The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: https://www.tandfonline.com/loi/ijmf20

Perinatal diagnosis and management of early-

onset Marfan syndrome: case report and
systematic review

Amanda Veiga-Fernández, Laura Joigneau Prieto, Teresa Álvarez, Yolanda

Ruiz, Ricardo Pérez, Francisco Gámez, Virginia Ortega Abad, Fátima Yllana &
Juan De León-Luis

To cite this article: Amanda Veiga-Fernández, Laura Joigneau Prieto, Teresa Álvarez,
Yolanda Ruiz, Ricardo Pérez, Francisco Gámez, Virginia Ortega Abad, Fátima Yllana & Juan
De León-Luis (2019): Perinatal diagnosis and management of early-onset Marfan syndrome:
case report and systematic review, The Journal of Maternal-Fetal & Neonatal Medicine, DOI:
10.1080/14767058.2018.1552935

To link to this article: https://doi.org/10.1080/14767058.2018.1552935

Published online: 17 Jan 2019.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2018.1552935

REVIEW ARTICLE

Perinatal diagnosis and management of early-onset Marfan syndrome:

case report and systematic review


Amanda Veiga-Fern
andez, Laura Joigneau Prieto, Teresa Alvarez, Yolanda Ruiz, Ricardo Pe
rez,
Francisco G
amez, Virginia Ortega Abad, F
atima Yllana and Juan De Leo

n-Luis
~
on, Madrid, Spain
Hospital General Universitario Gregorio Maran

ABSTRACT ARTICLE HISTORY

Early onset Marfan syndrome is the most severe form of Marfan syndrome diagnosed during peri- Received 26 February 2018
natal period. Early onset Marfan syndrome is associated with high mortality rates, usually within Accepted 23 November 2018
the first 2 years of life. First, we present a case of prenatally diagnosed early onset Marfan syn-
KEYWORDS
drome in a dichorionic diamniotic twin pregnancy, where suspicion was raised at 35 weeks of ges-
Congenital Marfan
tation. Ultrasound and fetal magnetic resonance imaging were used to assess prenatal findings in syndrome; diaphragmatic
the affected fetus. She presented right diaphragmatic eventration, elongation of humerus and hernia; early onset Marfan
femur and subluxation of the crystalline lens. She died 3 months after birth. Secondly, we present syndrome; magnetic
a PubMed-based review of the published articles on early onset Marfan syndrome, with pre- or resonance imaging;
postnatal suspicion or diagnosis. We found 39 articles published between 1981 and 2017, arising neonatal Marfan syndrome
information on 55 cases. Including ours, early onset Marfan syndrome was prenatally diagnosed in
34.54% of the cases. In these cases, the most frequent prenatal findings were cardiomegaly, dilata-
tion of the great vessels and mitral or tricuspid regurgitation. Mortality rate during the first
15 months after birth was 73.68%. In the postnatally diagnosed cases, the most frequent findings
were arachnodactyly, dilatation of the great vessels and mitral or tricuspid regurgitation. Mortality
rate was 61.11%. Overall genetic confirmation was performed in 67.27% of the cases. Prenatal
diagnosis of early onset Marfan syndrome is challenging but of utmost importance, since manage-
ment should take place in a tertiary care center, by a multidisciplinary team. Differential diagnosis
is essential in order to perform an adequate genetic counseling.

Introduction wide spectrum of severity. Hennekam’s strict definition

Marfan syndrome (MFS, OMIM # 154700) is a genetic dis-
order of the connective tissue, with a wide spectrum of
clinical variability with skeletal, cardiovascular, pulmonary,
and ocular involvement. It is caused by a mutation in
the fibrillin-1 encoded by the FBN1 gene on the chromo-
some 15q21.1, inherited in an autosomal dominant pat-
tern or appearing after de novo mutation [1,2]. FBN1 is a
relatively large gene containing 65 exons. There are
more than 1800 mutations described throughout these
exonic regions, leading to the wide spectrum of the dis-
ease manifestations in the neonates and fetuses [1–4].
However, mutations in exons 24–32 of FBN1 have been
described as being frequently present in patients with
early-onset Marfan syndrome (EOMS) [1–4].
EOMS is very rare (1:10.000). It is the most severe
form of Marfan syndrome in which patients usually die
of congestive heart failure within the first 2 years of life
[5]. While mutations in the exons 24–32 for EOMS were
thought to predict a phenotype, the exact definition of
EOMS remains debatable since the disease presents a
applied to neonates showing massive mitral and/or tri-
cuspid valve insufficiency with congenital pulmonary
emphysema [6]. We nowadays know that there are
other forms of EOMS not included in this description.
Prenatal suspicion of EOMS is challenging and
depends on findings of fetal anomalies (ultrasound
and/or magnetic resonance imaging). Fetuses can pre-
sent with mitral and/or tricuspid insufficiency, joint con-
tractures, arachnodactyly, luxation of both crystalline
lenses, among others. A multidisciplinary approach is
mandatory and genetic test should be offered to con-
firm the diagnosis [5,7,8].
We present a case of EOMS in a dichorionic diamni-
otic twin pregnancy. We describe the findings of pre-
natal ultrasound and fetal magnetic resonance, as well
as the postnatal evolution. Finally, we present a
PubMed-based review of the published articles or per-
sonal communications between 1981 and 2017 on
EOMS, with pre- or postnatal suspicion or diagnosis
and the sonographic findings reported.

CONTACT Juan De Le

on-Luis jdeleonluis@yahoo.es n

Hospital General Universitario Gregorio Mara~ on, Madrid, Spain
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2

A. VEIGA-FERNANDEZ
Material and methods
Case report
We first report a case of prenatal suspicion of EOMS
detected in the materno-fetal unit of our center dur-
ing the third trimester. We report the ultrasound as
well as the fetal magnetic resonance imaging findings,
the evolution during the pregnancy, and neonatal
management and outcome.
Systematic review
We performed a PubMed and Ovid-based literature
review, searching all the published articles or personal
communications on this topic between 1981 and
2017. We used the keywords “Neonatal Marfan syn-
drome,” “Congenital Marfan syndrome” and “Early
onset Marfan Syndrome.” All the titles and abstracts
were analyzed by two independent researchers to
exclude those articles that did not meet our inclusion
criteria. We included the articles where prenatal or
postnatal ultrasound and clinical findings were
described, with or without prenatal suspicion of neo-
natal Marfan syndrome. We excluded articles that did
not assess neonatal findings. We excluded articles not
written in English or Spanish.
The articles included in the review were subse-
quently analyzed by the same two researchers, evalu-
ating the compliance with the inclusion and exclusion
criteria to diminish the risk of bias. However, there
could be a selecting bias due to nonreporting of sin-
gle cases. Any disagreement was resolved by discus-
sion. A data extraction sheet was performed including
authors, year of publication, number of cases (N), ges-
tational age at diagnosis of EOMS, prenatal sono-
graphic findings, perinatal clinical and/or imaging
findings, evolution of the affected patient, family his-
tory of Marfan syndrome, and molecular analysis
results. Main results are expressed as rates (%).
We have followed the PRISMA Statement for the
review [9].
Results
Case report
A 38 years old nulliparous woman with a dichorionic-
diamniotic twin pregnancy was referred to our fetal
medicine unit at 28 weeks of gestation due to suspi-
cion of right diaphragmatic hernia associated with car-
diomegaly in the first fetus.
Neither the patient nor her husband had any ill-
nesses. They were not consanguineous. They both had
a normal phenotype. The pregnancy had been
achieved by in-vitro fertilization. She was diagnosed
with hypothyroidism during the first trimester for
which she received a substitutive treatment, and with
gestational diabetes during the second trimester
treated with diet and exercise. The rest of the preg-
nancy was uneventful.
The ultrasound performed at our center at 28 weeks
showed a dichorionic-diamniotic pregnancy with a
fetus with femoral and humeral lengths over 99th cen-
tile and a right diaphragmatic hernia or eventration.
The echocardiography showed a cardiomegaly with
dilatation of the great vessels and redundant atrioven-
tricular valves (Figure 1(A,B)).
The other fetus had a biometry concordant with
gestational age, without abnormal findings.
The patient declined to perform an amniocentesis
to analyze fetal karyotype and perform molecular ana-
lysis. Posterior ultrasounds showed no signifi-
cant changes.
A fetal magnetic resonance was performed at
35 weeks of gestation, confirming the presence of a
right diaphragmatic eventration associated with mild
pulmonary hypoplasia. It also described bilateral lux-
ation of both crystalline lenses (Figure 2), which was
confirmed with ultrasonography (Figure 3).
These findings helped to raise the suspicion
of EOMS.
An elective cesarean section was performed at
37 weeks. The neonates weighted: 2530 g (affected
fetus) and 2220 g (normal fetus). Apgar scores at
minutes 1 and 5 and arterial blood cord pH values
were normal for both neonates.
The affected neonate showed a marfanoid habitus
(Figure 4). An echocardiography confirmed the pre-
natal findings and described a mild mitral regurgita-
tion, persistent ductus arteriosus and redundant
interatrial septum with patent foramen ovale. She pre-
sented a posterior diaphragmatic eventration with nor-
mal diaphragmatic movements. An ophthalmological
examination confirmed bilateral crystalline lens sublux-
ation with a small diameter of the anterior chamber.
She posteriorly presented a worsening of the mitral
regurgitation that required initiation of captopril
1.5 mg/8 hours at the 6th day of life. The echocardiog-
raphy performed at 20 days of life showed a redun-
dant interatrial septum with bidirectional shunt,
elongated atrioventricular valves, mild tricuspid regur-
gitation and mild mitral regurgitation associated to
mild dilatation of the left atrium and elongation of the
aortic root. A multidisciplinary committee evaluated
the case and a conservative treatment was decided

Figure 1. A fetal ultrasound performed at 34 weeks of gesta-
tion showing (A) an elongated aortic arch and redundant duc-
tus arteriosus in B mode. In the upper right corner, the image
shows a severe dilatation of the aortic arch (15.05 mm) with a
highly elongated sinus of Valsalva. (B) Dilated and redundant
ductus arteriosus with color Doppler ultrasound. Ao: Aorta;
Aor: Aortic root; DA: Ductus arteriosus.
(respiratory support with nasal BIPAP, captopril, ome-
prazole, domperidone, and D3 vitamin through gas-
trostomy). She died at 3 months of life.
Literature review
We included 39 articles for the systematic review,
gathering data from 54 cases (55 considering our
case) (Figure 5, Table 1). Nineteen cases (34.54%) had
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3
Figure 2. Fetal magnetic resonance imaging in T2 sequence,
performed at 35 weeks of gestation showing luxation of the
crystalline, and suggesting the presence of arachnodactyly.
prenatal ultrasound anomalies that helped raise the
prenatal suspicion of EOMS and 36 (65.45%) were
diagnosed on the postnatal period, without prenatal
ultrasound findings. Analyzing the cases with prenatal
suspicion (n ¼ 19), we found that the most common
prenatal finding was valve prolapse and tricuspid
regurgitation and/or mitral regurgitation present in 16
cases (84.21%). Cardiomegaly was found in 15 cases
(78.95%), dilation of great vessels in 14 cases (73.68%),
diaphragmatic defect (hernia or eventration) in 4 cases
(21.05%) and crystalline lens luxation in 3 cases
(15.79%). The family history of Marfan syndrome was
positive in 3 cases (15.79%), negative in 15 cases
(78.95%) and unknown in 1 case (5.26%).
There was 1 termination of pregnancy (5.26%), 1
fetus died in utero (5.26%), 1 unknown case (5.26%),
14 infants died during the first 15 months of life
(73.68%) and 2 patients were alive at the moment of
publication of the article (alive at 15 months and
5 years old) (10.53%).
Molecular confirmation was only performed in 11
cases (57.89%).
In the cases with postnatal diagnosis (n ¼ 36), the
most frequent findings were arachnodactyly, present
in 31 cases (86.11%), pulmonary and aortic dilatation
present in 26 cases (72.22%), valve prolapse and

Table 1. Literature search on the prenatal and postnatal cases with suspicion of EOMS.
Author
Cases with prenatal ultrasound findings
Koenigsberg et al.
(1981) [5]
Chaoui et al. (1994) [10]
Lopes et al. (1995) [11]
Wang et al. (1996) [12]
Ng et al. (1999) [13]
Lopes et al. (2006) [14]
Ramaswamy et al.
(2006) [15]
Stadi
e et al. (2007) [16]
Sutherell et al. (2007) [17]
Barnett et al. (2010) [18]
Chao et al. (2010) [19]
Gavil
an et al. (2011) [20]
4
Evolution of the
GA at diagnosis affected patient Family history of
in weeks Prenatal sonographic findings Perinatal clinical and/or imaging findings (fetus/neonate) Marfan syndrome Molecular results
24 Long bones overgrowth Normal prenatal echocardiography Termination Mother and sibling No
of pregnancy


37 Cardiomegaly Dilatation of the aortic and pulmonary roots; TR, MR, Dead at 1st day No No
AoR, PR of life
A. VEIGA-FERNANDEZ
34 Cardiomegaly, intrauterine Dilatation of the aortic and pulmonary roots; AV valve Dead at 2 months Father No
growth restriction prolapse, mild TR, severe MR, mild AoR and PR of life
Prenatal Cranial malformation, dia- Scaphocephaly, plagiocephaly, pectus carinatum, left Dead at 3 months No Double mutant allele in
phragmatic abnormality, thoracolumbar scoliosis, dextrocardia, joint contrac- of life exon 26 of FBN1:
limb anomaly, TR and PR. tures, arachnodactyly, camptodactyly, loose redun- - T3212G transver-
dant skin, bilateral optic nerve colobomata with no sion that results in an
lens subluxation. Situs solitus, dextrocardia, prolaps- I1071 S amino acid sub-
ing TV and MV, TR and MR, right ventricular hyper- stitution.
trophy and right hemidiaphragm eventration. - A3219T transver-
sion resulting in an
E1073D amino acid
substitution
29 Cardiomegaly TV prolapse, mild to severe TR and PR Dead at 3 months No Mutation in the exon 25,
of life FBN1, c1032G > A
33 Cardiomegaly, dilatation of the Dilatation of the aortic and pulmonary roots, ductus Intrauterine demise No Mutation in the exon
aortic and pulmonary roots arteriosus dilatation at 39 weeks 26, FBN1
of gestation
29 Cardiomegaly Dilatation of the aortic and pulmonary roots, AV Alive at last follow- No No
valve prolapse up (15
months old)
22 Mild MR, femur overgrowth, Dilatation of the aortic root, mild TR, MR, AoR, and PR Dead at 9 days of life No No
cardiomegaly
26 Flexion contractures Large dysplastic ears, prominent nasolabial folds, broad Dead at 4th day No c 3256T > C, in exon
nasal bridge, high arched palate, arachnodactyly, of life 26, FBN1
joint contractures, pes planus, dolichocephaly, hypo-
tonia, redundant skin folds, cardiomegaly, bilateral
atrioventricular valve leaflet dysplasia and prolapse,
biauricular enlargement, severe TR, moderate MR,
Aortic root dilation, mild AoR
30 Right diaphragmatic hernia Dolichocephaly, arachnodactyly, bilateral crystalline lens Dead at 7 months No Mutation in exon 25, FBN1,
luxation, mitral prolapse, MR, cardiomegaly, dilata- of life c.3202 T > G (p.C1068G).
tion of the aortic root, right diaphragmatic hernia,
pseudo polymicrogyria
33 Ascites, polyhydramnios Dolichocephaly, facial asymmetry, pectus excavatum, Dead at 3 days of life No Mutation in exon 26,
arachnodactyly, articular contractures, cardiomegaly, FBN1, (c.3208G > C)
dilatation of the aortic root, mitral prolapse, MR,
TR, AoR
28 Cardiomegaly Cardiomegaly, dilatation of aortic and pulmonary roots, Dead at 3 months No Mutation in exon 29,
mild AV valve prolapse, mild to moderate TR, of life FBN1, c.3602G > A
DV agenesia
35 Dilatation of aortic and pul- Cardiomegaly, Dilatation of aortic and pulmonary roots, Dead at 40 days No Mutation in exon 32,
monary roots AV valve prolapse, mild TR, MR y AoR. Elongated of life FBN1 c.3964 þ 1G > C
and hyperflexed hands and feet
(continued)
Table 1. Continued.
Author
Herman et al. (2013) [21]
Hawkins et al. (2014) [22]
Maeda et al. (2016) [23]
Nazarali et al. (2017) [24]
Our case
Cases without prenatal ultrasound findings
Lonnqvist et al. (1996) [25] PN (newborn)
Bresters et al. (1999) [26]
Jacobs et al. (2002) [27]
N. Revencu et al
(2004) [28]
Summers et al. (2005) [1]
Tekin et al. (2007) [29]
GA at diagnosis
in weeks Prenatal sonographic findings
3rd trimester Left congenital diaphrag-
matic hernia
Prenatal Mega cisterna magna
33 Massive MR and TR. Dilatation Massive MR and TR, dilatation of the ascending aorta,
of the ascending aorta
Prenatal 1st identical twin.
Cardiomegaly,
hydrocephalus
Prenatal 2nd identical twin.
Cardiomegaly
28 Dichorionic-diamniotic twin
pregnancy with one
affected fetus: Long bones
overgrowth, cardiomegaly,
and suspicion of diaphrag-
matic eventration
Unknown
PN (infant) Uneventful pregnancy
PN (newborn) Uneventful pregnancy
PN (newborn) Uneventful pregnancy
PN (6 months of life) Uneventful pregnancy
PN (newborn) Uneventful pregnancy
PN (newborn) Uneventful pregnancy
Evolution of the
affected patient Family history of
Perinatal clinical and/or imaging findings (fetus/neonate) Marfan syndrome Molecular results
Dysmorphic (long face) and ‘senile’ appearance, micro- Unknown Mother and No
gnathia, crumpled ears, and arachnodactyly. Patent grandfather
foramen oval. Hiatus hernia with intrathoracic stom-
ach (organoaxial volvulus).
Dolichocephaly, arachnodactyly, pigeon chest, joint con- Dead at 14 months No Heterozygote mutation
tractures, enophthalmos, micrognathia, high palate. of life c.3203G (p.Cys 1068Tyr)
Cardiomegaly, interauricular communication Ostium in exon 25, FBN1
Secundum, dysplastic mitral valve with mild MR and
AoR. Mega cisterna magna.
Dead at 2 months Unknown (c.IVS30 þ 1G > A) in exon
arachnodactyly, joint contracture of life 30 FBN1
Decreased left ventricular function, TV and MV prolapse, Alive at last follow- No Heterozygous large deletion
aortic root dilation, patent foramen ovale. up (5 years old) including exons 32 to 37
Arachnodactyly, flexion contractures, hyperkyphosis, of the FBN1 gene.
bilateral corneal edema, bilateral cataract and dislo-
cated lenses, glaucoma.
Decreased left ventricular function, TV and MV prolapse, Dead at 9 months No No
aortic root dilation, patent foramen ovale. of life
Arachnodactyly, flexion contractures.
Cardiomegaly, dilatation of the aortic and pulmonary Dead at 3 months No No
roots, AV valve prolapse, elongated femur, bilateral of life
luxation of crystalline lenses, ductus arteriosus dilata-
tion, elevated liver with intrathoracic DV and hepatic
venous outflow, arachnodactyly, posterior right dia-
phragmatic eventration, mild pulmonary hypoplasia
Arachnodactyly, poly valvular disease, dilated aortic Unknown Unknown I1048T in exon 25 of FBN1
root, arachnodactyly, and loose skin.
Arachnodactyly, joint contractures, hypertrophic stenosis Dead at 3 months No I1048T in exon 25 of
of the pylorus, AV valve prolapse, dilatation or the of life FBN1, 3276 > C.
aortic and pulmonary roots, aneurysm of the sinus
of Valsalva of the pulmonary valve, cardiac myxoma-
tous degeneration
Birth length >90th centile, arachnodactyly, joint con- Dead at 3.5 months Unknown I1048T in exon 25 of FBN1
tractures, dilated aortic root, MR, diaphragmatic of life
eventration, emphysema, craniofacial features
Diaphragmatic eventration, bilateral uretero-hydroneph- Dead at 3 days of life Unknown Mutation in exon 25,
rosis bilateral with bladder dilatation FBN1, 3165T > G
Dysmorphic face, dislocated hips, adducted thumbs, Alive at the last fol- No Mutation in exon 25, FBN1,
joint contractures and hypermobility, muscle weak- low-up (14 G > A at nucleotide pos-
ness, hypotonia, arachnodactyly. At age 4: MV and years old) ition 3131 that converts
TV leaflets showed mild to moderate prolapse. the codon TGC, coding
Myopia, bilateral lens dislocation, iridodonesis, for cysteine at position
astigmatism. 1044, to TAC, coding for
tyrosine (C1044Y)
Long bones overgrowth, joint contractures, bilateral Dead at 2 months No No. 1st affected sibling
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
crystalline lens luxation, dilatation of the aortic root of life
Long bones overgrowth, joint contractures, megalocor- Dead at 3 months One sibling. No. 2nd affected sibling
nea, pectus excavatum, dolichocephaly, dilatation of of life
5
the aortic root
(continued)
 6

Table 1. Continued.
Evolution of the
GA at diagnosis affected patient Family history of
Author in weeks Prenatal sonographic findings Perinatal clinical and/or imaging findings (fetus/neonate) Marfan syndrome Molecular results
PN (newborn) Uneventful pregnancy Long bones overgrowth, arachnodactyly, dolichoceph- Dead at 4 months Two siblings. Heterozygous mutation
aly, megalocornea, crystalline lens luxation, dilatation of life c.3257 > A
of the aortic root, AV valve prolapse, TR, MR, (p.Cys1086Tyr) in FBN1.

inguinal hernia 3rd affected sibling. The

mosaicism of the muta-
tion was confirmed in
A. VEIGA-FERNANDEZ

the father.
Hugger et al. (2009) [30] PN (newborn) Placenta praevia with Long bones overgrowth, cardiomegaly, mega cisterna Dead at 2 days of life No Heterozygous deletion in
total occlusion magna, dilatation of the aortic root, TR, PR exon 24-26 of the FBN1
Laus et al. (2010) [31] PN (newborn) Uneventful pregnancy Arachnodactyly, joint contractures, dilatation of the Dead at 1st day Unknown No
aorta and pulmonary arteries, right diaphragmatic of life
hernia, bilateral pulmonary hypoplasia
Barnett et al. (2010) [18] PN (newborn) Uneventful pregnancy Dolichocephaly, pectus carinatum, arachnodactyly, joint Dead at 2 months No Mutation in the exon 30,
contractures, iris hipoplasia, cardiomegaly, AV valve of life FBN1, (c.3838 þ 1 G > A).
prolapse, dilatation of the aortic root, bicuspid aortic
valve, absent falx cerebri
Brito-Filho et al. (2012) [32] PN (newborn) Uneventful pregnancy Dilatation of the aortic root Alive at last follow- No No
up (9 years old)
Ghandi et al. (2013) [33] PN (47th-day-old) Uneventful pregnancy Enophthalmos, micrognathia, arachnodactyly, pectus Dead at 2 months No No
excavatum, bilateral inguinal hernia, right diaphrag- of life
matic eventration, dilatation of the aortic root, AV
valve prolapse, TR, MR, moderate pulmonary
hypertension
PN (90-day-old) No fetal abnormalities. Arachnodactyly, pectus excavatum, cardiomegaly, dilata- Dead at 3 months No No
Oligohydramnios tion of the aortic root, AV valve prolapse, MR, TR, of life
Pulmonary hypertension, interauricular communica-
tion (left-right shunt).
Eayrs et al. (2013) [34] PN (1st month Uneventful pregnancy Pulmonary hypertension, dysplastic tricuspid valve, Alive at last follow- Mother  c.5202delA mutation in
of life) severe TR, biventricular hypertrophy, patent foramen up (12 exon 41, FBN1
ovale, hypotonic, large hands and feet with arachno- months old)  Trisomy of chromo-
dactyly, wide carrying angle of elbows, ulnar devi- some 21
ation of wrists and small simple ears.
Elshershari et al. (2014) [35] PN (2 months of life) Uneventful pregnancy Aortic root dilation, dysmorphic facies, micrognathia, a Alive at last follow- Father Heterozygous c.3959G > A
high arched palate, long (97th centile) protruding up (6 months old) transition in exon
ears, arachnodactyly 31, FBN1.
Amado M. et al. (2014) [36] PN (newborn) Uneventful pregnancy Frontal bossing, redundant skin folds, prematurely aged Alive at last follow- No c.3458G > A in exon 27
appearance, dolichocephaly, deeply set eyes, retromi- up (34 with an amino acid sub-
crognathia, adduct contracture of thumbs, hindfoot months old) stitution of a cysteine by
deformity, hip dysplasia, contractures of the elbows, a tyrosine at position
arachnodactyly, MR and TR, aortic arch elongation 1153
(p.Cys1153Tyr), FNB1
Daskalaki et al. (2014) [37] PN (newborn) Urgent caesarian section at Arachnodactyly, pectus carinatum, ascending Aorta in Unknown Mother, two uncles Heterozygous variant FBN1:
33 þ 4 weeks (mother suf- the upper normal limits. and grandfather c.7656 C > G, located in
fered an acute dissection of exon 62
descending thoracic aorta)
S
ıpek et al. (2014) [38] PN (newborn) Uneventful pregnancy MR and TR, Aortic root dilatation, arachnodactyly, and Dead at 7 months No Intronic c.4211-32-13del
loose skin. Severe and inoperable heart anomalies. of life mutation in FBN1,
exon 35
(continued)
Table 1. Continued.
Author
Sureka et al. (2014) [39]
Ozyurt A et al. (2015) [40]
Kishore et al. (2015) [41]
Kale et al. (2015) [42]
Le Gloan et al. (2016) [43]
Peng et al. (2016) [44]
Evolution of the
GA at diagnosis affected patient Family history of
in weeks Prenatal sonographic findings Perinatal clinical and/or imaging findings (fetus/neonate) Marfan syndrome Molecular results
PN (newborn) Uneventful pregnancy Birth length >90th centile, Arachnodactyly, Joint con- Dead at 17 months No c.3143T > C mutation
tractures, Dilated aortic root, MR, right diaphragmatic of life resulting in an I1048T in
eventration, Craniofacial features exon 25 of FBN1
PN (4 months of life) Uneventful pregnancy Craniofacial features, arachnodactyly, joint contractures, Dead at 5 years No I1048T in exon 25 of FBN1
UMD ID: 506 hypermobility of the joints, senile appearance, nar- of life
row palatal arch, pectus carinatum, dolichostenome-
lia, pes planus, scoliosis, dilated aortic root, MR, AoR,
myopia, flat corneas, lens subluxation.
PN (1 year of life) Uneventful pregnancy Birth length >90th centile, craniofacial features, arach- Dead at 2.5 years No I1048T in exon 25 of FBN1
UMD ID: 629 nodactyly, pectus excavatum, myopia, moderate MR of life
and AoR, dilated aortic root.
PN (newborn) UMD Uneventful pregnancy Arachnodactyly, MR and TR, dilated aortic root, cranio- Unknown No I1048T in exon 25 of FBN1
ID: 1177 facial features.
PN (30th day Uneventful pregnancy Arachnodactyly, long bone overgrowth, prominent fore- Dead at 68 days No No
after birth) head, flat nose, high palate, low- set ears, enoph- of life
thalmos, dolichocephaly, articular laxity particularly
in wrists and ankles, hypotonia, cardiomegaly, dex-
trocardia, mitral valve prolapse, severe MR, moderate
TR, slight AoR and dilated left ventricle.
Supraventricular tachycardia. Mega cisterna magna.
PN (4 months old) Uneventful pregnancy Long bone overgrowth, arachnodactyly, joints hyperlax- Unknown No No
ity, dolichocephaly, metopic and bilateral coronal
craniosynostosis, pectus excavatum, cardiomegaly,
aortic root dilatation and left atrial enlargement, bia-
trial dilatation, and biventricular hypertrophy. Aortic
root dilatation, minimal AoR, severe MR and patent
foramen ovale.
PN (2 months old) Unknown Long bone overgrowth, enophthalmus, dolichocephaly, Dead at 2 months Unknown No
retrognathia, downward slanting palpebral fissure, of life
blue sclera, scoliosis, arachnodactyly, flat feet, joint
contractures, dilated aortic root, aortic sinuses, and
sinotubular junction. Severe Ao, mild MR and TR
PN (newborn) Uneventful pregnancy Long bone overgrowth, arachnodactyly, joint contrac- Unknown No No
tures, dilated aortic root, AoR, mitral and tricuspid
valve prolapse, moderate-severe TR, glaucoma
PN (newborn) Uneventful pregnancy Arachnodactyly, facial dysmorphism with senile appear- Dead at 4 months Mother Variant
ance and loose skin, Severe MR and TR, moderate of life (c.6163 þ 3_6163 þ 6del)
aortic root dilatation with moderate AoR, diaphrag- in the intron 49 of
matic hernia. the FBN1.
PN (8 months old) Uneventful pregnancy Arachnodactyly, bilateral knee and elbow joints, ‘senile’ Unknown No Four variants identified in
facial appearance, loose skin, pectus excavatum, FBN1:
micrognathia, pes planus, dolichocephaly, cardiomeg- - Homozygous syn-
aly, mitral valve prolapse and MR, tricuspid valve onymous variant in exon
hypertrophy and TR, left atrial chamber enlargement, 15 (c.1875 T > C,
and aortic root dilatation at the sinuses of Valsalva. p.Asn625Asn) (rs25458).
- Two heterozygous
missense variants in:
exon 26 (c.3331 T > C,
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
p.Cys1111Arg). Exon 27
(c.3442C > G,
p.Pro1148Ala)
7
(rs140598).
(continued)
 8

Table 1. Continued.
Evolution of the
GA at diagnosis affected patient Family history of
Author in weeks Prenatal sonographic findings Perinatal clinical and/or imaging findings (fetus/neonate) Marfan syndrome Molecular results
- Heterozygous
intronic variant (c.3464-
5G > A) (rs11853943).

Maeda et al. (2016) [23] PN (newborn) 1st identical twin. Dolichocephaly, enophthalmos, arachnodactyly. Massive Alive at the last fol- Unknown c.3217G > A in exon 26
Uneventful pregnancy MR and TR, prolapse of all leaflets. Severe scoliosis. low-up (10 of FBN1
Bilateral ectopia lentis years old)
A. VEIGA-FERNANDEZ

PN (newborn) 2nd identical twin. Low Arachnodactyly, contracture of the right finger joints, Dead at 3 months Unknown c.3217G > A in exon 26
birth weight. scoliosis, chest deformity. Cardiac status unknown. of life of FBN1
PN (10 months old) Uneventful pregnancy Enophthalmos, down-slanting palpebral fissures, and Alive at last follow- Unknown c.3677G > T in exon 29 of
arachnodactyly. Bilateral ectopia lentis, annu- up (8 years old) the FBN1
loaortic ectasia
PN (1st month Uneventful pregnancy Enophthalmos, arachnodactyly, joint contractures. Mitral Dead at 7 months Unknown (c.3217G > A) in exon
of life) valve prolapse and annuloaortic ectasia of life 26, FBN1
PN (newborn) Uneventful pregnancy Enophthalmos, down-slanting palpebral fissures, arach- Dead at 1 year of life Unknown c.IVS29 þ 1G > A in exon
nodactyly, moderate MR and TR with prolapse 29 of the FBN1
Sun Heo et al. (2017) [45] PN (newborn) Uneventful pregnancy Dolichocephaly, micro- and retrognathia, down-slanting Dead at 6 months Unknown c.3217G > A in exon 26 of
palpebral fissures, crumpled ears, arachnodactyly, of life the FBN1 gene,
adducted thumb, reduced elbow extension, pectus (p.Glu1073Lys)
excavatum, dilated aortic root, grade 4 hydronephro-
sis and severe hydroureter in the right kidney,
dilated cisterna magna and eventration of the right
hemidiaphragm
Carande et al. (2017) [46] PN (6 weeks of life) No fetal abnormalities. Plagiocephalic, arachnodactyly, joint contractures, Alive at last follow- No FBN1gene mutation
Oligohydramnios kyphoscoliosis, aortic root dilatation, atrioventricular up (14 (exon26,c.3143T > C)
valve prolapse, TR, dysplastic mitral valve, MR, pul- months old)
monary hypertension.
GA: Gestational age at the moment of clinical suspicion of EOMS; TR: tricuspid valve regurgitation; MR: mitral valve regurgitation, AoR: Aortic valve regurgitation; PR: pulmonary valve regurgitation; AV: atrioven-
tricular; TV: tricuspid valve; MV: mitral valve; DV: ductus venosus; FBN1: fibrillin-1 gene; PN: postnatal; UMD ID: patient ID numbers for these cases from the Universal Marfan Database.

Table 2. Main features of EOMS and their prevalence in cases of prenatal and postna-
tal suspicion.
Prenatal suspicion of EOMS
Average age at first diagnostic suspicion
Cardiomegaly
Ectopia lentis
Diaphragmatic hernia or eventration
Average age of death
Alive on the last follow-up
Family history of Marfan syndrome
Molecular confirmation
Newborn: equal or less than 30 days of life.
tricuspid regurgitation and/or mitral regurgitation in
26 cases (72.22%), cardiomegaly in 6 cases (16.67%)
and crystalline lens luxation in 6 cases (16.67%).
Family history of Marfan syndrome was positive in 6
cases (16.67%), negative in 19 cases (52.78%) and
unknown in 11 cases (30.56%).
Twenty-two infants (61.11%) died during the first
5 years of life, eight cases (22.22%) were alive at the
moment of the publication of the article (alive at 6,
12, 14 and 34 months and at 8, 9, 10 and 14 years).
We do not have information on the evolution of 6
cases (16.67%).
Overall, family history of Marfan syndrome was
positive in 9 cases (16.36%), negative in 34 cases
(61.82%) and unknown in 12 cases (21.82%). Molecular
confirmation was performed in 37 cases (67.27%) find-
ing different mutations of the FBN1 gene.
Discussion
We present a case of prenatal suspicion of EOMS in a
nonidentical twin pregnancy. The affected fetus pre-
sented a diaphragmatic eventration and cardiomegaly
as initial sonographic anomalies. In our case, molecular
confirmation was not performed during the pregnancy.
We also present a systematic review of all the
articles on EOMS published, including those with pre-
natal ultrasound anomalies (with or without molecular
confirmation of EOMS) and those without prenatal
ultrasound anomalies (Table 1). Most of the published
cases of EOMS are diagnosed after birth without any
prenatal suspicion.
EOMS is not easily diagnosed during the fetal life even
when ultrasound findings are present since these are usu-
ally unspecific and of late presentation [1]. Most cases
(65.45%) are diagnosed after birth (Table 2). Ghent criteria
used to diagnose Marfan syndrome are not useful during
the perinatal period and cannot be used to diagnose pre-
natal cases [3,6]. Even Hennekam’s criteria in EOMS are
restricted to those neonates with massive mitral and/or tri-
cuspid insufficiency with pulmonary emphysema [6],
severe mitral and/or tricuspid valve insufficiency, ectopia
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 9
Postnatal suspicion of EOMS
30 weeks Newborn: 61.11% (22/36)
78.95% (15/19) 16.67% (6/36)
15.79% (3/19) 16.67% (6/36)
21.05% (4/19) 19.44% (7/36)
3.5 months 6.75 months
10.52% (2/19) 26.67% (8/30)
15.79% (3/19) 24% (6/25)
57.89% (11/19) 72.22% (26/36)
lentis, arachnodactyly, and joint contractures, most of
them described in the literature (Table 1). However, these
criteria could be applied during the fetal period in fetuses
with cardiomegaly. Other prenatal ultrasound findings
associated with EOMS are dilatation of the aortic and pul-
monary roots, elongation of both arteries, diaphragmatic
hernia or eventration, and overgrowth of the femoral or
humeral length. Ectopia lentis and diaphragmatic defects
are not frequently found in both prenatal and postnatal
cases. Fetal magnetic resonance imaging can be useful in
prenatal diagnosis of Marfan syndrome as it can help to
differentiate between diaphragmatic hernia and diaphrag-
matic eventration [47], diagnose crystalline lens sublux-
ation as in our case, and can confirm other findings
associated with EOMS.
Prenatal suspicion of EOMS should alert the clinician.
However, suspicion is only raised in 1 in 6 cases during
prenatal period and in 1 in 3 cases in postnatal period.
Follow-up should take place in a tertiary care center,
and should include prenatal echocardiography and
obstetric ultrasound within a multidisciplinary approach.
Patients with positive familial history should receive
prenatal counseling, however, most of the cases of
EOMS appear without previous familial cases, and are
due to de novo mutations (Table 2). When EOMS is
prenatally suspected, invasive diagnosis should be dis-
cussed with the patient [6–16,47]. Confirmation of the
diagnosis relies on the presence of molecular changes
in the FBN1. It is noteworthy that in 42% of the pre-
natally suspected cases and 27% of the postnatally
suspected cases a definitive diagnosis was not per-
formed (Table 2). Reasons for this could be the fact
that it is an invasive technique, that it can sometimes
be difficult to perform, or the cost of the technique,
added to the fact that the disease is fatal in most of
the cases. Moreover, the sensitivity of the genetic
study is still low mainly due to high variability in the
anomalies found in the gene [21–24]. Molecular con-
firmation of the genetic disorder is of the uttermost
importance for further counseling. Indeed, some enti-
ties could present with traits similar to EOMS
(Loeys–Dietz syndrome, Ehlers–Danlos syndrome, and
10

A. VEIGA-FERNANDEZ

Figure 3. Fetal ultrasound performed at 36 þ 4 weeks of gestation showing an axial view of the head with a bilateral crystalline
lens subluxation.
Figure 4. Newborn at the pediatric intensive care unit on her
first day of life. Generalized hypotonia and severe arachnodac-
tyly are noteworthy.
Familial Thoracic Aortic Aneurysm and Dissection) and
differential diagnosis could rely on the genetic study.
Prenatal diagnosis of EOMS is challenging and of
most importance. A multidisciplinary approach in a
tertiary care center is mandatory, not only during the
pregnancy but also during delivery and postnatally.
Patients should be informed that mortality rate is high
[3,11,14], being higher in cases with prenatal suspicion
(Table 2). This may be related to the severity of the
anomalies (worse in prenatal cases) so that they can
be observed before or with their time of evolution,
especially for valve disease.
Despite the fact that cardiomegaly is present in
most of the cases of EOMS with postnatal diagnosis it
was only reported in 16.67% of the patients (Table 2).
This difference could be explained by an incomplete
description in postnatal cases referring exclusively to
the specific cardiac anomalies (valve regurgitation,
arterial root dilation, etc.) without referring to the
inherent heart enlargement.
The main limitation of the case we present, as it is in
most of the reported cases of prenatal diagnosis, is that
we could not assure the diagnosis before or after birth
since the parents patient refused to perform an invasive
test at 28 weeks when suspicion was raised and also
postnatally. As we have seen in the literature review
EOMS is more frequently diagnosed after birth than in
the prenatal period. Prenatal diagnosis is preferable but
not mandatory, as postnatal management can be pre-
pared according to ultrasound and MRI findings.

Figure 5. Flowchart showing the steps of the bibliographic research.
Conclusions
In the presence of a sonographic suspicion of EOMS, a
thorough search of other anomalies should be per-
formed. Periodic ultrasound examinations should be
scheduled to assess fetal cardiac function. Prenatal
invasive diagnosis should be offered to the patient. A
multidisciplinary approach is mandatory, and delivery
should be prepared in a tertiary care center.
Disclosure statement
No potential conflict of interest was reported by the authors.
References
[1] Summers KM, Nataatmadja M, Xu D, et al.
Histopathology and fibrillin-1 distribution in severe
early-onset Marfan syndrome. Am J Med Genet A.
2005;139(1):2–8.
[2] Attanasio M, Lapini I, Evangelisti L, et al. FBN1 muta-
tion screening of patients with Marfan syndrome and
related disorders: detection of 46 novel FBN1 muta-
tions. Clin Genet. 2008;74(1):39–46.
[3] Loeys BL, Dietz HC, Braverman AC, et al. The revised
Ghent nosology for the Marfan syndrome. J Med
Genet. 2010;47(7):476–485.
[4] Collod-B
eroud G, Le Bourdelles S, Ades L, et al.
Update of the UMD-FBN1 mutation database and cre-
ation of an FBN1 polymorphism database. Hum
Mutat. 2003;22(3):199–208.
[5] Koenigsberg M, Factor S, Cho S, et al. Fetal Marfan
syndrome: prenatal ultrasound diagnosis with
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 11
pathological confirmation of skeletal and aortic
lesions. Prenat Diagn. 1981;1(4):241–247.
[6] Hennekam RC. Severe infantile Marfan syndrome ver-
sus neonatal Marfan syndrome. Am J Med Genet A.
2005;139(1):1.
[7] Shinawi M, Boileau C, Brik R, et al. Splicing mutation in
the fibrillin-1 gene associated with neonatal Marfan syn-
drome and severe pulmonary emphysema with trache-
obronchomalacia. Pediatr Pulmonol. 2005;39(4):374–378.
[8] Foundation TM, The Marfan Foundation. 2018s.
Available from: http://www.marfan.org.
[9] Liberati A, Altman DG, Tetzlaff J, et al. The Prisma
statement for reporting systematic reviews and meta-
analyses of studies that evaluate health care interven-
tions: explanation and elaboration. PLOS Med. 2009;
6(7):e1000100.
[10] Chaoui R, Bollmann R, Go € ldner B, et al. Fetal cardio-
megaly: echocardiographic findings and outcome in
19 cases. Fetal Diagn Ther. 1994;9(2):92–104.
[11] Lopes LM, Cha SC, de Moraes EA, et al.
Echocardiographic diagnosis of fetal Marfan syndrome at
34 weeks’ gestation. Prenat Diagn. 1995;15(2):183–185.
[12] Wang M, Kishnani P, Decker-Phillips M, et al. Double
mutant fibrillin-1 (FBN1) allele in a patient with neo-
natal Marfan syndrome. J Med Gen. 1996;33(9):760–763.
[13] Ng DK, Chau KW, Black C, et al. Neonatal Marfan syn-
drome: a case report. J Paediatr Child Health. 1999;
35(3):321–323.
[14] Lopes KR, Delezoide AL, Baumann C, et al. Prenatal
Marfan syndrome: report of one case and review of
the literature. Prenat Diagn. 2006;26(8):696–699.
[15] Ramaswamy P, Lytrivi ID, Nguyen K, et al. Neonatal
Marfan syndrome: in utero presentation with aortic
and pulmonary artery dilatation and successful repair
of an acute flail mitral valve leaflet in infancy. Pediatr
Cardiol. 2006;27(6):763–765..
12

A. VEIGA-FERNANDEZ
[16] Stadie
R, Geipel A, Heep A, et al. Prenatal diagnosis of
Marfan syndrome. Ultrasound Obstet Gynecol. 2007;
30(1):119–121.
[17] Sutherell J, Zarate Y, Tinkle BT, et al. Novel fibrillin 1
mutation in a case of neonatal Marfan syndrome: the
increasing importance of early recognition. Congenit
Heart Dis. 2007;2(5):342–346.
[18] Barnett CP, Wilson GJ, Chiasson DA, et al. Central ner-
vous system abnormalities in two cases with neonatal
Marfan syndrome with novel mutations in the fibrillin-
1 gene. Am J Med Genet A. 2010;152A(9):2409–2412.
[19] Chao SC, Chen JS, Tsai CH, et al. Novel exon nucleotide
substitution at the splice junction causes a neonatal
Marfan syndrome. Clin Genet. 2010;77(5):453–463.
[20] Gavil
an C, Herraiz I, Granados MA, et al. Prenatal diag-
nosis of neonatal Marfan syndrome. Prenat Diagn.
2011;31(6):610–613.
[21] Herman TE, Siegel MJ, Mathur A, et al. Neonatal
Marfan syndrome with hiatus hernia and intrathoracic
stomach. J Perinatol. 2013;33(8):652–653.
[22] Hawkins M, Alcalde A, Yebra J, et al. Marfan neonatal
syndrome: a case report. 53rd Annual Meeting of the
European Society for Paediatric Endocrinology (ESPE).
Dublin, Ireland, September 18–20, 2014: Abstracts.
Horm Res Paediatr. 2014;82(Suppl 1):1–508.
[23] Maeda J, Kosaki K, Shiono J, et al. Variable severity of
cardiovascular phenotypes in patients with an early-
onset form of Marfan syndrome harboring FBN1
mutations in exons 24–32. Heart Vessels. 2016;31(10):
1717–1723.
[24] Nazarali S, Nazarali SA, Antoniuk A, et al. Childhood
glaucoma in neonatal Marfan syndrome resulting
from a novel FBN1 deletion. Can J Ophthalmol. 2017;
52(5):e171–e173.
[25] Lo€nnqvist L, Karttunen L, Rantam€aki T, et al. A point
mutation creating an extra N-glycosylation site in
fibrillin-1 results in neonatal Marfan syndrome.
Genomics. 1996;36(3):468–475.
[26] Bresters D, Nikkels PG, Meijboom EJ, et al. Clinical,
pathological and molecular genetic findings in a case
of neonatal Marfan syndrome. Acta paediatr. 1999;
88(1):98–101.
[27] Jacobs AM, Toudjarska I, Racine A, et al. A recurring
FBN1 gene mutation in neonatal Marfan syndrome.
Arch Pediatr Adolesc Med. 2002;156(11):1081–1085.
[28] Revencu N, Quenum G, Detaille T, et al. Congenital
diaphragmatic eventration and bilateral uretero-
hydronephrosis in a patient with neonatal Marfan
syndrome caused by a mutation in exon 25 of the
FBN1 gene and review of the literature. Eur J Pediatr.
2004;163(1):33–37.
[29] Tekin M, Cengiz FB, Ayberkin E, et al. Familial neo-
natal Marfan syndrome due to parental mosaicism of
a missense mutation in the FBN1 gene. Am J Med
Genet A. 2007;143A(8):875–880.
[30] Hugger C, K€ uhn T, Niethammer K, et al. P03.13:
Neonatal Marfan syndrome. Ultrasound Obstet
Gynecol. 2009;34(S1):190–190.
[31] Laus F, Juliano C, Cabral V. Congenital Marfan syn-
drome leading to early neonatal death: autopsy case
report: 598. Histopathology. 2010;57(Sup 1):215–216.
[32] Brito-Filho SL, Oporto V, Campos O, et al. A case of
neonatal Marfan syndrome with good late follow-up:
is it possible to avoid an early unfavourable outcome?
Cardiol Young. 2013;23(2):301–303.
[33] Ghandi Y, Zanjani KS, Mazhari-Mousavi SE, et al.
Neonatal Marfan syndrome: report of two cases. Iran
J Pediatr. 2013;23(1):113–117.
[34] Eayrs K, Shettihalli N, Adwani S. Down syndrome
masked by Marfan syndrome in a neonate. BMJ Case
Rep. 2013;2013:1–3.
[35] 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.
[36] Amado M, Calado MA, Ferreira R, et al. Neonatal
Marfan syndrome: a successful early multidisciplinary
approach. BMJ Case Rep. 2014;2014:1–4.
[37] Daskalaki A, Kapsambeli H, Sideri B, et al. A new vari-
ant of Marfan syndrome in a neonate. Case report
and review of the literature. Invited Lectures. J
Maternfetal Neonat Med. 2014;27(Suppl. 1):1–437.
[38] S
ıpek A, Jr., Grodeck
a L, Baxov
a A, et al. Novel FBN1
gene mutation and maternal germinal mosaicism as
the cause of neonatal form of Marfan syndrome. Am
J Med Genet A. 2014;164A(6):1559–1564.
[39] Sureka D, Stheneur C, Odent S, et al. A recurrent
fibrillin-1 mutation in severe early onset Marfan syn-
drome. J Pediatr Genet. 2014;3(3):157–162.
[40] Ozyurt A, Baykan A, Argun M, et al. Early onset
Marfan syndrome: atypical clinical presentation of two
cases. Balkan J Med Genet. 2015;18(1):71–76.
[41] Kishore S, Kumar P, Bhutia E, et al. Marfan syndrome
with huge dilatation of the aortic root in early
infancy. Poster and case report presentations.
Echocardiography. 2015;32:A16–A69.
[42] Kale Y, Isik DU, Celik U, et al. Neonatal Marfan syn-
drome with angle-closure glaucoma, tricuspid and
mitral insufficiency. Genet Couns. 2015;26(1):95–98.
[43] Le Gloan L, Hauet Q, David A, et al. Neonatal Marfan
syndrome: report of a case with an inherited splicing
mutation outside the neonatal domain. Mol
Syndromol. 2016;6(6):281–286.
[44] Peng Q, Deng Y, Yang Y, et al. A novel fibrillin-1 gene
missense mutation associated with neonatal Marfan
syndrome: a case report and review of the mutation
spectrum. BMC Pediatr. 2016;16:60.
[45] Heo JS, Song JY, Choi EY, et al. Atypical neonatal
Marfan syndrome with p.Glu1073Lys mutation of
FBN1: the first case in Korea. J Korean Med Sci. 2017;
32(1):1–3.
[46] Carande EJ, Bilton SJ, Adwani S. A case of neonatal
Marfan syndrome: a management conundrum and
the role of a multidisciplinary team. Case Rep Pediatr.
2017;2017:8952428.
[47] ubbard AM, Crombleholme TM, Adzick NS, et al.
Prenatal MRI evaluation of congenital diaphragmatic
hernia. Am J Perinatol. 1999;16(8):407–413.