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Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disease caused by mutations in the RMRP gene. Beside dwarfism, CHH has a wide spectrum of clinical manifestations including variable grades of combined immunodeficiency, autoimmune complications, and malignancies. Previous reports in single CHH patients with significant immunodeficiencies have demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for the severe immunodeficiency, while growth failure remains unaffected. Because long-term experience in larger cohorts of CHH patients after HSCT is currently unreported, we performed a European collaborative survey reporting on 16 patients with CHH and immunodeficiency who underwent HSCT. Immune dysregulation, lymphoid malignancy, and autoimmunity were important features in this cohort. Thirteen patients were transplanted in early childhood ( approximately 2.5 years). The other 3 patients were transplanted at adolescent age. Of 16 patients, 10 (62.5%) were long-term survivors, with a median follow-up of 7 years. T-lymphocyte numbers and function have normalized, and autoimmunity has resolved in all survivors. HSCT should be considered in CHH patients with severe immunodeficiency/autoimmunity, before the development of severe infections, major organ damage, or malignancy might jeopardize the outcome of HSCT and the quality of life in these patients.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency with microthrombocytopenia, eczema, recurrent infections, autoimmune disorders, and malignancies that are life-threatening in the majority of patients. In this long-term, retrospective, multicenter study, we analyzed events that occurred in 96 WAS patients who received transplants between 1979 and 2001 who survived at least 2 years following hematopoietic stem-cell transplantation (HSCT). Events included chronic graft-versus-host disease (cGVHD), autoimmunity, infections, and sequelae of before or after HSCT complications. Three patients (3%) died 2.1 to 21 years following HSCT. Overall 7-year event-free survival rate was 75%. It was lower in recipients of mismatched related donors, also in relation with an older age at HSCT and disease severity. The most striking finding was the observation of cGVHD-independent autoimmunity in 20% of patients strongly associated with a mixed/split chimerism status (P < .001), suggesting that residual-host lymphocytes can mediate autoimmune disease despite the coexistence of donor lymphocytes. Infectious complications (6%) related to splenectomy were also significant and may warrant a more restrictive approach to performing splenectomy in WAS patients. Overall, this study provides the basis for a prospective, standardized, and more in-depth detailed analysis of chimerism and events in long-term follow-up of WAS patients who receive transplants to design better-adapted therapeutic strategies Udgivelsesdato: 2008/1/1

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency with microthrombocytopenia, eczema, recurrent infections, autoimmune disorders, and malignancies that are life-threatening in the majority of patients. In this long-term, retrospective, multicenter study, we analyzed events that occurred in 96 WAS patients who received transplants between 1979 and 2001 who survived at least 2 years following hematopoietic stem-cell transplantation (HSCT). Events included chronic graft-versus-host disease (cGVHD), autoimmunity, infections, and sequelae of before or after HSCT complications. Three patients (3%) died 2.1 to 21 years following HSCT. Overall 7-year event-free survival rate was 75%. It was lower in recipients of mismatched related donors, also in relation with an older age at HSCT and disease severity. The most striking finding was the observation of cGVHD-independent autoimmunity in 20% of patients strongly associated with a mixed/split chimerism status (P < .001), suggesting that residual-host lymphocytes can mediate autoimmune disease despite the coexistence of donor lymphocytes. Infectious complications (6%) related to splenectomy were also significant and may warrant a more restrictive approach to performing splenectomy in WAS patients. Overall, this study provides the basis for a prospective, standardized, and more in-depth detailed analysis of chimerism and events in long-term follow-up of WAS patients who receive transplants to design better-adapted therapeutic strategies.

BACKGROUND AND OBJECTIVES: Unrelated donor bone marrow transplant (UD-BMT) has become an attractive, alternative source of hematopoietic cells for patients lacking a matched sibling. The aim of this paper is to report on 520 patients below 19 years of age undergoing UD BMT in 31 Italian centers between September 1989 and December 2001, and to focus on the results achieved in the 423 patients grafted before December 2000. DESIGNS AND METHODS: In 1989 the Italian Bone Marrow Transplant Group (GITMO) and the Italian Association for Pediatric Hematology and Oncology (AIEOP) established the Italian Bone Marrow Donor Registry (IBMDR) to facilitate donor search and marrow procurement for patients lacking an HLA identical sibling. By the end of December 2001, 296,720 HLA-A, B typed volunteer donors had been cumulatively registered and 3,411 searches had been activated for Italian patients. At least one HLA-A, B, DRB1 matched donor was found for 54% of the patients and 520 UD BMTs were performed in patients below 19 years of age before December 2001. Since 1999 more than 90% of the patients < or = 14 years old, and more than 50% of the patients 15-18 years old undergoing UD BMT have been treated in AIEOP institutions. In 50% of the cases donors were found in the IBMDR, and in 50% they were found in 14 other Registries. The average time from search activation to transplant was 6 months for diseases other than chronic myeloid leukemia (CML), while for CML it was 8.7 months. RESULTS: Actuarial 100-day transplant-related mortality (TRM) was 32% in patients grafted between 1989 and 1997, and 21% for patients grafted after 1998 (p = 0.003). Twenty-eight per cent of the patients developed grade III or IV acute graft-versus-host disease (GvHD), and 20% developed extensive chronic GvHD. The rate of disease-free survival at three years was 37% for patients with acute lymphoblastic leukemia, 38% for acute myeloid leukemia or myelodysplastic syndrome patients, 59% for patients with inbo, BACKGROUND AND OBJECTIVES: Unrelated donor bone marrow transplant (UD-BMT) has become an attractive, alternative source of hematopoietic cells for patients lacking a matched sibling. The aim of this paper is to report on 520 patients below 19 years of age undergoing UD BMT in 31 Italian centers between September 1989 and December 2001, and to focus on the results achieved in the 423 patients grafted before December 2000. DESIGNS AND METHODS: In 1989 the Italian Bone Marrow Transplant Group (GITMO) and the Italian Association for Pediatric Hematology and Oncology (AIEOP) established the Italian Bone Marrow Donor Registry (IBMDR) to facilitate donor search and marrow procurement for patients lacking an HLA identical sibling. By the end of December 2001, 296,720 HLA-A, B typed volunteer donors had been cumulatively registered and 3,411 searches had been activated for Italian patients. At least one HLA-A, B, DRB1 matched donor was found for 54% of the patients and 520 UD BMTs were performed in patients below 19 years of age before December 2001. Since 1999 more than 90% of the patients < or = 14 years old, and more than 50% of the patients 15-18 years old undergoing UD BMT have been treated in AIEOP institutions. In 50% of the cases donors were found in the IBMDR, and in 50% they were found in 14 other Registries. The average time from search activation to transplant was 6 months for diseases other than chronic myeloid leukemia (CML), while for CML it was 8.7 months. RESULTS: Actuarial 100-day transplant-related mortality (TRM) was 32% in patients grafted between 1989 and 1997, and 21% for patients grafted after 1998 (p = 0.003). Twenty-eight per cent of the patients developed grade III or IV acute graft-versus-host disease (GvHD), and 20% developed extensive chronic GvHD. The rate of disease-free survival at three years was 37% for patients with acute lymphoblastic leukemia, 38% for acute myeloid leukemia or myelodysplastic syndrome patients, 59% for patients with inbo

From December '89 to July '96, 36 children aged 1 month-9 years with genetic diseases underwent BMT from unrelated donor (UD) in one of the 7 Italian Institutions participating in this program. The diseases leading to BMT included immunodeficiencies (17), Fanconi Anemia (7), storage diseases (6), thalassemia (3), FEL (2) and osteopetrosis (1). Twenty-seven pairs were A, B, DRB1 matched. The remaining 9 pairs received the marrow from a donor mismatched for one (5) or more (4) antigens. Nine patients received a radiation containing regimen, 26 patients were conditioned with chemotherapy alone, the remaining patient was infused with donor marrow without any conditioning therapy. GvHD prophylaxis included CSA, MTX, and serotherapy (ALG or 'in vivo' Campath 1G) prior to BMT in 23 cases, CSA and MTX in 4 cases, CSA alone (7) or in combination with T-cell depletion (2) in the remaining 9 cases. Thirty-five children (97%) showed donor engraftment; the remaining child failed to engraft. Four children developed secondary graft failure. Actuarial 2 year disease-free survival was 57%; grade III-IV acute GvHD developed in 7 of 35 evaluable patients (20%); chronic GvHD developed in 5 of 22 (23%). We conclude that severe immunodeficiencies, FEL and osteopetrosis represent an absolute indication for UD-BMT. Prognosis of UD BMT for FA could improve in patients grafted in an early phase, UD BMT in thalassemia is acceptable only in a restricted subset of patients, selected for very serious reasons such as poor compliance to desferoxamine or alloimmunization to minor blood group antigens.

Bone marrow transplantation (BMT) using HLA-partially matched family donors has produced disappointing results (25-30% of long-term survivors) in patients with severe aplastic anemia. We describe two children affected by severe aplastic anemia, not responsive to immunosuppressive therapy, who underwent allogeneic bone marrow transplantation using a HLA-partially matched family donor. Both cases presented 2 first class HLA-antigens (A and B) disparity between donor and recipient. The pretransplant conditioning regimen consisted of cyclophosphamide, thoracoabdominal irradiation, cytosine-arabinoside, and antilymphocyte globulin. As graft versus host disease (GVHD) prophylaxis, Cyclosporine-A was administered at usual dosages for 6 months. A full marrow engraftment was observed in both cases. Only grade I acute GVHD, promptly responsive to corticosteroid therapy, developed with no chronic GVHD. Five months after transplant, both children progressively developed hypertension, renal function impairment, thrombocytopenia, and severe normochromic anemia, with erythropoietin serum levels lower than expected for the haematocrit. After antihypertension treatment and supportive therapy, the clinical picture progressively improved, while treatment with recombinant human erythropoietin completely corrected the long-lasting anemia. The two children are alive and well 28 months after the transplant, with a Karnofsky score of 100% and a normal peripheral blood count. The authors suggest that, once immunosuppressive therapy has failed, BMT from donors other than HLA-identical sibling is a feasible approach in children affected by severe aplastic anemia, not having an HLA-identical donor.

The pattern of X-chromosome inactivation was analyzed, by means of two different DNA probes (pSPT-PGK and M27 beta), in several cell lineages derived from females belonging to a pedigree with X-linked immunodeficiency with hyper-IgM (HIGM1). Non-random X-chromosome inactivation was demonstrated in T cells, B cells, and neutrophils, but not in fibroblasts, of obligate carriers, suggesting that different hematopoietic cell lineages are primarily involved in HIGM1. Preferential inactivation of the paternally derived X-chromosome was demonstrated by analysis of segregation of the alleles defined by the pSPT-PGK and M27 beta probes. The possibility that the HIGM1 mutation may confer a proliferative and/or differential advantage to hematopoietic precursors carrying the mutated allele on the active X-chromosome is discussed.

In the last fifteen years, therapeutic use of intravenous immunoglobulin on one hand, and of bone marrow transplantation on the other, have largely modified survival rate and prognosis for many primary immunodeficiency diseases. At the same time, major advances in molecular genetics have allowed mapping of several immunodeficiency genes and made prenatal diagnosis feasible. Furthermore, for many X-linked immunodeficiencies, carrier detection can be also accomplished by means of analysis of the pattern of X-chromosome inactivation. As a whole, these techniques have substantially contributed to a more accurate genetic counseling in the families.