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(Hunter Syndrome) Complicated by Autoimmune Hemolytic Anemia

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(Hunter Syndrome) Complicated by Autoimmune Hemolytic Anemia Bone Marrow Transplantation (2000) 25, 1093–1099 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Case report Unrelated umbilical cord blood transplantation in infancy for mucopolysaccharidosis type IIB (Hunter syndrome) complicated by autoimmune hemolytic anemia CA Mullen1,2, JN Thompson3, LA Richard and KW Chan1 Departments of 1Pediatrics and 2Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas; 3Laboratory of Medical Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA Summary: a median of 21 years in type IIB.8 Allogeneic BMT has been used to treat Hunter disease, but remains controversial This report describes unrelated umbilical cord blood since it often fails to reverse CNS impairment9–11 and car- transplantation for a 10-month-old infant boy with ries with it substantial early mortality and morbidity. Here, mucopolysaccharidosis IIB (Hunter syndrome), an X- we report treatment of an infant with mucopolysacch- linked metabolic storage disorder due to deficiency of arisosis type IIB with transplantation of unrelated umbilical iduronate sulfatase. Two years after transplant ෂ55% cord blood cells and its complication by autoimmune hemo- normal plasma enzyme activity has been restored and lytic anemia. abnormal urinary excretion of glycosaminoglycans has nearly completely resolved. The boy has exhibited nor- mal growth and development after transplant. Nine Case report months after transplant he developed severe auto- immune hemolytic anemia and required 14 months of The patient is the only child of a couple with a maternal corticosteroid treatment to prevent clinically significant family history of Hunter syndrome. The mother’s brother anemia. Bone marrow transplantation for Hunter syn- was diagnosed with Hunter syndrome in 1979 at age 3 years drome and post-transplant hemolytic anemia are when he exhibited the physical stigmata of the disorder. reviewed. Bone Marrow Transplantation (2000) 25, The diagnosis was corroborated by detection of large 1093–1097. amounts of glycosaminoglycans in the urine. This uncle Keywords: mucopolysaccharidosis; Hunter syndrome; exhibited growth retardation; at age 20 years his weight autoimmune hemolytic anemia; bone marrow transplan- was 40 kg and height 4 feet. He experienced multiple upper tation respiratory tract infections related to airway obstruction, hepatosplenomegaly, severe contractures with limitation of range of joints in all limbs, and deafness. He died at age 20 years due to cardiac dysfunction, the most common Hunter disease, mucopolysaccharidosis II, is an uncommon cause of death in type IIB mucopolysaccharidosis. He was X-linked disorder caused by mutations in the gene for idu- above average in intelligence, attended a regular school 1–4 ronate-2-sulfatase. Affected individuals are deficient in until the 7th grade when physical disability caused his iduronate-2-sulfatase activity and accumulate a variety of withdrawal, and had no neurological problems other than glycosaminoglycans in a wide variety of tissues. Patients deafness. develop macrocephaly, thick skin, coarse facies, hepatos- Because of the family history the patient was screened plenomegaly, cardiac valve abnormalities, joint contrac- for Hunter disease at age 1 month. He had profound tures, airway compromise, deafness, and cranial nerve and deficiency of iduronate-2-sulfatase activity and substan- central nervous system degeneration. A variety of tially elevated urinary glycosaminoglycans (Table 1). 5,6 mutations have been identified. The disease is hetero- Mutational analysis demonstrated an A to G substitution in geneous and is categorized as IIA (with substantial central intron 6 at the 8th base upstream of exon 7 (1004–8AG). nervous system impairment) and IIB (in which CNS The mother, grandmother and two maternal aunts were car- impairment is not a prominent feature). No effective medi- riers of the same mutation. At 4 months he was evaluated cal treatment exists. Premature death occurs in both vari- for allogeneic HSC transplant. His growth and development 7 ants, with death at a median of 11 years in type IIA and were normal, but he had mild hepatomegaly. Repeat labora- tory evaluation confirmed absence of enzyme activity and abnormal excretion of urinary glycosaminoglycans (Table Correspondence: Dr C Mullen, Univ. of Texas MD Anderson Cancer Center, Dept of Pediatrics, Box 88, 1515 Holcombe Blvd, Houston, TX 1). Echocardiography was normal. Neuropsychological 77030, USA evaluation using Bayley scales at age 9 months showed a Received 17 September 1999; accepted 18 January 2000 mental age of 9 months and a motor age of 10 months. UCBT for Hunter syndrome CA Mullen et al 1094 Table 1 Iduronate 2-sulfatase activity and excretion of urinary glycosaminoglycans Patient age Iduronate 2-sulfatase Urinary glycosaminoglycans (months) (% normal control) Uronic acid Hexosamine Electrophoresis mg/g creatinine mg/g creatinine components 1 0.1% ND ND dermatan sulfate heparan sulfate 4 0.5% 341 82 dermatan sulfate heparan sulfate chondroitin sulfate 10 BMT 12 8% 142 39 dermatan sulfate heparan sulfate chondroitin sulfate 18 22% 42* 5* dermatan sulfate heparan sulfate chondroitin sulfate 28 9% 38* 4* no pattern* 36 55%* 21* 2* dermatan sulfate heparan sulfate chondroitin sulfate * Indicates normal values, ‘ND’ indicates not done. Uronic acid was measured by the carbazole reaction and the hexosamine N-sulfate was measured by the MBTH reaction. Separation of glycosaminoglycan components was by cellulose acetate electrophoresis. The iduronate 2-sulfatase activity was measured by the method previously described.26 At 10 months his physical growth was normal, but GVHD. He was treated for 2 months with corticosteroids hepatomegaly persisted. and improved. He continued to receive tacrolimus. At age 10 months he underwent allogeneic HSC trans- His hepatomegaly resolved and he continued to grow and plant after autologous bone marrow storage. He received a develop normally. RFLP analysis 8 months after BMT preparative regimen consisting of busulfan (40 mg/m2 p.o. demonstrated his marrow was 100% donor in origin. Bio- every 6 h days −9to−6), cyclophosphamide (50 mg/kg i.v. chemical tests 2 years after transplant demonstrated serum days −5to−2), anti-thymocyte globulin (15 mg/kg every iduronate-2-sulfatase levels 55% of the concurrent normal day days −3, −2, −1), and methylprednisolone 20 mg/kg control. (The patient’s activity was within the range of days −2 and −1. For GVHD prophylaxis he received tacro- normal.) He exhibited normal urinary excretion of the gly- limus (0.03 mg/kg/day i.v. starting day −1) and methotrex- cosaminoglycans uronic acid and hexosamine N-sulfate, ate (5 mg/m2 i.v. days 1, 3, 6 and 11). He received an unre- but qualitative electrophoresis of urine still demonstrated lated umbilical cord blood unit containing 3.9 × 107 total small amounts of dermatan sulfate, heparan sulfate and nucleated cells/kg recipient weight and 0.55 × 106 CD34+ chondroitin sulfate (Table 1). cells/kg recipient weight. The patient was blood group A− The post-BMT course was complicated at 9 months by and the donor unit was A+. The patient and donor were severe hemolytic anemia (hemoglobin 6.3 g/dl, 36% reti- partially HLA-matched. The patient was A 2,24, B 50,62, culocytes, LDH 1607 IU/l, indirect bilirubin 0.9 mg/dl, DRB1 1301,1303, DQB1 0603,0301. The donor unit was direct bilirubin 0.1 mg/dl). Initially the patient had a normal A 2,24, B 7,62, DRB1 1301,1302, DQB1 0603,0604. The platelet count but within 2 weeks developed thrombocyto- patient engrafted and achieved an absolute neutrophil count penia (33 000/␮l). Leukopenia was never observed. Both of 500 cells/␮l on day 23. He was discharged from the direct and indirect antiglobulin (Coombs’) tests were posi- hospital on day 28. He became independent of PRBC trans- tive for IgG but negative for complement. This warm auto- fusion after day 23 and of platelet transfusion after day 46. antibody was determined to have an anti-e specificity. Tests The transplant was marked by two episodes of gram-posi- for anti-platelet and anti-nuclear antibodies were negative. tive bacteremia, one episode of limited gastrointestinal He was treated with prednisone 2 mg/kg/day. Thrombocy- bleeding while thrombocytopenic, and mucositis requiring topenia resolved within 4 weeks, and hemoglobin levels total parenteral nutrition for several weeks. also rose (12 g/dl). Two months later he was weaned from Two weeks after transplant he developed grade 3 skin prednisone, but one 1 month thereafter, following an upper GVHD involving Ͼ80% of his body (nonblistering rash) respiratory tract infection, his hemolytic anemia worsened and also developed grade 2 gastrointestinal GVHD (2–7 (8 g/dl). Reinstitution of prednisone was followed by nor- diarrheal stools/day). Methylprednisolone 2 mg/kg was malization of hemoglobin levels. Three months later added with resolution of GVHD symptoms. He was tapered another attempt to wean the patient from steroids failed. off corticosteroids by day 60. At day 131 he experienced Splenectomy was considered but not performed. The substantial skin rash again and a biopsy was consistent with patient remained on prednisone and tacrolimus and Bone Marrow Transplantation UCBT for Hunter syndrome CA Mullen et al 1095 remained stable, although he continued to have elevated qualitative measure of urinary electrophoresis demonstrate reticulocyte counts and was Coombs’ test positive. Seven- trace amounts of abnormal
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