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with hypoplastic left heart syndrome and related anomalies: The single ventricle reconstruction trial. Circulation 2010; 125: 2081– 91. 8 McBride ME, Huddleston CB, Balzer DT, Goel D, Gazit AZ. Hypoplastic left heart associated with Scimitar syndrome. Pediatr. Cardiol. 2009; 30: 1037–8. 9 Bartram U, van Praagh S, Keane JF et al. Mitral and aortic atresia associated with hypoplastic right lung, crossover segment of right

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Bone marrow transplant for a girl with bone marrow failure and cerebral palsy Yuichi Kodama, Yasuhiro Okamoto, Yuichi Shinkoda, Takayuki Tanabe, Takuro Nishikawa, Yuni Yamaki, Koichiro Kurauchi and Yoshifumi Kawano Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan Abstract

Bone marrow transplantation (BMT) has been used with increasing frequency to treat congenital bone marrow failure syndrome (CBMFs) successfully. Decision to perform BMT, however, is difficult in the case of comorbidity because of regimen-related toxicities. We describe here a child with CBMFs, severe cerebral palsy (CP) at Gross Motor Function Classification System level V and mental retardation (MR) who was transfusion dependent despite various medications. She underwent BMT from an HLA-1 locus-mismatched unrelated donor. Although engraftment was successful, no neurological improvement was seen 5 years after BMT. While CBMFs patients who have CP and MR could undergo transplantation safely, they may not benefit neurologically from BMT.

Key words bone marrow transplantation, cerebral palsy, congenital bone marrow failure, mental retardation.

Congenital bone marrow failure syndrome (CBMFs) has a varying etiology and diverse presentation. For instance, it includes Fanconi anemia, Diamond–Blackfan anemia, Kostmann syndrome and autosomal dominant thrombocytopenia. Some patients, however, cannot be diagnosed as having specific CBMFs.1 Bone marrow transplantation (BMT) is a curative treatment for patients with CBMFs. Patients with CBMFs share many similar issues regarding BMT, including the scarcity of a suitable HLA-matched non-affected sibling, congenital anomalies with associated organ dysfunction, a possible increased risk of regimen-related toxicity, a history of multiple red blood cell transfusions, alloimmunization, and risk of occult infection.2 Therefore, the decision to perform BMT is complex and involves various issues including risk/benefit, timing and the specific regimen. In the field of regenerative medicine, it has been confirmed that bone marrow (BM) includes mesenchymal stem cells that contribute to reconstitution of the central nervous system.3 Transplanted BM generates new neurons in human brains.4 Recently, Correspondence: Yasuhiro Okamoto, MD, Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. Email: [email protected] Received 8 February 2013; revised 1 October 2013; accepted 17 December 2013. doi: 10.1111/ped.12297

© 2014 Japan Pediatric Society

some reports have suggested that stem cell transplantation may be beneficial for cerebral palsy (CP) in an animal model.5 Because there is no effective treatment for CP, patients or their parents have been seeking stem cell transplantation for CP.3 Two clinical protocols using autologous cord blood stem cells for the treatment of CP are currently being trialled.3 We describe here a child with CBMFs comorbid with CP and mental retardation (MR) who underwent BMT from an HLA-1 locus-mismatched unrelated donor after conditioning with fludarabine (Flu), cyclophosphamide (CY), and anti-thymocyte globulin (ATG). Although she achieved normal hematopoiesis, CP and MR did not improve even 5 years after BMT.

Case report A girl was born by urgent cesarean at 36 weeks of gestation due to fetal hydrops as the first child of healthy, unrelated parents. There was no history of hereditary disease or early death in her family. She was light for gestational age. The Apgar score was 4 at both 1 and 5 minutes. Generalized edema, purpura, and petechiae were evident at birth. She did not have any malformation. She was transferred to the neonatal intensive care unit to receive mechanical ventilation due to respiratory failure. Complete blood count (CBC) was as follows: white blood cell (WBC), 6500/μL; hemoglobin (Hb), 2.7 g/dL; and platelet count, 3000/μL. Coagulation tests including prothrombin time, activated partial thromboplastin time and fibrinogen, were normal.

BMT for a girl with BMF and CP BM analysis showed hypocellularity with no ringed sideroblasts. Once her general condition was stabilized, she was transferred to the university hospital for detailed examination and treatment of pancytopenia. CBC was as follows: WBC, 1550/μL; Hb, 7.5 g/ dL; mean corpuscular volume, 95.5 fL; platelet count, 40 000/ μL; and absolute reticulocyte count (ARC), 56 970/μL. The following tests were performed for the evaluation of CBMFs. On cytogenetics the karyotype was normal (46, XX). There was no increase in chromosomal breakage with mitomycin C. Pancreatic enzyme was normal. Cerebellar hypoplasia was not evident. There were no deficiencies in vitamin B12 or folic acid. Flow cytometry was normal for CD55 and CD59 expression on red blood cell surface. Lactic acid and pyruvic acid levels were normal. Amino acid analysis and organic acid analysis were normal. Mitochondrial DNA responsible for Pearson syndrome was confirmed not to be deleted on long-polymerase chain reaction. Therefore, her disorder did not satisfy the specific diagnostic criteria of BM failure. She did not respond to treatment with prednisolone and i.v. immune globulin. Consequently, she required multiple red blood cell and platelet transfusions. After combination therapy including cyclosporine A, androgen, and granulocyte colony stimulating factor, she became transfusion independent (WBC, 3000–4000/μL; Hb, 7–9 g/dL; platelet count, 10 000–20 000/μL) and was discharged from hospital at the age of 1 year, but neurological problems were evident. At the age of 1 year she was not able to control her head or roll over. She had mild ataxia and severe spastic muscular hypertonia. There was also severe psychological development retardation. Her developmental quotient (DQ) was 17. At the age of 3, her platelet count, absolute neutrophil count (ANC) and ARC were

Bone marrow transplant for a girl with bone marrow failure and cerebral palsy.

Bone marrow transplantation (BMT) has been used with increasing frequency to treat congenital bone marrow failure syndrome (CBMFs) successfully. Decis...
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