Marfan Syndrome

Introduction
Marfan syndrome is one of the most common inherited connective tissue disorders. It is
named after Antoine Marfan, a French paediatrician, who described the condition in his
five-year-old patient in 1896. It is associated with a classical phenotype along with multi-
system dysfunction including the cardiovascular, ocular, musculoskeletal, neurological and
respiratory systems (OMIM, 2015)

Epidemiology & Genetics

The prevalence of Marfan syndrome is 1 in 5000 people, worldwide. (OMIM, 2015) Marfan
syndrome is inherited in an autosomal dominant fashion with high penetrance and
variable severity. Genetic mutations involving the FBN1 gene which encodes for fibrillin-1,
a connective tissue protein has been the implicated as the causative factor in the majority
of cases (McKusick, 1991). 25% of cases present de novo, with no family history. Those with
Marfanoid features or with a strong family history may undergo genetic testing.

Clinical Features
Patients with Marfan syndrome are often tall with disproportionately long limbs and digits
often accompanied by a scoliotic spine and thoracic lordosis. Pectus excavatum or pectus
carinatum deformity of the chest may be present also. The face appears to be long and
narrow with deep set eyes; retrognathia and malar hypoplasia may be additional facial
features. Examination of the oral cavity will reveal a high-arched palate and crowded

Fig. 1. Positive wrist sign in someone with Marfan syndrome

Periodontal conditions in patients with Marfan syndrome- a multicentre case control study, BMC Oral Health, 2013
teeth. Joint laxity and flexibility is also a feature of Marfan syndromethis can be
demonstrated by the thumb and wrist signs (fig 1). Due to the large variation in
presentation for Marfan syndrome, the Ghent criteria is often used to aid diagnosis.

Marfanoid patientsthose who may display some of the physical features listed above but
do not meet the criteria for Marfan syndrome, should be investigated for other differentials
such as Multiple Endocrine Neoplasia type 2B, Loeys- Dietz syndrome, Ehlers-Danlos
syndrome and arachnodactyly. (Wright and Connolly, 2016)

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Cardiovascular Features
Cardiovascular complications of Marfan syndrome are the primary cause of morbidity and
mortality in these patients. The main issue is aortic root disease which may lead to
aneurysmal dilatation, aortic insufficiency and aortic dissection. Aortic root dilatation is
found in 60-80% of adults with Marfan syndrome. Mitral valve prolapse or regurgitation is
another common feature of Marfan syndrome, but is often subclinical and missed in the
growing child. More importantly, it predisposes to infective endocarditis; proper dental
hygiene and prompt treatment of infections should be implemented in order to avoid
sepsis. Electrical cardiac disturbances such as atrial fibrillation, Wolff-Parkinson White
and ventricular arrhythmias have also been associated with Marfan syndrome. (Stuart and
Williams, 2007)

Assessment of cardiovascular state

Those diagnosed with Marfan syndrome need to be
regularly monitored by a cardiologist. The 2010
ACC/AHA/AATS guidelines recommend performing an
echocardiogram for all patients at diagnosis and at 6
months for baseline measures and to assess rate of aortic
root enlargement. The typical echocardiogram picture
features an onion-shaped aortic valve (fig. 2).
The aortic root is measured and the value is then Fig. 2. Echocardiogram of a
incorporated into a formula which takes patient size and young girl with Marfan
body surface area into consideration to determine the Z- syndrome showing the
score. Increases in aortic root diameter greater than classical onion-shaped
1.7mm per year, increased aortic stiffness or aortic aortic valve
diameter greater than 55mm and dilatation at the aortic
Marfan Syndrome- An
sinotubular junction confer a high risk of aortic dissection. Echocardiographers Perspective,
(Stuart and Williams, 2007)

Other measures such as left ventricular dimension and function, aortic stiffness index,
mitral valve prolapse and pulmonary valve diameter are also assessed.

Treatment
General advice:
Historically, the advice given to most patients with Marfan syndrome was to avoid
competitive or contact sport due to the small risk of aortic dissection with exercise. This
advice still holds truehowever, it is important for the patient not to avoid activity
altogether and to remain active to prevent development of conditions such as diabetes and
obesity which may contribute to arterial stiffness later on. Specific exercise programs
should be developed for children to prevent isolation and stigmatisation from being
excluded from physical activities at school.
Female sufferers should also be counselled on the risks of aortic dissection during
pregnancy.

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Medical Treatment:
The Cardiac Society of Australia and New Zealand recommend -blockers as first line
therapy for aortic root dilatation. Its negative inotropic effect reduces the myocardial
contractility and it is thought to also improve the aortas elasticity (Wright and Connolly,
2016). For those who are unable to tolerate -blockade, calcium channel blockers and ACE
inhibitors remain acceptable alternatives. Habashi et als mice studies have shown
promising evidence that losartan, which has dual mechanisms in reducing blood pressure
and TGF antagonising ability may be successful in slowing down aortic root dilatation.
(2006). The phase III clinical trial published in 2015, however, demonstrated that there
was no significant difference between the rate of aortic root enlargement and atenolol in 3
years. (Forteza et al, 2015) Thus, losartan can be added to the list of medications that can
be used as a substitute for -blockers. There is no clinical evidence which shows starting
medical therapy prior to the development of aortic root dilatation adds any additional
benefit.

Surgical Treatment:
Local guidelines suggest prophylactic aortic surgery in adults with Marfan syndrome when
the aortic root diameter is greater than 5 cm or greater than 4.5cm with family history of
dissection, aortic growth greater than 5-10 mm per year or when significant aortic
insufficiency is present (Cardiac Society of Australia and New Zealand, 2011). Patients
should be warned of the 1-2% mortality rate during the prophylactic procedure. The
mortality rate of operating on an acute ascending aortic dissection, on the other hand, is
20%. Acute dissection also confers a 50-70% mortality rate at 10 years. Therefore, regular
monitoring and early prophylactic surgery is paramount.

There are two main techniques used for aortic root replacement. The first and more
traditional approach is a composite valve graft which involves replacing both the aortic
root and the valve with a prosthesis. The coronary arteries are then reimplanted. Other
valve repairs or replacements can be performed in the same surgery. The second technique
is valve-sparing aortic root replacement: this involves leaving the aortic valve in place
whilst providing a conduit or graft to the remaining aorta. The benefit of valve-sparing
aortic root replacement is eliminating the need for anticoagulation after surgery, however,
in the Johns Hopkins study, 5 out of the 40 patient who underwent remodelling with
placement of a conduit, 5 out of the 40 patient required valve replacement later on for
aortic insufficiency. (Wright and Connolly, 2016)

Conclusion
Marfan syndrome is a rare genetic condition that affects multiple systems. Once diagnosed
patients should undergo regular monitoring and follow-up with a multidisciplinary team,
including a cardiologist. Thanks to early diagnosis and high clinical suspicion- the life
expectancy of these patients is comparable to the normal population. Regular monitoring
with echocardiogram with early referral for surgery is vital to prevent long-term morbidity
and mortality.

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References

Forteza, A., Evangelista, A., Snchez, V., Teixid-Tur, G., Sanz, P., Gutirrez, L., Gracia, T., Centeno, J.,
Rodrguez-Palomares, J., Rufilanchas, J., Cortina, J., Ferreira-Gonzlez, I. and Garca-Dorado, D. (2015).
Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized
clinical trial. European Heart Journal, vol. 37, no. 12, pp.978-985.

Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C,
Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL,
Dietz HC, 2006, Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan
syndrome. Science. Vol. 312, no. 5770 pp. 117.

Marfan.org. (n.d.). Calculation of Systemic Score | The Marfan Foundation. [online] Available at:
https://www.marfan.org/dx/score [Accessed 29 Aug. 2016].

McKusick V, 1991, The defect in Marfan syndrome, Nature. Vol. 352, no. 6333, pp. 27981.

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