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 type IIB (Hunter ) 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 activity has been restored and lytic anemia. abnormal urinary excretion of 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 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 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 , thick skin, coarse facies, hepatos- Because of the family history the patient was screened plenomegaly, cardiac valve abnormalities, 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- 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 . 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 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 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 glycosaminoglycans. This sug- teen months after transplant he was successfully weaned gests that complete body-wide correction has not yet from tacrolimus without exacerbation of GVHD. Predni- occurred. Tissue assessing lysosomal morphology sone was slowly tapered over 6 months while blood counts have not been performed in this patient. In other patients remained stable. Twenty-six months post transplant he is tissue biopsies have become normal after improvement in off all immunosuppressant drugs and is growing and urinary glycosaminoglycans.10 Clinically this patient has developing normally. His blood counts are normal had regression of hepatomegaly. Follow-up over the next (hemoglobin 12.7 g/dl, WBC 9400 cells/␮l, platelets 10 years should indicate whether the transplant will prevent 235 000/␮l, reticulocytes 0.4%). He continues to have a long-term organ dysfunction. positive direct Coombs’ test. Nine months after transplant the patient developed severe hemolytic anemia. Alloimmune hemolysis was an unlikely explanation for the process since more than 7 months had Discussion transpired since the last transfusion of red cells or platelets. Moreover, the specificity of the responsible IgG was anti- Hematopoietic stem cell transplantation for Hunter syn- e, and was not directed against either major or minor blood drome is controversial because published series of BMT group antigens associated with blood group incompati- in Hunter variants with substantial CNS impairment have bilities. Autoimmune hemolytic anemia and other auto- demonstrated little improvement in CNS functioning.9–11 immune disorders have been reported after hematopoietic This result has been also seen in other metabolic storage stem cell transplantation,15,16 although they have not been diseases with substantial CNS components.12 Moreover, extensively reported after umbilical cord blood transplan- lifelong prevention of cardiac dysfunction (the most com- tation. Autoantibodies have been observed in 8% of patients mon cause of death in type IIB8) has yet to be proven, with chronic GVHD,17 and autoimmune cytopenias do although there has been a report of reversal of cardiac val- occur (although the manifestations are more commonly vular abnormalities as measured by echocardiography in a thrombocytopenia or neutropenia).18 Hemolytic anemia is 14-year-old boy with type IIB Hunter syndrome who also associated with a variety of lymphocytic malignancies underwent BMT.13 Some have argued that transplant may and immunodeficiency states. In these settings responses have a role in such disorders if it can be performed quite to corticosteroids are often incomplete and transient. The early in life12 before irreversible organ damage occurs. In prognosis for complete remission of the hemolytic anemia many cases this is not possible since the diagnosis is not in these conditions is poorer than in patients with idiopathic made until early childhood after the disease has become autoimmune hemolytic anemia, possibly because of the clinically evident. In this case the decision to proceed with underlying disorders.19,20 This patient had a quick and satis- unrelated donor HSC transplant was based on several con- factory response to steroids, possibly portending a good siderations. First, the diagnosis was made in the first few prognosis. The significance of a very brief period of asso- months of life before irreversible organ damage occurred. ciated thrombocytopenia is unknown, especially since anti- Second, while the mutations in Hunter syndrome are platelet antibodies were never identified. Hemolytic anemia extremely heterogeneous and a strict genotype–phenotype with immune thrombocytopenia (Evan’s syndrome) has a correlation has not been established,6 the family history poorer prognosis than hemolytic anemia.20–22 In this patient indicated that CNS impairment was not a primary feature the immunopathogenesis of the hemolytic anemia is of the disease in this kindred. Moreover, the storage disease unknown. It is conceivable that given the blood group produced unacceptable quality of life and was ultimately incompatibility the patient (Rh−) may have some residual lethal for the maternal uncle. Third, an unrelated umbilical recipient B cells that react against the incompatible donor cord blood unit with acceptable HLA-matching could be (Rh+) Rho (although the IgG identified was not identified and procured within 3 months. Early experience specific for the typical anti-D antigen which represents the with UCB transplantation for more common conditions (eg most common antigen disparity in Rh incompatibility). leukemia) has indicated that while fatal GVHD can occur, RFLP analysis indicates 100% donor hematopoiesis, but the incidence of grades 3 and 4 GVHD for a particular does not exclude microchimerism. More likely is the possi- degree of mismatching may be less than that seen with bility that the hemolytic anemia is truly autoimmune since unrelated donor marrow or peripheral blood stem cell trans- the direct antiglobulin test demonstrated red cell bound plantation.14 Clinical results 2 years after transplant indicate IgG1 antibodies with anti-e specificity. Such warm auto- that biochemical measures of the Hunter syndrome are antibodies are the most common type identified in auto- being corrected. While BMT can correct the enzyme immune hemolytic anemia. The direct antiglobulin test did deficiency in marrow-derived cells but not other somatic not identify red cell bound complement. However, several cells, the enzymatic activity of these marrow-derived cells series reviewing warm (IgG) autoimmune hemolytic ane- may be able to substantially reduce the total body burden mia have demonstrated that while both IgG and comp- of glycosaminoglycans either directly or indirectly by lement can be detected on red cells in half to two-thirds of release of iduronate 2-sulfatase and subsequent uptake by cases, a sizable fraction (up to a third) may be associated other tissues through endocytosis.10 The results in this with IgG only, or even complement alone.23 This auto- patient are compatible with this hypothesis. One parameter immunity could be a manifestation of GHVD. Alterna- of body burden of glycosaminoglycans is the quantity of tively, the autoimmunity may be the product of immune glycosaminoglycans in urine, while the more sensitive dysregulation following transplant.15 If so, with time and

Bone Marrow Transplantation UCBT for Hunter syndrome CA Mullen et al 1096 the absence of tacrolimus, normal immune homeostasis 6 Gort L, Chabas A, Coll MJ. Hunter disease in the Spanish may be established and the hemolytic process may com- population: molecular analysis in 31 families. J Inher Metabol pletely abate. Similarly to the Hunter syndrome this is a Dis 1998; 21: 655–661. possibility that will only be established with time. 7 Young ID, Harper PS. The natural history of the severe form While the decision to proceed with an unrelated umbili- of Hunter’s syndrome: a study based on 52 cases. Dev Med Child Neurol 1983; 25: 481–489. cal cord blood transplant for Hunter syndrome IIB can be 8 Young ID, Harper PS. Mild form of Hunter’s syndrome: clini- justified, it is emotionally very difficult for both parents and cal delineation based on 31 cases. Arch Dis Child 1982; 57: caregivers. In this case the parents were fully informed of 828–836. the very substantial risks of early death and substantial mor- 9 McKinnis EJ, Sulzbacher S, Rutledge JC et al. Bone marrow bidity from transplant, but accepted them after concluding transplantation in Hunter syndrome. J Pediatr 1996; 129: that the quality of life without transplant was unacceptable. 145–148. A substantial possibility of long-term survival was con- 10 Li P, Thompson JN, Hug G et al. Biochemical and molecular sidered to be better than a very high probability of reduced analysis in a patient with the severe form of Hunter syndrome survival (median 21 years in Hunter IIB) with substantial after bone marrow transplantation. Am J Med Genet 1996; 64: disabilities. Other people of good will could reach another 531–535. 11 Vellodi A, Young E, Cooper A et al. Long-term follow-up decision. Until technology experiences sub- 24,25 following bone marrow transplantation for Hunter disease. J stantial improvements, the increased availability of Inher Metabol Dis 1999; 22: 638–648. umbilical cord blood units for transplantation may increase 12 Whitley CB, Belani KG, Chang PN et al. Long-term outcome the number of transplants performed for conditions other of following bone marrow transplantation. than cancer such as immunodeficiencies, metabolic storage Am J Med Genet 1993; 46: 209–218. diseases and hemoglobinopathies in which survival without 13 Bergstrom SK, Quinn JJ, Greenstein R, Ascensao J. Long- transplant is expected to be a decade or more.14 We believe term follow-up of a patient transplanted for Hunter’s disease it is imperative that in such situations the process of infor- type IIB: a case report and literature review. Bone Marrow med consent should be exceptionally thorough and in some Transplant 1994; 14: 653–658. circumstances may require ethics consultation. While many 14 Rubinstein P, Carrier C, Scaradavou A et al. Outcomes among 562 recipients of placental-blood transplants from unrelated families of affected children are extremely well informed donors. New Engl J Med 1998; 339: 1565–1577. about the underlying genetic condition, they often have 15 Chen FE, Owen I, Savage D et al. Late onset haemolysis and little or no understanding of the risks or intensity of BMT. red cell autoimmunisation after allogeneic bone marrow trans- It is critical that parents fully appreciate the probabilities plant. Bone Marrow Transplant 1997; 19: 491–495. of graft rejection, early death from infection, hemorrhage, 16 Sherer Y, Shoenfeld Y. Autoimmune diseases and auto- regimen-related toxicity, and graft-versus-host disease. immunity post-bone marrow transplantation. Bone Marrow They must also understand that BMT will not reverse CNS Transplant 1998; 22: 873–881. damage. Our point of view is that BMT cannot be ethically 17 Sullivan KM, Witherspoon RP, Storb R et al. Prednisone and justified in patients who have already experienced a azathioprine compared with prednisone and placebo for treat- substantial decline in CNS function. ment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow trans- plantation. Blood 1988; 72: 546–554. 18 Hart DNJ, Fearnley DB. The effect of GvHD on the hemato- Acknowledgements poietic system. In: Ferrara JLM, Deeg HJ, Burakoff SJ (eds). Graft-vs.-Host Disease, 2nd edn. Marcel Dekker: New York, This work was supported in part by Clinical Oncology Career 1997, pp 447–477. Development Award CDA-96-61 from the American Cancer 19 Drobyski WR, Potluri J, Sauer D, Gottschall JL. Autoimmune Society (CAM). hemolytic anemia following T cell-depleted allogeneic bone marrow transplantation. Bone Marrow Transplant 1996; 17: 1093–1099. References 20 De Lord C, Marsh JC, Smith JG et al. Fatal autoimmune pan- cytopenia following bone marrow transplantation for aplastic 1 Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: anaemia. Bone Marrow Transplant 1996; 18: 237–239. Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The Meta- 21 Wang WC. Evans syndrome in childhood: pathophysiology, bolic Basis of Inherited Disease, 6th edn. McGraw-Hill: New clinical course, and treatment. Am J Pediatr Hematol Oncol York, 1995, pp 2465–2494. 1988; 10: 330–338. 2 Young ID, Harper PS, Newcombe RG, Archer IM. A clinical 22 Kottaridis PD, Rees H, Smith G et al. A fatal case of auto- and genetic study of Hunter’s syndrome. 2. Differences immune thrombocytopenia with an IgM anti-GPIb/IX follow- between the mild and severe forms. J Med Genet 1982; 19: ing one antigen mismatched unrelated donor bone marrow 408–411. transplantation. Bone Marrow Transplant 1999; 23: 739–741. 3 Young ID, Harper PS. Incidence of Hunter’s syndrome. Hum 23 Gilliland BC. Autoimmune hemolytic anemia. In: Rossi EC, Genet 1982; 60: 391–392. Simon TL, Moss GS, Gould SA (eds). Principles of Trans- 4 Young ID, Harper PS, Archer IM, Newcombe RG. A clinical fusion Medicine, 2nd edn. Williams & Wilkins: Baltimore, and genetic study of Hunter’s syndrome. 1. Heterogeneity. J 1996, pp 101–120. Med Genet 1982; 19: 401–407. 24 Braun SE, Aronovich EL, Anderson RA et al. Metabolic cor- 5 Li P, Bellows AB, Thompson JN. Molecular basis of iduron- rection and cross-correction of mucopolysaccharidosis type II ate-2-sulphatase gene mutations in patients with mucopolysac- (Hunter syndrome) by retroviral-mediated gene transfer and charidosis type II (Hunter syndrome). J Med Genet 1999; 36: expression of human iduronate-2-sulfatase. Proc Natl Acad 21–27. Sci USA 1993; 90: 11830–11834.

Bone Marrow Transplantation Commentary C Peters and W Krivit 1097 25 Stroncek DF, Hubel A, Shankar RA et al. Retroviral transduc- and Sanfilippo types A, B, C, and D and procedures for 35 tion and expansion of peripheral blood lymphocytes for the measurement of SO4-glycosaminoglycans. In: Hommes F treatment of mucopolysaccharidosis type II, Hunter’s syn- (ed). Techniques in Diagnostic Human Biochemical Genetics: drome. Transfusion 1999; 39: 343–350. A Laboratory Manual. John Wiley & Sons: New York, 1991, 26 Thompson JN, Nowakowski RW. Enzymatic diagnosis of pp 567–586. selected mucopolysaccharisoses: Hunter, Morquio, Type A,

Commentary Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome)

C Peters and W Krivit

Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

Summary: basal ganglia.6 The disease is also associated with general atrophy, ventriculomegaly, increased signal in basal gang- Hunter syndrome is an X-linked metabolic storage dis- lia, thalamus and brainstem, and increased periventricular order arising from deficiency of iduronate sulfatase signal in white matter.7 Neuropsychological consequences enzyme activity. Despite the successful use of hematopo- of MPS IIA are similar to those of Hurler syndrome, except ietic cell transplantation for a variety of lysosomal and that many behavioral abnormalities such as hyperactivity peroxisomal storage diseases, limited benefit occurs fol- and aggression are also present.8 In general, males with lowing transplantation in either the severe or mild MPS IIB experience milder with great forms of Hunter syndrome. A brief ethical commentary variability in age of onset and severity. is provided on the case of a boy with mucopolysacchar- Transplantation using bone marrow, umbilical cord idosis IIB (ie the mild form) who received an unrelated blood, or peripheral blood hematopoietic cells has been umbilical cord blood transplant to improve his future effective treatment for selected lysosomal and peroxisomal quality of life. Bone Marrow Transplantation (2000) 25, inherited metabolic storage diseases such as Hurler syn- 1097–1099. drome,9–11 Maroteaux–Lamy,12 X-linked adrenoleukodys- Keywords: Hunter syndrome; hematopoietic cell trans- trophy,13 metachromatic leukodystrophy14 and globoid-cell plantation; ethical issues; quality of life leukodystrophy.15 Consideration of hematopoietic cell transplantation (HCT) and its implementation for these metabolic diseases must take into account the natural his- Hunter syndrome, an X-linked metabolic storage disorder tory of the disease and its status at HCT, likelihood of with a reported incidence between one in 34 000 and one achieving stabilization or improvement in somatic and/or in 162 000,1–4 is due to deficiency of iduronate sulfatase neuropsychologic parameters, and the probability of sur- enzyme activity. A member of the mucopolysaccharidosis vival with the transplant. Of particular concern to transplan- (MPS) family of lysosomal diseases, MPS II evidences a ters, neurologists and geneticists has been the effect of the wide spectrum of clinical severity ranging from the early disease on the central nervous system and the prospects for onset severe form (MPS IIA) to the more insidious form, amelioration due to the significant morbidity and mortality namely MPS IIB.5 Boys with MPS IIA exhibit significant of HCT. Furthermore, the likelihood of a fatal disease com- somatic features such as coarse facies, progressive hearing plication occurring within several months to as long as 5 loss, hepatosplenomegaly, cardiomyopathy, dysostosis- years accompanied by deteriorating quality of life has been multiplex, macrocephaly, central nervous system deterio- a major motivating force for patients, families and their ration, and neuropsychological impairments. As in Hurler physicians to accept the significant ‘up-front’ risks of HCT. syndrome, cribiform (multicystic) changes reflecting stor- In this issue of Bone Marrow Transplantation, Mullen age material in the perivascular Virchow–Robin spaces are et al16 describe a 10-month-old boy with MPS IIB who noted, particularly in white matter, corpus callosum, and was transplanted with unrelated umbilical cord blood and achieved full donor-derived engraftment. The course was complicated by bacteremia, mucositis, limited gastrointes- Correspondence: Dr C Peters, Pediatric Hematology/Oncology, Blood and tinal hemorrhage, grade III skin and grade II gastrointes- Marrow Transplantation, University of Minnesota, Box 477, Rm D-580 Mayo Bldg, 420 Delaware St SE, Minneapolis, MN 55455, USA tinal GVHD, and severe autoimmune hemolytic anemia Received 31 January 2000; accepted 4 February 2000 requiring 2 years of steroid and other significant immuno-

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