18 (1), 2015
l
71-76
DOI: 10.1515/bjmg-2015-0008
ORIGINAL ARTICLE
EARLY ONSET MARFAN SYNDROME:
ATYPICAL CLINICAL PRESENTATION OF TWO CASES
Ozyurt A1,*, Baykan A2, Argun M2, Pamukcu O2, Halis H3, Korkut S3,
Yuksel Z4, Gunes T3, Narin N2
*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
ABSTRACT
Early onset Marfan Syndrome (eoMFS) is a rare,
severe form of Marfan Syndrome (MFS). The disease has a poor prognosis and most patients present
with resistance to heart failure treatment during the
newborn period. This report presents two cases of
eoMFS with similar clinical features diagnosed in the
newborn period and who died at an early age due to
the complications related to the involvement of the
cardiovascular system.
Keywords: Craniosynostosis; Early onset Marfan Syndrome (eoMFS); Heart failure; Neonatal Marfan Syndrome (MFS); Pediatric; Supraventricular
tachycardia
INTRODUCTION
Marfan syndrome (MFS) is an autosomal dominant disorder characterized by elastic tissue involvement: typically skeletal, cardiovascular, pulmonary,
skin and ocular malformations occur.The disease
is caused by mutations in FBN1, encoding fibrillin
1
2
3
4
Department of Pediatric Cardiology, Mersin Women Health And
Children Hospital, Mersin, Turkey
Division of Pediatric Cardiology, Erciyes University Faculty of
Medicine, Kayseri, Turkey
Division of Neonatology, Erciyes University Faculty of Medicine,
Kayseri, Turkey
Department of Medical Genetics, Mersin Women Health and
Children Hospital, Mersin, Turkey
1 protein which provides force bearing structural
support in elastic and nonelastic connective tissue,
located on the chromosome 15q21.1. The prevalence
of the disease has been reported as 0.02-0.03% and
approximately 25.0% of patients are sporadic due to
de novo mutations. Early onset MFS (eoMFS) represents the most severe end of the spectrum of MFS,
which is clinically distinguished from the other forms
by its association with severe mitral and/or tricuspid
valve insufficiency showing a relentless progression
resulting in heart failure and death within the first 2
years of life [1]. Early onset MFS is usually caused by
de novo mutations between exons 24 and 32 of FBN1
[2,3]. Early diagnosis in the neonatal period and the
initiation of anticongestive treatment are crucial to
prevent the early development of the refractory heart
failure in the newborns. This study presents two cases
of eoMFS and a review of the literature.
CLINICAL REPORT
Case 1. A 30-day-old female infant was born to
a 21-year-old (gravida 3, parity 2) healthy mother
through spontaneous vaginal delivery at week 39 of
gestation. The prenatal history of the mother indicated a regular prenatal care and a fetal ultrasound
which could not find any abnormalities. There was no
consanguinity between the parents and both of them
were phenotypically normal. The infant was admitted
to the pediatric emergency service with palpitation on
the 30th day after birth. On admission, her medical
state was serious and she was pale in appearance.
71
EARLY ONSET MARFAN SYNDROME
Figure 1. Clinical features of the patients: a) arachnodactyly of patient 1; b) Steinberg sign of patient 1; c-d) lateral
and frontal views of the patient 2; e) craniosynostosis seen in 3D CT of patient 2.
The size of the anterior fontanelle was measured as
2 cm (mean) and the size of the posterior fontanel
was measured as 0.5 cm (55th centile). On physical
examination, arachnodactyly in fingers and toes (Figure 1a and 1b), prominent forehead, flat nose, high
palate, low-set ears, enophtalmos, dolicocephaly,
articular laxity particularly in wrists and ankles and
a wrist sign was noted. Her weight was 4060 g (7597th percentile), height was 62 cm (>97th percentile),
arm span was 65 cm (>97th percentile) (arm span/
height ratio: 1.04), upper segment (US) was 40 cm,
lower segment (LS) was 25 cm (US/LS: 1.6). No
pathological reflex was detected in her neurological examination, however, a generalized hypotonia
was noted. Heart auscultation revealed a 3/6 systolic
murmur along the left sternal border and a gallop
rhythm. The liver was palpable approximately 4 cm
below the right costal margin. The heart rate was 168/
min., respiratory rate was found as 70/min. The chest
72
X-radiograph (CXR) revealed cardiomegaly. She underwent an echocardiographic evaluation that demonstrated dextrocardia, mitral valve prolapses (MVP)
(Figure 2a and 2b), severe mitral insufficiency (Mi)
(Figure 2c), moderate tricuspid insufficiency, slightly
insufficient aortic valve (Ai) (Figure 2c) and dilated
left ventricle (LVEDd: 23 cm, Z score: 3.1); aortic
root measurements were as follows: Ao: 12 mm, Z
score: 2.17. The patient was diagnosed with eoMFS
based on the clinical and echocardiographic findings.
The patient’s blood level of homocysteine was found
within normal limits. The eye examination did not
reveal any abnormality. A mega cisterna magna was
detected by transfontanelle ultrasound examination.
She developed a supraventricular tachycardia (SVT)
on the second day of observation. She was diagnosed
with nosocomial pneumonia on the 20th day after
the admission. She developed respiratory arrest on
the 25th day and consequently she was intubated
BALKAN JOURNAL OF MEDICAL GENETICS
Ozyurt A, Baykan A, Argun M, Pamukcu O, Halis H, Korkut S, Yuksel Z, Gunes T, Narin N
Figure 2. Echocardiographic features of patients: a, b, c) apical 5 chamber view of patient 1. Mitral valve prolapsus
was seen in 2a and 2b; aortic and mitral insufficiency seen in color Doppler echocardiography examination in 2c.
d) apical 5 chamber view of patient 2.
and mechanical ventilator support was provided. The
infant died on the 38th day after her admission (68
days after birth) due to multiple organ failure resulting from cardiogenic shock.
Case 2. A 4-month-old boy was admitted with
history of nausea, vomiting, cough and lack of appetite. Marfanoid features were detected on physical examination. His facial features were typical
of MFS, the leg and arm length were measured as
27 and 20 cm, respectively. The US/LS was 0.74
(normal: <0.85), arachnodactyly and positive thumb
signs were present, the joints were hyperextensible.
The subcutaneous fat tissue was decreased. He had
dolichocephaly with large frontal fontanel (1 × 2
cm) along with craniosynostosis (Figure 1c, 1d and
1e). Chest examination revealed a pectus excavatum
deformity. In his cardiac examination, a 3/6 systolic
murmur was heard on the left sternal border. The
CXR revealed right pericardial infiltration, cardio-
megaly, aortic root dilatation and left atrial enlargement. An echocardiogram demonstrated a normal
sinus rhythm with a right axis deviation, biatrial
dilatation and biventricular hypertrophy. Aortic root
dilatation, MVP, minimal aortic valve insufficiency,
severe mitral valve insufficiency and patent foramen
ovale were detected in echocardiographic evaluation. Cranial computerized tomography (CT) scans
revealed craniosynostosis in metopic and bilateral
coronal sutures. Due to his Marfanoid features along
with MVP and aortic root dilation, the patient was
diagnosed as eoMFS.
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
73
EARLY ONSET MARFAN SYNDROME
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 se-
Table 1. Scoring of systemic features.
Dysmorphic Features
Scores
Wrist and thumb sign (1 point each)
3
Pectus carinatum deformity [pectus excavatum or chest asymmetry (1 point)]
2
Hind foot deformity [plain pes planus (1 point)]
2
Pneumothorax
2
Dural ectasia
2
Protrusioacetabuli
2
Reduced US/LS and increased arm/height and no severe scoliosis
1
Scoliosis or thoracolumbar kyphosis
1
Reduced elbow extension
1
Facial features (3/5) (dolichocephaly, enophthalmos, down slanting palpebral fissures, malar hypo-plasia, retrognathia)
1
Skin striae
1
Myopia >3 diopters
1
Mitral valve prolapse (all types)
1
US: upper segment; LS: lower segment.
74
BALKAN JOURNAL OF MEDICAL GENETICS
Ozyurt A, Baykan A, Argun M, Pamukcu O, Halis H, Korkut S, Yuksel Z, Gunes T, Narin N
vere 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, valvu-
lar 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.
REFERENCES
1.
2.
HennekamRC. Severe infantile Marfan syndrome versus neonatal Marfan syndrome. Am
J Med Genet A. 2005; 139(1): 1.
Tiecke F, Katzke S, Booms P, Robinson PN,
Neumann L, Godfrey M, et al. Classic, atypically
Table 2. Features of differential diagnosis with early onset Marfan syndrome.
Differential Diagnosis
Gene
The Main Distinctive Features
Loeys-Dietz syndrome (LDS)
TGFBR1/2
bifid uvula/cleft palate, arterial tortuosity, hyper-telorism,
diffuse aortic/ and arterial aneurysms, craniosynostosis,
clubfoot, cervical spine insta-bility, thin and velvety skin,
easy bruising
Shprintzen-Goldberg syndrome (SGS)
FBN1 and others
craniosynostosis, mental retardation
Congenintal contractural arachnodactyly (CCA)
FBN2
crumpled ears, contractures
Weill-Marchesani syndrome (WMS)
FBN1, ADAMTS10
microspherophakia, brachydactyly, joint stiffness
Ectopialentis syndrome (ELS)
FBN1, LTBP2
lack of aortic root dilatation
Homocystinuria
ADAMTSL4, CBS
thrombosis, mental retardation
Familial thoracic aortic aneurysm syndrome (FTAA)
TGFBR1/2, ACTA2
lack of Marfanoid skeletal features, levidoreticu-laris,
irisflocculi
FTAA with bicupid aortic valve (BAV)
‒
‒
FTAA with patent ductus arteriosus (PDA)
MYH11
‒
Arterial tortuosity syndrome (ATS)
SLC2A10
generalized arterial tortuosity, arterialstenosis, facial
dysmorphism
Ehlers-Danlos syndrome
(vascular, valvular, kyphoscoliotictype)
COL3A1, COL1A2,
PLOD1
middle sized artery aneurysm, severe valvular insuffiency,
translucent skin, dystrophic scars, facial characteristics
75
EARLY ONSET MARFAN SYNDROME
3.
4.
5.
6.
7.
76
severe and neonatal Marfan syndrome: Twelve
mutations and genotype phenotype correlations
in FBN1 exons 24-40. Eur J Hum Genet. 2001;
9(1): 13-21.
Kirschner R, Hubmacher D, Iyengar G, Kaur J,
Fagotto-Kaufmann C, BrömmeD, et al. Classical and neonatal Marfan syndrome mutations in
fibrillin-1 cause differential protease susceptibilities and protein function. J Biol Chem. 2011;
286(37): 32810-32823.
Apitz C, Mackensen-Haen S, Girisch M, Kerst
G, Wiegand G, Stuhrmann M, et al. Neonatal
Marfan syndrome: Unusually large deletion of
exons 24-26 of FBN1 associated with poor prognosis. Klin Pediatr. 2010; 222(4): 261-263.
Faivre L, Masurel-Paulet A, Collod-Beroud G,
Callewaert BL, Child AH, Stheneur C, et al.
Clinical and molecular study of 320 children
with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with
pathogenic FBN1 mutations. Pediatrics. 2009;
123(1): 391-398.
Milewicz DM, Duvic M. Severe neonatal Marfan
syndrome resulting from a de novo 3-bp insertion into the fibrillin gene on chromosome 15.
Am J Hum Genet. 1994; 54(3): 447-453.
Strigl S, Quagebeur JM, Gersony WM. Quadrivalvar replacement in infantile Marfan syndrome. Pediatr Cardiol. 2007; 28(5): 403-405.
8.
9.
10.
11.
12.
13.
14.
Tekin M, Cengiz FB, Ayberkin E, Kendirli T,
Fitoz S, Tutar E, et al. Familial neonatal Marfan
syndrome due to parental mosaicism of a missense mutation in the FBN1 gene. Am J Med
Genet A. 2007; 143A(8): 875-880.
Elshershari H, Harris C. Paternal fibrillin-1
mutation transmitted to an affected son with
neonatal marfan syndrome: The importance of
early recognition. Cardiol Young. 2014; 24(4):
735-738.
Loeys BL, Dietz HC, BravermanAC, Callewaert
BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome.
J Med Genet. 2010; 47(7): 476-485.
Frank RE Jr. Supraventricular tachycardia vs.
Marfan’s syndrome. J Insur Med. 1997; 29(3):
204-207.
Yetman AT, Temple J, Erickson CC. Radio frequency ablation of a left-sided atrioventricular
pathway in a patient with Marfan syndrome.
Cardiol Young. 2002; 12(5):494-495.
Porciani MC, Attanasio M, Lepri V, Lapini I,
Demarchi G, Padeletti L, et al. Prevalence of
cardiovascular manifestations in Marfan syndrome. Ital Heart J Suppl. 2004; 5(8): 647-652.
Mégarbané A, Hokayem N. Craniosynostosis
and marfanoid habitus without mental retardation: Report of a third case. Am J Med Genet.
1998; 77(2): 170-171.