Original article

Korean J Pediatr 2016;59(2):59-64 Korean J Pediatr 2016;59(2):59-64

http://dx.doi.org/10.3345/kjp.2016.59.2.59
pISSN 1738-1061eISSN 2092-7258
Korean J Pediatr

Infantile Marfan syndrome in a Korean tertiary

referral center
Yeon Jeong Seo, MD, Ko-Eun Lee, MD, Gi Beom Kim, MD, PhD, Bo Sang Kwon, MD, Eun Jung Bae, MD, PhD, Chung Il Noh, MD, PhD
Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea

Purpose: Infantile Marfan syndrome (MFS) is a rare congenital inheritable connective tissue disorder Corresponding author: Gi Beom Kim, MD, PhD
with poor prognosis. This study aimed to evaluate the cardiovascular manifestations and overall Department of Pediatrics, Seoul National University
Childrens Hospital, 101 Daehak-ro, Jongno-gu,
prognosis of infantile MFS diagnosed in a tertiary referral center in Korea. Seoul 03080, Korea
Methods: Eight patients diagnosed with infantile MFS between 2004 and 2014 were retrospectively Tel: +82-2-2072-0266
evaluated. Fax: +82-2-743-3455
Results: Their median age at the time of diagnosis was 2.5 months (range, 020 months). The median E-mail: [email protected]
follow-up period was 25.5 months (range, 094 months). The median length at birth was 50.0 cm Received: 17 September, 2015
(range, 4853 cm); however, height became more prominent over time, and the patients were taller Revised: 18 October, 2015
than the 97th percentile at the time of the study. None of the patients had any relevant family history. Accepted: 23 October, 2015
Four of the 5 patients who underwent DNA sequencing had a fibrillin 1 gene mutation. All the patients
with echocardiographic data of the aortic root had a z score of >2. All had mitral and tricuspid valve
prolapse, and various degrees of mitral and tricuspid regurgitation. Five patients underwent open-heart
surgery, including mitral valve replacement, of whom two required multiple operations. The median
age at mitral valve replacement was 28.5 months (range, 569 months). Seven patients showed
congestive heart failure before surgery or during follow-up, and required multiple anti-heart failure
medications. Four patients died of heart failure at a median age of 12 months.
Conclusion: The prognosis of infantile MFS is poor; thus, early diagnosis and timely cautious treatment
are essential to prevent further morbidity and mortality.

Key words: Marfan syndrome, Mitral valve insufficiency, Newborn infant

Introduction
Marfan syndrome (MFS) is a multisystemic disorder of connective tissue inherited in an
autosomal dominant fashion1). It is caused by mutations in the extracellular matrix protein
fibrillin12). Current diagnostic manifestations include skeletal, ocular, cardiovascular,
pulmonary, cutaneous, and central nervous system abnormalities as well as a family
history3,4). There have been numerous case reports of MFS in infancy; however, infantile
MFS is still rarely diagnosed at younger ages, because morphological characteristics of
the syndrome are age-dependent, phenotypic variability is remarkable, and most patients
show de novo mutations3). Cardiovascular abnormalities are the major cause of death in
infantile MFS, and the most common presenting findings are mitral and/or tricuspid valve
Copyright 2016 by The Korean Pediatric Society
regurgitation, which is less common in classic MFS5,6). Long-term follow-up and proper
management including open-heart surgery in a timely manner would have beneficial This is an open-access article distributed under the
terms of the Creative Commons Attribution Non-
effects on the prognosis of the patients. However, little is known about infantile MFS in Commercial License (http://creativecommons.org/
South Korea. The aim of this study was to evaluate cardiovascular manifestations and the licenses/by-nc/4.0/) which permits unrestricted non-
commercial use, distribution, and reproduction in any
overall prognosis of recently diagnosed cases of infantile MFS in a tertiary referral center medium, provided the original work is properly cited.

http://dx.doi.org/10.3345/kjp.2016.59.2.59 59
Seo YJ, et al. Infantile Marfan syndrome

Table 1. Clinical findings of the patients with infantile Marfan syndrome

At birth At diagnosis At the time of study
Follow-up
Case Sex Body weight Height Presenting symptom Body weight Height Mortality
Age (mo) period (mo) Age (mo)
kg (percentile) cm (percentile) (kg, percentile) (cm, percentile)
1 F 3.48 (5075) NA 12 Cannot stand up alone at 12 mo 94 130 32.5 (2550) 159.6 (>97) Expired
2 F 2.5 (<3) NA 8 Murmur 39 47 12.6 (<3) 88.5 (1025) Alive
3 F 3.35 (5075) 51 (5075) 0 Murmur 17 20 7.3 (<3) 86.6 (7590) Expired
4 F 3.7 (7590) NA 2 NA 0 4 6.5 (2550) 69.2 (>97) Expired
5 M 3.09 (2550) 50(2550) 20 Myopia 44 100 23.7 (1025) 135.7 (7590) Alive
6 F 2.9 (1025) 49 (2550) 3 Murmur 34 38 14.5 (5075) 111 (>97) Alive
7 M 3.31 (2550) 53 (9095) 0 Desaturation at birth 5 5 7.6 (2550) 72.1 (9597) Alive
8 F 2.56 (35) 48 (2550) 0 Prenatal US 0 0 2.7 (510) 48 (2550) Expired
NA, not available; US, ultrasonography.

in South Korea. Table 2. Revised Ghent nosology pattern in each of the patients with
infantile Marfan syndrome
Ectopia FBN1 gene Systemic
Case Family history Aorta (z3)
lentis mutation score
Materials and methods
1 Negative 35.4 mm (6.10) NA NA 6
Between 2004 and 2014, among the 180 patients who had 2 Negative NA NA NA
been followed up for MFS during this period, eight patients 3 Negative 31.0 mm (7.57) + 6
were clinically diagnosed with infantile MFS at Seoul National 4 Negative 20.9 mm (5.02) NA + 3
University Hospital. Diagnosis of MFS was based on the revised 5 Negative 32.4 mm (5.46) + + 13
Ghent criteria4,7). Systemic score is one of the diagnostic criteria 6 Negative 25.1 mm (6.37) + + 6
and is calculated according to the most selective systemic features 7 Negative 16.5 mm (4.66) + 2
and the score greater than or equal to 7 points was considered a 8 Negative 13.8 mm (3.87) NA NA 4
positive systemic score4). All available medical records were re NA, not available; FBN1, Fibrillin 1.
viewed retrospectively, including gender, birth weight and height,
age at diagnosis, follow-up duration, other systemic involvement, Three of the patients (cases 1, 2, and 4) were lost to follow-
family history, echocardiographic findings, gene testing, opera up at our hospital. By asking other hospital physicians and the
tions, medications, and mortality. This study was approved by the statistical service of the Ministry of Government Administration
Institutional Review Boards of Seoul National University Hospital and Home Affairs, we learned that two of these patients died
(IRB number: H-1501-016-636), and informed consent was waiv during follow-up at other hospitals and one patient is still alive.
ed because of its retrospective nature. Among the 5 patients who were followed up at our hospital, 3
patients are still alive, but the other 2 died during follow-up. One
patient (case 3) died from heart failure despite several operations,
Results including mitral valve replacement (MVR). This patient was
referred to our hospital for myocarditis but she was diagnosed
1. Demographic findings with decompensated heart failure due to mitral valve chordae
Table 1 shows the demographic data of 8 patients (2 boys and rupture from MFS. The other patient (case 8) died from heart
6 girls) with infantile MFS. Five patients had medical records failure 3 days after birth despite intensive inotropic support. The
reporting height at birth, and the median was 50.0 cm (range, 48 median age of mortality was 12 months (range, 0131 months).
53 cm). Among these 5 patients, only one patient was taller than All patients had no family history of MFS; however, MFS was
the 90th percentile of height at birth. Their ages at the time of suspected in the mother of one patient, though we did not per
diagnosis ranged from 0 to 20 months (median age, 2.5 months) form genetic confirmation for this mother (Table 2). Among the
and the median follow-up duration was 25.5 months (range, 094 eight patients, ophthalmic examination was performed on five,
months). The most common presenting symptom was a heart and three of these had lens subluxation. We performed a fibrillin
murmur, in three patients, and one patient was diagnosed in 1 (FBN1) gene mutation test in 5 patients, and 4 of these were
utero. At the time of this study, four of the 8 patients were taller identified as having a FBN1 gene mutation. There was only 1
than the 95th percentile of height. patient whose systemic score of Ghent nosology was greater or

60 http://dx.doi.org/10.3345/kjp.2016.59.2.59
 Korean J Pediatr 2016;59(2):59-64

Table 3. Cardiovascular complications and treatment of each of the patients with infantile Marfan syndrome
MV annulus, TV annulus, Aortic annulus, Medications at
Case MVP MR TVP TR AR CHF Op. Age at Op.
mm (z score) mm (z score) mm (z score) last follow-up
1 + 39.5 (4.10) Severe + NA Mild 24.2 (5.96) Moderate Present 1. MVR 1.48 mo SRN, CTP, DGX,
2. Valve-sparing aortic 2.5 yr 8 mo CVD, FRS, WFR
root replacement 3.8 yr 10 mo
3. AVR
2 + NA Severe NA NA Moderate NA Mild Present - - ENL, DGX
3 + 30 (5.14) Severe NA Moderate NA Trace Present 1. MV repair, TV 1.3 mo DGX, FRS, SRN,
annuloplasty 2.5 mo LST, WFR, ENL
2. MVR 3.8 mo
3. Bilateral lensectomy 4.16 mo
4. Lung volume reduc
tion
4 + 25.7 (3.76) Severe + 22.5 (1.81) Moderate 13.6 (4.50) None Present MVR Less than 1 yr at LST, FRS, SRN,
other hospital PRN
5 + 37.4 (3.84) Moderate + NA Mild 19.9 (4.19) Trace Present MVR 69 mo WFR, ATN, LST
6 + 29.3 (4.42) Moderate + NA Mild 13.6 (4.13) None Present MVR 9 mo WFR, ATN, LST
7 + 14.8 (1.30) Mild + 12.8 (-0.22) Moderate 9 (2.46) Trace None - - ATN
8 + 13.9 (1.47) Mild + 17.3 (1.82) Severe 8.7 (3.10) Mild Present - - Inotropics
MV, mitral valve; MVP, mitral valve prolapse; MR, mitral regurgitation; TVP, tricuspid valve prolapse; TV, tricuspid valve; TR, tricuspid regurgitation; AR, aortic
regurgitation; CHF, congestive heart failure; Op., operation; NA, not available; MVR, mitral valve replacement; AVR, aortic valve replacement; SRN, spironolactone;
CTP, captopril; DGX, digoxin; CVD, carvedilol; FRS, furosemide; WFR, warfarin; ENL, enalapril; LST, losartan; PRN, propranolol; ATN, atenolol.

equal to 7 points. Dilatation of the aortic sinus diameter is defined 569 months). Among them, 2 patients needed multiple opera
as a z score greater than28). One patient did not have echocardio tions. One of these patients underwent MVR at a 4-year-old, a
graphic records of aortic sinus diameter, and the z score of the David operation at a 5.7-year-old, and aortic valve replacement
other seven patients was greater than 2, with a median z value of at an 8.9-year-old. The other patient underwent mitral valve
5.46 (range, 3.877.57). repair and tricuspid valve annuloplasty at the age of 3 months,
and MVR at the age of 5 months. All patients except for the one
2. Cardiovascular manifestations and treatment who died at 3 days of age took multiple medications, including
All patients had mitral valve prolapse (MVP) and the z score losartan and atenolol. The patients with congestive heart failure
of the mitral valve annulus in five of the seven patients who were also prescribed diuretics and digoxin.
had accurate measurements of mitral valve annulus size was
greater than 2 (Table 3). All patients had various degrees of mitral
regurgitation (MR) at initial echocardiography. The MR was mild Discussion
in 2 patients, moderate in 2 patients, and severe in 4 patients at
the time of diagnosis. In our series of 8 cases of infantile MFS, most patients showed
Other than 1 patient who had no medical record of tricuspid significant atrioventricular valve dysfunction and resulting con
valve findings from echocardiography, all of the patients had gestive heart failure symptoms. Five patients required early MVR
tricuspid valve prolapse. Only 3 patients had an echocardiographic for heart failure symptoms. The prognosis of infantile MFS is very
record of the tricuspid valve annulus diameter and the z score grave and half of infantile MFS patients showed mortality at the
was less than 2. All eight patients had various degrees of tricuspid median age of 12 months in our series.
regurgitation (TR). The TR was mild in 3 patients, moderate in 4 MFS is a systemic disorder of connective tissue. The prevalence
patients, and severe in 1 patient. of MFS has been estimated to be approximately 12 per 10,000
Six patients had medical records of aortic annulus diameter individuals without gender or ethnic differences; however, the
and all of them had an aortic annulus z score greater than 2. Six true incidence is difficult to determine because the manifestations
patients had aortic regurgitation (AR), and the AR was trivial in 3 of the disease become more obvious with age1,9,10).
patients, mild in 2 patients, and moderate in 1 patient. No patients A 5-year-old child who had congenital contractures, long
had severe AR. There were seven patients with congestive heart extremities, and spider-like digits was first described by French
failure before surgery or during follow-up. pediatrician Antoine Marfan in 189611). Later, involvements of
Five patients underwent open-heart surgery, and MVR was the ocular and cardiovascular system were noted and the first
performed in all cases at the median age of 28.5 months (range, diagnostic criteria for the disorder were established in 1988

http://dx.doi.org/10.3345/kjp.2016.59.2.59 61
Seo YJ, et al. Infantile Marfan syndrome

(Berlin nosology)12). Currently, the diagnosis relies on features of can be a useful tool to evaluate infantile MFS. Erkula et al.18) re
the skeletal, ocular, cardiovascular, cutaneous, central nervous, ported that the mean height at birth in MFS patients approached
and pulmonary systems in addition to family history and FBN1 the 90th percentile of the general population in both males and
mutations4,7). females, suggesting that excessive growth in MFS patients begins
Infantile or neonatal MFS is rarely diagnosed and is a type of prenatally. However, among the 5 patients for whom we found
MFS that is atypical and has a severe effect on the cardiovascular height at birth data in our series, only 1 patient showed greater
system13). In older or classic MFS, cardiovascular events leading than 90 percentile of height. Congenital emphysema is also
to death are mostly aortic dissection or ruptures; however, deaths common in neonatal MFS and the syndrome can be suspected
among neonatal MFS patients are associated with CHF due to when a neonate presents pulmonary emphysema with typical
MR or TR14). In addition, infantile MFS has higher mortality rate manifestations5,19,20). A characteristic phenotype of affected in
within the first year of life than classic MFS of which the mean fants includes an aged face, arachnodactyly, dolichocephaly,
age at death is 33.5 years of life15,16). It is considered to usually high-arched palate, micrognathia, joint hyperflexibility, joint
be caused by a new mutation, not because of a positive family
history15). In our 8 patients, all patients had no definitive family
history. One patient had suspected mother, but she had never
been diagnosed with MFS.
Even though infantile MFS is rare and difficult to diagnose,
there are clues as to whether a newborn has infantile MFS. If fetal
ultrasound reveals cardiomegaly and marked valvular lesions,
fetal echocardiography should be performed and cautiously
examined for both, atrioventricular prolapse and aortic root dila
tation17). In addition to the fetal echocardiography, length at birth

Fig. 2. Case 7. (A) Loose skin and arachnodactyly. (B, C) Arachnodactyly

of the hand and foot at 14 days of age.

Fig. 1. Case 3. (A) Dolichocephaly. (B, C) Arachnodactyly of the hands at Fig. 3. Aged face. (A) Case 5 at 130 months old and (B) case 7 at age 5
5 months of age. months of age.

62 http://dx.doi.org/10.3345/kjp.2016.59.2.59
 Korean J Pediatr 2016;59(2):59-64

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Devereux RB, et al. The revised Ghent nosology for the Marfan
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In spite of using multiple medications, valve surgery is generally R, et al. Report of the National Heart, Lung, and Blood Institute
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and maturation in Marfan syndrome. Am J Med Genet 2002;109:
No potential conflict of interest relevant to this article was 100-15.
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