Losartan in Combination with Propranolol Slows the Aortic Root Dilatation in Neonatal Marfan Syndrome

Abstract

Neonatal Marfan syndrome, in contrast to classical Marfan syndrome, is characterized by rapidly progressive multi-valvular cardiac disease and death from congestive heart failure, typically within the first year of life. Due to the rarity of this condition, treatment for neonatal Marfan syndrome has not been well studied. In this report, a combination of losartan and propranolol reduced the aortic root dilatation rate after three months of losartan therapy. Genetic analysis in this patient revealed a mutation in exon 25 of the FBN1 gene, which typically results in a shorter life expectancy. However, the patient's heart failure was controlled by losartan, propranolol and other anti-congestive medications, which may have prolonged his survival.

Full text

Short Communication
Losartan in combination with propranolol
slows the aortic root dilatation in neonatal
Marfan syndrome
Lu-Hang Liu
a,b
, Shan-Miao Lin
b
, Dar-Shong Lin
c,d,e
,
Ming-Ren Chen
b,d,e,
*
a
Pediatric Cardiology Department, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan
b
Pediatric Cardiology Department, Mackay Children’s Hospital, Taipei, Taiwan
c
Pediatric Genetics Department, MacKay Children’s Hospital, Taipei, Taiwan
d
Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan
e
Mackay Medical College, Taipei, Taiwan
Received Sep 7, 2016; received in revised form Apr 10, 2017; accepted Jul 18, 2017
Available online 31 July 2017
Key Words
FBN1;
losartan;
neonatal Marfan
syndrome
Abstract Neonatal Marfan syndrome, in contrast to classical Marfan syndrome, is character-
ized by rapidly progressive multi-valvular cardiac disease and death from congestive heart fail-
ure, typically within the first year of life. Due to the rarity of this condition, treatment for
neonatal Marfan syndrome has not been well studied. In this report, a combination of losartan
and propranolol reduced the aortic root dilatation rate after three months of losartan therapy.
Genetic analysis in this patient revealed a mutation in exon 25 of the FBN1 gene, which typically
results in a shorter life expectancy. However, the patient’s heart failure was controlled by losar-
tan, propranolol and other anti-congestive medications, which may have prolonged his survival.
Copyright ª2017, Taiwan PediatricAssociation. Published by Elsevier Taiwan LLC. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).
1. Case report
A full-term male neonate with 3012 g weight (25th
percentile) and body length of 54.3 cm (>97th percentile)
had a weak cry and shallow respiration after birth. He
appeared dysmorphic with frontal bossing, sunken eyes,
crumpled ears, long slender fingers and toes with arach-
nodactyly, hyperextensible joints, and excess skin with
reduced skeletal muscle and subcutaneous tissue, giving
him a senile appearance (Fig. 1A). Cardiac examination
revealed a hyperactive precordium. There was no obvious
murmur at birth, but a diastolic murmur at the left para-
sternal border and a high-pitched systolic murmur at the
apex were heard at five months of age.
Image studies showed slender and bowed long bones,
lumbar scoliosis (Fig. 1B), and right diaphragmatic
* Corresponding author. Pediatric Cardiology Department,
Mackay Children’s Hospital, Taipei, Taiwan.
E-mail address: mingren44@gmail.com (M.-R. Chen).
http://dx.doi.org/10.1016/j.pedneo.2017.07.005
1875-9572/Copyright ª2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: http://www.pediatr-neonatol.com
Pediatrics and Neonatology (2018) 59, 211e213

eventration (Fig. 1CeD). Transthoracic echocardiography
demonstrated prolapsing atrioventricular valves with
redundant tissue and mild regurgitation bilaterally
(Fig. 1EeF). The aortic root and pulmonary root (Fig. 1GeH)
were markedly dilated. Mutation analysis of the FBN1 gene
revealed a de novo point mutation ec.3143T >C in exon 25
with an amino acid substitution of an isoleucine by a threo-
nine at position 1048 (p.I1048T) ewhich supported the
diagnosis of neonatal Marfan syndrome (nMFS). The family
history was negative for Marfan syndrome.
Figure 1 (A) The male neonate was dysmorphic with a senile appearance, crumpled ears, long, slender fingers and toes, and
arachnodactyly. (B) Bone radiographs demonstrated slender and bowed long bones as well as lumbar scoliosis. (C) The chest
radiograph showed the right hemidiaphragm bulging up against the right lung. (D) An abdominal ultrasound revealed right dia-
phragmatic eventration. Transthoracic echocardiography demonstrated (E) mitral valve prolapse, (F) tricuspid valve prolapse, (G) a
dilated aortic root measuring 13.7 mm at the sinuses of Valsalva with Z-score Z3.52, and (H) severe dilation of the pulmonary root
at 24 mm with Z-score Z6.83. (I) Progression in aortic root size at the sinuses of Valsalva recorded in cm and Z-score.
212 L.-H. Liu et al

The patient was commenced on propranolol (1.6 mg/kg/
day) on his fourth day of life. He developed progressive
dyspnea and frequent cyanosis in the following months, and
was subsequently diagnosed with severe tracheo-
bronchomalacia. Repeat echocardiography showed an
enlarging aortic root as well as progressive mitral,
tricuspid, aortic, and pulmonary valve regurgitation. He
was started on losartan at seven months of age on 1.4 mg/
kg/day once daily under closely monitoring of blood pres-
sure. We increased the dosage to 2 mg/kg/day three
months later, and he tolerated well without hypotension,
hyperkalemia or renal dysfunction. Digoxin and furosemide
were added at 10 months of age. The rate of aortic root
dilatation was greatest between three to seven months,
and slowed after he reached 10 months of age (Fig. 1I). At
the age of 11 months, tracheobronchomalacia, recurrent
lower respiratory tract infections, and prolonged ventilator
dependence necessitated a tracheostomy. He was put on
continuous positive airway pressure support at 12 months,
but this was escalated to bi-level positive airway pressure
support at 16 months. He needed a nasogastric tube
because of his feeding problems. He was unable to walk due
to his weak muscle power; but could move about in a baby
walker. At the age of 24 months, he died of bilateral re-
fractory pneumothoraces.
2. Discussion
The nMFS, in contrast to classical Marfan syndrome (MFS), is
characterized by rapidly progressive multi-valvular cardiac
disease and death from congestive heart failure, typically
within the first year of life. The pneumothorax resulting in
our patient’s death may represent an unusual phenotype.
The presence of valvular insufficiencies and diaphragmatic
abnormalities are predictive of a shorter life expectancy,
and are mostly found in patients with a de novo mutation in
exons 25 and 26 of the FBN1 gene.
1
The FBN1 gene is found
on chromosome 15 and contains 65 exons. Mutations in the
so-called “neonatal region” of FBN1 exons 24e32 are asso-
ciated with a high risk of rapid progressive cardiac disease.
2
Of the six previously reported cases known to have an
identical mutation with our patient at c.3143T >CinFBN1
exon 25, four died of cardiac insufficiency before 4 months
of age, one died suddenly at five years of an unknown cause,
and one was one month old at the last follow-up.
1
Recent studies have shown a decrease in aortic root size
Z-score after losartan and/or b-blocker therapy in children
and adolescents with MFS.
3
However, their efficacy in nMFS
was limited to some case reports. Among the four nMFS
patients previously reported to be on combined b-blocker
and losartan treatment,
4e6
three received a mitral valvu-
loplasty, two had a decreased aortic root size Z-score,
5,6
and all four patients survived beyond the age of two
years. Our patient lived longer than most others with the
same mutation on the poor prognosis region. Without suf-
ficient nMFS patients to conduct a randomized controlled
trial, we cannot know whether the remarkable aortic root
Z-score change resulted from losartan alone or from a
combination of losartan and propranolol. Our experience
was in line with the recommendation emade on the basis
of current evidence ethat a combination of a b-blocker
and an ARB should be considered in MFS patients with se-
vere aortic dilatation.
3
The commonly accepted surgical indications for trache-
obronchomalacia in infant are acute life threatening events
and recurrent pneumonias.
7
Considering the progressive
tendency of aortic and pulmonary dilatation in this patient,
tracheostomy was performed while waiting for appropriate
time for simultaneous cardiovascular and airway surgery. For
pneumothorax in Marfan patients, the surgical timing would
be 48 h after the first episode if there was no rapid resolu-
tion under treatment.
8
In this patient, bilateral pneumo-
thoraces complicated with severe tracheobronchomalacia
and heart disease making anesthesia and surgery unprom-
ising under the condition of cyanosis and refractory shock
status. After discussing with the surgeon and his parents of
the grave prognosis, we decided palliative care.
As a conclusion, we recommend that early use of both a
b-blocker and losartan should be considered for nMFS pa-
tients to prevent rapidly progressive aortic root dilatation.
Conflict of interest
None.
Acknowledgement
We thank Dr. Chen-Hao Lee for his help in interpreting the
genetic analysis of this patient.
References
1. Stheneur C, Faivre L, Collod-Be
´roud G, Gautier E, Binquet C,
Bonithon-Kopp C, et al. Prognosis factors in probands with an
FBN1 mutation diagnosed before the age of 1 year. Pediatr Res
2011;69:265e70.
2. Faivre L, Collod-Beroud G, Loeys BL, Child A, Binquet C,
Gautier E, et al. Effect of mutation type and location on clinical
outcome in 1,013 probands with Marfan syndrome or related
phenotypes and FBN1 mutations: an international study. Am J
Hum Genet 2007;81:454e66.
3. Singh MN, Lacro RV. Recent clinical drug trials evidence in
Marfan syndrome and clinical implications. Can J Cardiol 2016;
32:66e77.
4. Amado M, Calado MA, Ferreira R, Lourenc¸o T. Neonatal Marfan
syndrome: a successful early multidisciplinary approach. BMJ
Case Rep 2014. pii: bcr2013202438. http://dx.doi.org/10.1136/
bcr-2013-202438.
5. Maeda J, Kosaki K, Shiono J, Kouno K, Aeba R, Yamagishi H.
Variable severity of cardiovascular phenotypes in patients with
an early-onset form of Marfan syndrome harboring FBN1 muta-
tions in exons 24e32. Heart Vessels 2016;31:1717e23.
6. Hirano Y, Murakami Y, Sasaki T, Fujino M, Kawasaki Y, Ehara E,
et al. A case of neonatal marfan syndrome with medical man-
agement (propranolol, losartan etc.) since 1 month of age and
mitral valve replacement at 5 years of age. Pediatr Cardiol Card
Surg 2014;30:671e5. [Article in Japanese].
7. de TreyLA, Dudley J, Ismail-Koch H, Durward A, Bellsham-Revell H,
Blaney S, et al. Treatment of severe tracheobronchomalacia: ten-
year experience. Int J Pediatr Otorhinolaryngol 2016;83:57e62.
8. MacDuff A, Arnold A, Harvey J, BTS Pleural Disease Guideline
Group. Management of spontaneous pneumothorax: British
thoracic society pleural disease guideline 2010. Thorax 2010;65:
ii18e31.
Losartan and propranolol in neonatal Marfan syndrome 213