the dura caused by fibrillin-1
deficiency.24 As the dural sac bal-
loons, it may erode the surrounding
bone, which already is weakened by
the genetic mutation. These changes
pose challenges to surgical fixation
and create a high likelihood of
fracture and dural injury.
Clinical photograph showing the thumb Although pain is common in
sign and the wrist sign. The thumb sign patients with dural ectasia, the exact
consists of the projection of the entire cause of pain has not been estab-
distal phalanx of the thumb beyond the
ulnar border of the clenched fist. The
lished. Not every patient with dural
wrist sign denotes the ability of ectasia experiences pain. Various
the thumb to cover the entire nail of the causal theories exist, implicating
little finger when wrapped around the pressure on the periosteum, erosion
contralateral wrist.
Clinical photograph showing a 32- of the surrounding lumbosacral ele-
year-old man with Marfan syndrome ments, traction of the nerve roots,
and pectus carinatum (outward study, Gjolaj et al20 found that, com- direct pressure by the anterior
protrusion of the sternum). pared with patients with AIS, patients meningocele on the abdominal organs,
(Copyright Adam D. Bitterman, DO, with MFS scoliosis had higher rates of
Hempstead, NY.) or microfractures of the sacrum from
intraoperative cerebrospinal fluid thinning of the bone.23,25-28
leaks, considerably more implant-
Spine related complications, and more
Scoliosis in patients with MFS revision procedures as a result of Protrusio Acetabuli
progresses rapidly. The radiographic fixation failure and spine fracture. As patients with MFS live longer,
findings of MFS scoliosis are indis- Although the authors found no sub- orthopaedic surgeons will face more
tinguishable from those of adolescent stantial difference in the estimated challenges involving management of
idiopathic scoliosis (AIS). Non- volume of intraoperative blood loss, degenerative joint disease. One of the
surgical management of MFS scolio- other studies have reported higher main causes of osteoarthritis in
sis may involve the use of a brace; blood loss21 and longer surgical times patients with MFS is protrusio ace-
however, compared with AIS, MFS than in patients with AIS.22 tabuli, which is one of the skeletal
scoliosis is less responsive to brac- Formulation of an appropriate criteria for diagnosis in the revised
ing.17,18 Therefore, bracing typi- preoperative plan for spinal fixation Ghent nosology.7 This protrusion of
cally is used only in skeletally is essential. Unique anatomic features the medial wall of the acetabulum
immature patients with scoliotic of MFS include narrow pedicles, wide into the pelvic cavity is initially
curves between 15° and 25°.16 This transverse processes, and vertebral asymptomatic. On an AP radiograph
option can be offered to patients scalloping18 (Figure 3). In addition, of the pelvis, the medial protrusion
with greater degrees of curvature, bone mineral density may be lower of the acetabulum $3 mm beyond
although the low likelihood of suc- than that of the general pop- the ilioischial (Kohler) line is diag-
cess should be discussed.16 Curve ulation.16 Adequate distal fixation, nostic for protrusio acetabuli. Other
progression may continue beyond often into the pelvis or sacrum, may radiographic features include cross-
skeletal maturity. Surgery should be lessen the need for revision. ing of the teardrop by the medial
considered for curves .45°.19 acetabular wall and a center-edge
Techniques of curve correction are Dural Ectasia angle of Wiberg .40°7 (Figure 5).
well documented, but surgeons should Dural ectasia, or enlargement of the Ligamentous laxity combined with
be aware of the higher revision and dural sac, may occur throughout the bony abnormality may lead to joint
complication rates in patients with spinal column but most often is seen degeneration, ultimately resulting in
MFS compared with patients with in the lumbosacral spine (Figure 4). It a symptomatic hip. In children with
AIS. In a retrospective case-controlled is a highly specific diagnostic feature protrusio acetabuli, fusion of the

606 Journal of the American Academy of Orthopaedic Surgeons

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 Adam D. Bitterman, DO, and Paul D. Sponseller, MD, MBA

Figure 3 Figure 4

Sagittal T2-weighted magnetic

resonance image of the lumbosacral
spine showing dural ectasia from L3
through S2. Caudal widening of the
thecal sac occurs, causing the
diameter at S1 to be greater than that
at L4. Erosions of the vertebral
bodies and dilatation of
cerebrospinal-fluid–containing sacs
are present through the vertebral
foramina and into the pelvis.

Figure 5

Preoperative (A) and postoperative (B) AP radiographs of the spine

demonstrating scoliosis in a patient with Marfan syndrome, which is
characterized by narrow, dysplastic pedicles; wide transverse processes; and
few vertebrae per curve. A, Preoperative AP radiograph showing the scoliotic
curve at T1 through L1. B, AP radiograph obtained 2 years after surgical
correction with fusion rods and pedicle screws.

triradiate cartilage in extreme pro- Thakkar et al31 showed that patients AP radiograph demonstrating
trusion (ie, a center-edge angle .45°) who needed THA because of pain protrusio acetabuli, which occurs
is a surgical approach that was had more severe protrusio acetabuli when the center-edge angle of
Wiberg is .40° or the acetabular wall
advocated by Steel.29 In adults with than did the MFS population as a
protrudes $3 mm medial to the
this condition, total hip arthroplasty whole. The authors also noted that, ilioischial (Kohler) line (arrow).
(THA) with appropriate bone graft- in patients with MFS, complications
ing of the medial wall has provided after THA (eg, dislocations, revision,
symptomatic relief.30 infection, implant loosening) were likely are caused by impingement on
Not all patients with MFS and not correlated with the presence of the deeper acetabulum or ligamen-
protrusio acetabuli require THA, but protrusio acetabuli. Dislocations tous laxity, and implant loosening

September 2017, Vol 25, No 9 607

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Marfan Syndrome: A Clinical Update

Figure 6 pregnant women with MFS at high

Lifestyle Considerations risk of aortic dilatation and even
dissection.34 Avoiding hypertension
Athletic Participation during pregnancy is important, and
Patients with MFS can participate in b-blockers are an appropriate first-
low-impact athletic activities and line therapy.
those that do not require sudden,
quick bursts of strength and energy. Quality of Life
It is important to avoid activities
MFS may create a substantial mental
that raise the heart rate or blood
and physical burden on the patient,
pressure and those that involve
with different areas of concern for
impact. Sports that are contra-
each person. According to Rao
indicated include gymnastics and
et al,35 in the United States, the
contact sports such as basketball,
quality of life of patients with MFS is
rugby, and American football,
lower than that of control subjects
Clinical photograph depicting the
which pose a risk to the lenses of the
without the disease.
variable appearance of the feet in eye and the aorta. Physical educa-
Pain is one of the most common
Marfan syndrome, with characteristic tion activities that include these
findings of long and narrow feet, as concerns for patients with MFS. A
sports should be avoided by ado-
well as flattening of the medial arch, recent systematic review of the litera-
increased medial midfoot pressure,
lescent patients. The degree of
ture estimated that the prevalence of
hindfoot valgus, and toe deformity. restriction depends on the severity of
pain in these patients is 47% to 92%.36
disease suggested by the symptoms
Adults with MFS report limited phys-
and imaging studies.
may be caused by MFS-related ical capacity, reduced endurance, and
Despite much research, no definitive
osteoporosis or osteopenia.31 No ultimately, depression and anxiety.
consensus exists about the appropri-
study has identified the ideal surgical Through appropriate diagnosis and
ate cardiovascular and musculoskele-
approach for patients with ligamen- treatment, along with timely rehabili-
tal screening for patients with MFS
tous laxity. Thakkar et al31 reported tation, patients are better able to lead
who want to compete in sports. Skel-
good functional outcomes after THA productive lives. Optimal treatment of
etal findings are typically the first
for protrusio acetabuli in patients chronic pain in patients with MFS
recognized signs of MFS,33 and elec-
with MFS, with outcomes that were should be a focus of future research.
trocardiography and echocardiogra-
comparable to those in patients
phy are the mainstays of screening for
without MFS.
patients with skeletal findings. It may Summary and Future
be impractical to use such tools unless Research
Pes Planus substantial clinical suspicion exists
Pes planus, or flatfoot deformity, is for MFS. Further focus should be MFS can restrict a patient’s career
common in patients with MFS. The placed on the development and im- aspirations, athletic participation,
feet of these patients are longer and plementation of screening tools to financial security, and social life.7
narrower than those of patients identify patients whose participation Medical advances have enabled
without MFS, making it difficult to in specific sports may be unsafe. patients to live relatively normal life
find correctly sized shoes (Figure 6). spans, but the symptoms of the dis-
Loss of the longitudinal arch is ease occur over a longer period and
thought to be caused by underlying Pregnancy often require treatment by ortho-
ligamentous laxity.32 Symptom Patients with MFS may elect to paedic surgeons, whose under-
management is the mainstay of undergo preimplantation genetic standing of the disease can facilitate
treatment. Appropriate shoes and testing before conception. Genetic early diagnosis and timely treatment.
corrective orthoses may help to counseling may aid in understanding Orthopaedic surgery in patients
avoid or delay surgical correction. the risks associated with the genetic with MFS is challenging. The risk
Scant research is available on the transmission of MFS. for postoperative complications in
surgical techniques for pes planus or Pregnant women with MFS require this population is higher than that
ligament augmentation, or on the strict surveillance throughout preg- of patients without MFS. Patient
outcomes of flatfoot reconstruction nancy. The hormonal and hemody- comorbidities present additional
in this patient population. namic changes of pregnancy put challenges. It is imperative that

608 Journal of the American Academy of Orthopaedic Surgeons

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 Adam D. Bitterman, DO, and Paul D. Sponseller, MD, MBA

cardiovascular abnormalities are syndrome. J Med Genet 2010;47(7): Marfan syndrome. Spine (Phila Pa 1976)
476-485. 2002;27(18):2003-2012.
considered as part of preoperative
risk stratification. 8. Dietz HC, Cutting GR, Pyeritz RE, et al: 22. Liang W, Yu B, Wang Y, et al: Comparison
Marfan syndrome caused by a recurrent de of posterior correction results between
Future research should focus on novo missense mutation in the fibrillin Marfan syndrome scoliosis and adolescent
preventing and managing the osseous gene. Nature 1991;352(6333):337-339. idiopathic scoliosis: A retrospective case-
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diagnostic criteria for the Marfan syndrome. PD: Characterization of the symptoms
pathways offers promise for new Am J Med Genet 1996;62(4):417-426. associated with dural ectasia in the Marfan
treatments. In addition, researchers patient. Am J Med Genet A 2005;134A(1):
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classical Marfan syndrome. Hum Mutat HC, Sponseller PD: Toward an understanding
patients with MFS. A better under- 2004;24(2):140-146. of dural ectasia: A light microscopy study in a
standing of the causes of MFS pain murine model of Marfan syndrome. Spine
11. Loeys B, Nuytinck L, Delvaux I, De Bie S, De
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