EARLY ONSET MARFAN SYNDROME:
ATYPICAL CLINICAL PRESENTATION OF TWO CASES
Ozyurt A, Baykan A, Argun M, Pamukcu O, Halis H, Korkut S,
Yuksel Z, Gunes T, Narin N
*Corresponding Author: Abdullah Ozyurt, M.D., Division of Pediatric Cardiology, Erciyes University
Faculty of Medicine, Kayseri, Turkey, 38039. Tel: +903522076666, Ext. 25036. Fax: +903524375825.
E-mail: duruozyurt@yahoo.com.tr
page: 71
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DISCUSSION
In the present study, we report the clinical characteristics
of two patients diagnosed as eoMFS according
to the typical phenotypic appearance and
radiological evaluation. The “classical” MFS is a rare (an incidence of 1-3/10,000), autosomal dominant
disorder caused by mutations in the FBN1 gene
located on chromosome 15q21.1 that encodes the
protein fibrillin-1. Pathogenesis is related to abnormal
biosynthesis of fibrillin-1, which is the major
constituent of elastin, the main structure in the elastic
tissues. Therefore, musculoskeletal, central nervous
and cardiovascular systems are in the first place; additionally,
eyes, lungs, skin and other systems can be
affected by the disease [3-5].
The term eoMFS has been used instead of neonatal
MFS that was more commonly used previously.
The eoMFS is a rare form of the classical MFS and
differentiates from the latter in terms of genetic, phenotypic
and prognostic features [4]. Joint contractures,
mitral valve prolapse, and mitral, tricuspid,
and pulmonary regurgitations were more prevalent
in eoMFS. However, aortic regurgitation is less frequent.
The prognosis in eoMFS is much worse than
that of the classical MFS, the average age of death
has been reported as 16.3 months in eoMFS, while
classic MFS patients may live several decades [6].
Although both are autosomal dominant, approximately
75.0% of classical MFS cases are inherited,
whereas eoMFS is predominantly sporadic. While
only two cases of familial eoMFS were reported in
the literature, one of these cases was reported from
Turkey [7,8]. Although mutations have been observed
along the entire length of the fibrillin-1 gene (FBN1)
in classical MFS, mutations in eoMFS cluster in a
relatively small region of FBN1, usually between
exons 24 and 32 [1,3-5]. The present study suggests
that enhanced proteolytic susceptibility, especially
in the linker region between TB3 and cbEGF11, and
functional loss between central fibrillin-1 and heparin/
heparan sulfate interactions contribute to the
development of the more severe eoMFS as compared
to MFS [3].
Consistent with the medical literature, congestive
heart failure secondary to the atrioventricular valve
involvement and severe atrioventricular (AV) valve
insufficiencies, was the main feature in both cases.
There was no family history in both cases. Since the
genetic studies are not covered by health insurance
in our country and the families could not afford the
expenses, genetic studies could not be performed.
The diagnosis of MFS relies on typical dysmorphic
features and diagnostic studies such as echocardiography.
Genetic studies are used to support the
diagnosis and to provide prenatal genetic counseling
to the family in future pregnancies. The dysmorphic
features-based Ghent criteria have been used in the
diagnosis of MFS and were revised in 2010 [9]. According
to the Ghent criteria, the positivity of two
out of four criteria consisting of an aortic diameter at
the sinuses of Valsalva above the indicated Z score or
aortic root dissection, ectopialentis, systemic features
(>7) and positive FBN1 mutation, is considered as
sufficient for the diagnosis of classical MFS in patients
without a family history (Table 1). According
to Loeys et al. [10], eoMFS is not considered as a
separate category, but rather represents the most severe end of the MFS spectrum. As the current studies
have indicated, the Ghent criteria should be revised
for the neonatal form of the disease.
The clinical features depend on the degree of
the affected organ systems. Marfan syndrome is an
autosomal dominant disorder characterized by elastic
tissue disorder, but various mutations may cause
clinically different phenotypes, and consequently,
MFS has a wide clinical spectrum. The association
of SVT and MFS was documented in two cases in
the medical literature and one of these patients was
successfully treated by catheter ablation [10,11]. In
another study, the presence of a variety of arrhythmias
was shown in 13% of the patient with MFS [12].
The impaired conduction system in MFS may be
secondary to the severe atrial and ventricular dilation
resulting from severe valve insufficiencies or primary
involvement of the conduction system characterized
as fibrous tissue. On the other hand, craniosynostosis
and dolichocephalyare not common in MFS, and
these dysmorphic skeletal features have been reported
in a few cases in the literature [13]. These findings
can be suggested as a rare finding of eoMFS.
Several conditions have been recognized that
present overlapping clinical manifestations with
MFS in the cardiovascular, ocular or skeletal systems.
These include conditions associated with aortic
aneurysms [Loeys-Dietz syndrome (LDS), bicuspid
aortic valve, familial thoracic aortic aneurysm, valvular Ehler-Danlos syndrome (vEDS), arterial tortuosity
syndrome], ectopialentis (ectopialentis syndrome,
Weill-Marchesani syndrome, homocystinuria, Stickler
syndrome) or systemic manifestations of MFS
[Shprintzen-Goldberg syndrome, congenital contractural
arachnodactyly, LDS, MASS phenotype and
Mitral Valve Prolapsus syndrome (MVPS)] (Table 2).
The eoMFS has variable clinical presentations
and should be taken into consideration in the differential
diagnosis of connective tissue disorders.
Supraventricular tachycardia and craniosynostosisdolichocephaly
may be associated with eoMFS.
Certainly, current approaches in the treatment and
diagnosis of this severe disorder will be developed by
sharing the experiences of large prospective case series
including successful management of the disease.
Declaration of Interest. The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of this article.
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