Patent Ductus Arteriosus and Pulmonary Hypertension
Transkript
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 hastalktr. Hurler sendromu olan çocuklar do÷umda normal gibi görünseler de, tedavisiz brakldklarnda, vücuttaki tüm organlarda glikozaminoglikanlarn (GAG) birikmesi sonucu ilerleyici mental ve fiziksel kötüleúme göstermektedir. Bu hastalarda ölüm genellikle kardiyak ya da solunum yetmezli÷i nedeniyle olmaktadr ve sklkla ikinci dekattan önce olmaktadr. Son yllarda, Hurler sendromu olan hastalarn tedavisinde kemik ili÷i transplantasyonu (KøT) ve enzim replasman tedavisi gündeme gelmiútir. Burada biz 2 yaúnda Hurler sendromu ve dilate kardiyomiyopatisi olan, 20 aylkken HLA 6/6 benzer olan halasndan kemik ili÷i transplantasyonu yaplan ve KøT sürecinde patent duktus arteriyozus ve pulmoner hipertansiyonunda kötüleúme saptanan bir kz 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 REFERENCES 1. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. The Metabolic and Molecular Bases of inherited Disease 2001; 8th edition: 3421-52. 2. Stone JE. Urine analysis in the diagnosis of mucopolysaccharide disorders. Ann Clin Biochem 1998;35: 207-25. 3. Kliegman R, Muenzer J. Mucopolysaccharidoses. Richard E. Behrman, Robert M. Kliegman, Hal B. Jenson, Nelson Textbook of Pediatrics, 17th Edition, Philedelphia: Saunders 2004: 482-86 4. Muenzer J, Fisher A. Advances in the treatment of mucopolysaccharidoses type 1. N Engl J Med 2004;350: 1932-4. 5. Krivit W, Peterss C, Shapiro E. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidoses, fucosidoses, aspartylglucosaminuria, Hurler, MaroteauxLamy, and Sly syndromes, and Gaucher disease type III. Curr Opin Neurol 1999;12: 167-76. 6. Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 2002;30: 215-22. 48 7. Ma X, Liu Y, Tittiger M, Hennig A, Kovacs A, Popelka S, et al. Improvements in Mucopolysaccharidoses I Mice After Adult Retroviral Vector-mediated Gene Therapy with immunomodulation. Mol Ther 2007;15: 889-902. 8. Chan D, Lia M, Yam MC, Lic K, Fok TF. Hurler syndrome with cor pulmonale secondary to obstructive sleep apnea treated by continuous positive airway pressure Journal of Paediatrics and Child Health 2003;39: 558-9. Correspondence: Ugur CANPOLAT M.D. Hacettepe University Adult Cardiology, Ankara e-mail: dru_canpolat@yahoo.com Arrival date : 26.01.2009 Acceptance date : 10.02.2009