Patent Ductus Arteriosus and Pulmonary Hypertension

Patent Ductus Arteriosus and Pulmonary Hypertension

The New Journal of Medicine 2009;26: 50-52
The New Journal of Medicine 2009;26: 46-48
Case report
Patent Ductus Arteriosus and Pulmonary
Hypertension During the Course of Bone Marrow
Transplantation For Hurler Syndrome
U÷ur CANPOLAT 1, Alpay ÇELøKER 2, Yasemin IùIK BALCI 3, Mualla ÇETøN 3,
Serap KALKANOöLU SøVRø 4, Duygu UÇKAN 5
1
5
Hacettepe University Faculty of Medicine Department of Adult Cardiology, ANKARA
2
Hacettepe University Faculty of Medicine Pediatric Cardiology, ANKARA
3
Hacettepe University Faculty of Medicine Department of Pediatric Hematology, ANKARA
4
Hacettepe University Faculty of Medicine Pediatric Metabolism, ANKARA
Hacettepe University Faculty of Medicine Pediatric Bone Marrow Transplantation Unit, ANKARA
ÖZET
Hurler sendromu için kemik ili÷i transplantasyonu
sürecinde patent duktus arteriozus ve pulmoner
hipertansiyon
Hurler sendromu (MPS I-H), Į-L-idüronidaz enzimi eksikli÷i sonucu geliúen, nadir görülen otozomal resesif bir
hastalktr. Hurler sendromu olan çocuklar do÷umda normal
gibi görünseler de, tedavisiz brakldklarnda, vücuttaki
tüm organlarda glikozaminoglikanlarn (GAG) birikmesi
sonucu ilerleyici mental ve fiziksel kötüleúme göstermektedir. Bu hastalarda ölüm genellikle kardiyak ya da
solunum yetmezli÷i nedeniyle olmaktadr ve sklkla ikinci
dekattan önce olmaktadr. Son yllarda, Hurler sendromu
olan hastalarn tedavisinde kemik ili÷i transplantasyonu
(KøT) ve enzim replasman tedavisi gündeme gelmiútir.
Burada biz 2 yaúnda Hurler sendromu ve dilate kardiyomiyopatisi olan, 20 aylkken HLA 6/6 benzer olan halasndan kemik ili÷i transplantasyonu yaplan ve KøT sürecinde patent duktus arteriyozus ve pulmoner hipertansiyonunda kötüleúme saptanan bir kz hastay rapor
ettik.
ABSTRACT
Hurler syndrome (MPS I-H), which is caused by a
deficiency in L-iduronidase enzyme, is a rarely seen
autosomal recessive disease. Children with Hurler syndrome
appear nearly normal at birth but, left untreated, show a
progressive mental and physical deterioration caused by
a build up of glycosaminoglycans (GAGs) in all organs of
the body. Death is often caused by cardiac or respiratory
failure and usually occurs before the second decade of
life. In recent years, bone marrow transplantation (BMT)
and enzyme replacement therapy have been employed
in the management of patients with Hurler syndrome.
Here we report a 2 year old girl with Hurler syndrome
and severe dilated cardiomyopathy, who underwent BMT
at 20 months of age from her HLA 6/6 identical paternal
aunt. Patent ductus arteriosus (PDA) and worsening of
pulmonary hypertension was detected during the
course of BMT for Hurler syndrome.
Key Words : Bone marrow transplantation, mucopolysaccharidosis, patent ductus arteriosus, pulmonary
hypertension
Anahtar Kelimeler : Kemik ili÷i transplantasyonu,
mukopolisakkaridozis, patent duktus arteriyozus, pulmoner
hipertansiyon
INTRODUCTION
Hurler syndrome is an autosomal recessive inborn
error of metabolism due to a deficiency of-Liduronidase enzyme activity, which results in
accumulation of heparan sulphate and dermatan
sulphate substances. Progressive hepatosplenomegaly, cardiovascular disease, severe skeletal
abnormalities, hydrocephalus and mental retardation results in morbidity and early death, often by
5 years of age1.
Analysis of urinary glycosaminoglycans (GAGs) is
an initial diagnostic test2. An individual who is
suspected of an Hurler syndrome based on clinical
features, radiographic results or urinary GAG
screening test should have a definitive diagnosis
46
established by enzyme assay3. Bone marrow
transplantation (BMT) and enzyme replacement
therapy are both effective for management of
Hurler syndrome early in life before development
of irreversible changes1. Enzyme replacement
therapy is both expensive and not readily available
in developing countries. Therefore the treatment
of choice for a child diagnosed with Hurler
syndrome before the age of 2 years, with no
central nervous system damage, is hematopoietic
stem cell transplantation4. Following transplantation, donor leukocytes and macrophages with
normal-L-iduronidase activity assist in the removal
of GAGs from host tissue5. Recently mesenchymal
Canpolat50-52
et al.
The New Journal of MedicineU.2009;26:
stem cell infusions to BMT patients and gene
therapy which is currently at experimental phase
are promising approaches in patients with Hurler
syndrome6,7. BMT has resulted in significant clinical
improvement of somatic disease in Hurler
syndrome and increased long term survival.
Resolution or improvements have been noted in
hepatosplenomegaly, joint stiffness, coarse facial
appearance, obstructive sleep apnea, heart disease,
communicating hydrocephalus, and hearing loss.
However, the skeletal and ocular anomalies are
not corrected4. Patients particularly less than 24
months age can achieve a favorable long term
outcome with continuing cognitive development
after successful BMT5. Although many cardiovascular manifestations of Hurler syndrome are
present, patent ductus arteriosus (PDA) has not
been reported. Pulmonary hypertension attributed
to obstructive sleep apnea has been described,
however it has not been described with patent
ductus arteriosus in patients with Hurler syndrome8.
Here we present a 2 years old girl with Hurler
syndrome, who underwent BMT from her HLA 6/6
matched healthy paternal aunt at 20 months of
age and who developed worsening of pulmonary
hypertension due to PDA which was undetected
during the pretransplant work-up or through the
course of BMT.
CASE
The 2 year old girl was diagnosed with Hurler
syndrome at 14 months of age. Positive symptoms
and findings include irritability, tachypnea, coarse
facial appearance, pectus excavatus, hepatomegaly, 2/6 systolic ejection murmur. The family history
was consistent with first degree consanguinity.
Also increased excretion of urinary GAG, skeletal xray findings and deficient leukocyte -L-iduronidase
activity (performed in Royal Manchester Children’s
Hospital) were consistent with Hurler syndrome.
Therefore, patient was diagnosed with Hurler
syndrome and referred for BMT to the Hacettepe
University Pediatric Bone Marrow Transplantation
Unit.
Due to development of dilated cardiomyopathy
and heart failure during the disease course, the
patient was digitalized, and captopril, furosemide,
carnitin and carvedilol were used for stabilization
of symptoms before BMT. In addition, the patient
was placed on enzyme therapy for 3 months during
the pretransplant work-up. Enzyme treatment is
approved only for 3 months for BMT candidates in
Turkey. Daily brain natriuretic peptide (BNP) and
digoxin levels and periodical echocardiographic
examinations
were
performed
during
the
conditioning therapy and in the posttransplant
period. Classical myeloablative therapy was
preferred. BMT was performed from her HLA 6/6
matched ABO-compatible healthy paternal aunt
(24 years of age) following a conditioning regimen
which consisted of i.v. busulfex (4 mg/kg x4 d)
and cyclophosphomide (50 mg/kgx4 d). GVHD
prophylaxis included cyclosporine-A and methotrexate.
Unmanipulated bone marrow cells, including
8,5x108 nucleated cells/kg and 2x106 CD34/kg, were
given. Neutrophil and platelet engraftment >20x109/L
occured on days +16 and +22, respectively. The
posttransplant period was complicated with fever,
catheter infection and pancytopenia. Due to
preexisting cardiomyopathy, iv fluids were
administered cautiously with liberal use of diuretic
treatment. Interestingly, there was a sudden drop
in BNP levels after administration of bone marrow
cells. The BNP level (Figure-1) was normalized at
day +32 of BMT. The ejection fraction also
increased from 47% at pretransplant work-up to
65% at day+32 of BMT. These findings were
interpreted as improvement of cardiomyopathy by
BMT. The patient was discharged at day +34 of
BMT. The patient was followed periodically in the
outpatient clinic of the BMT Unit. At day +50 of
BMT, the BNP level of the patient markedly
increased to 418 pg/ml(N:0-100 pg/ml) with no
symptoms. On day +60 of BMT, the BNP level
increased to 644 pg/ml and irritability, tachypnea
and
dyspnea
on
exertion
were
present.
Echocardiography revealed worsening of pulmonary
hypertension and a mass compressing the right
atrium. Pulmonary thromboemboli, aneurysm and
congenital heart defects were considered in the
differential diagnosis. Thoracic computerized
tomography and ventilation-perfusion scintigraphy
were obtained and they were unremarkable.
Cardiac catheterization was performed and a PDA
of 6,5x3 mm in size was detected and was closed
with a 6,5x3 mm Flipper Detachable Coil.
Pulmonary pressure immediately dropped from 80
mmHg to 45 mmHg following the procedure. BNP
level decreased to normal limits. Although
pulmonary hypertension was still documented by
echocardiographic examination, the patient was
free of symptoms. Currently the patient is at day
+180, with >95% chimerism, with significant
improvement in facial features, cardiomyopathy,
mental and motor development. Since the skeletal
findings of the patient were only detectable by xray before BMT, good prognosis was anticipated.
47
U. Canpolat et al.
The New Journal of Medicine 2009;26: 50-52
Figure 1. THe BNP levels of the patient during the
course of BMT
DISSCUSSION
Although the features of Hurler syndrome
increasingly become apparent after 6 months of
age, early diagnosis of the disease is very
important in the effectiveness of treatment modality.
Bone marrow transplantation and enzyme replacement therapy are effective treatment modalities in
the management of disease especially early in life.
Both therapies can reverse or prevent many
somatic symptoms of Hurler syndrome1. The
patient’s life expectancy increases, hepatosplenomegaly resolves, cardiac disease is stabilized and
improvement in the range of motion of the joints,
airway disease, facial features, and hearing.
Skeletal
abnormalities,
such
as
dysostosis
multiplex, are stabilized but not reversed4. However,
the effectiveness of treatment is limited in
severely affected patients1.
The present patient underwent a successful BMT
at 20 months of age. Although a reduced intensity
conditioning therapy was considered due to
preexisting dilated cardiomyopathy, a classical
myeloablative regimen was administered because
the risk of graft failure in patients with Hurler
syndrome. Pretransplant administration of a three
month course of L-iduronidase enzyme therapy
failed to induce improvement in the clinical or
echocardiographic findings. Stabilization of cardiac
symptoms with digoxin, diuretics, blockers and
supportive medication (carnitine) were important
during the course of BMT. Close follow-up during
the BMT course is critically important to prevent
worsening associated with high dose chemotherapy
and i.v. fluids. In our patient, a sudden increase in
BNP levels followed by clinical symptoms of heart
failure was attributed to PDA and worsening of
pulmonary hypertension. In patients with Hurler
syndrome cor pulmonale due to upper airway
obstruction and many cardiac manifestations have
been described. To our knowledge, pulmonary
hypertension due to PDA has not been described8.
Long term follow up of the present case may
determine the effects of BMT on pulmonary
hypertension secondary to cardiac causes.
Abbreviations: MPS I-H, mucopolysaccharidosis type 1
–Hurler syndrome; GAGs, glycosaminoglycans; BMT, bone
marrow transplantation; HLA, human leukocyte antigen;
PDA, patent ductus arteriosus; BNP, brain natriuretic
peptide; GVHD, graft-vs.-host disease
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Correspondence:
Ugur CANPOLAT M.D.
Hacettepe University Adult Cardiology, Ankara
e-mail: [email protected]
Arrival date
: 26.01.2009
Acceptance date
: 10.02.2009