Immune status of patients with inherited bone marrow failure syndromes.

Immune function abnormalities have been reported in patients with Fanconi anemia (FA), dyskeratosis congenita (DC) and, rarely, in Shwachman-Diamond syndrome (SDS), and Diamond-Blackfan anemia (DBA), but large systematic studies are lacking. We assessed immunological parameters in 118 patients with these syndromes and 202 unaffected relatives. We compared the results in patients with reference values, and with values in relatives after adjusting for age, sex, corticosteroid treatment, and severe bone marrow failure (BMF). Adult patients (≥18 years) with FA had significantly lower immunoglobulins (IgG, IgA and IgM), total lymphocytes, and CD4 T cells than reference values or adult relatives (P < 0.001); children with FA had normal values. Both children and adults with FA had lower B- and NK cells (P < 0.01) than relatives or reference values. Patients with DC had essentially normal immunoglobulins but lower total lymphocytes than reference values or relatives, and lower T-, B-, and NK-cells; these changes were more marked in children than adults (P < 0.01). Most patients with DBA and SDS had normal immunoglobulins and lymphocytes. Lymphoproliferative responses, serum cytokine levels, including tumor necrosis factor-α and interferon-γ, and cytokine levels in supernatants from phytohemagglutinin-stimulated cultures were similar across patient groups and relatives. Only patients with severe BMF, particularly those with FA and DC, had higher serum G-CSF and Flt3-ligand and lower RANTES levels compared with all other groups or relatives (P < 0.05). Overall, immune function abnormalities were seen mainly in adult patients with FA, which likely reflects their disease-related progression, and in children with DC, which may be a feature of early-onset severe disease phenotype.

Bone marrow aplasia with pancytopenia and hemorrhage in a Japanese Black calf.

Severe leukopenia was incidentally found in a newborn Japanese Black calf by blood testing during the clinical trial of an iron dextran drug (day 1). At that time, no clinical problems were observed. On day 15, the calf presented with a high rectal temperature and tachypnea. Treatment with antibiotics and non-steroidal anti-inflammatory drugs did not improve clinical signs. Anemia, melena, and prolonged bleeding were also recorded. Necropsy findings revealed subcutaneous petechial hemorrhage and severe bone marrow aplasia. This is the first confirmed case of pancytopenia and hemorrhage associated with bone marrow aplasia in a Japanese Black calf.

Proximal radio-ulnar synostosis with bone marrow failure syndrome in an infant without a HOXA11 mutation.

SUMMARY: This report summarizes the clinical management of an infant with a proximal radio-ulnar synostosis and inherited bone marrow failure syndrome (PRUS/IBMFS). Molecular studies were negative for the characteristic HOXA11 mutation described earlier. He was successfully treated with a non-myeloablative hematopoietic stem cell transplantation from an human leukocyte antigen-identical sibling donor at the age of 3 months. We reviewed the literature on PRUS/IBMFS with an emphasis on the current understanding of the molecular mechanisms involved in the disease pathogenesis. Absence of the HOXA11 mutation in this case implies that molecular mechanisms beyond the HOXA11 gene, yet to be discovered, may contribute for the development of PRUS/IBMFS.

Congenital disorders of ribosome biogenesis and bone marrow failure.

Diamond Blackfan anemia (DBA) is a congenital bone marrow (BM) failure syndrome that typically results in macrocytic anemia within the first year of life. DBA is also associated with birth defects, increased incidence of cancer, and other cytopenias. Shwachman-Diamond syndrome (SDS) is a multisystem disease characterized by exocrine pancreatic dysfunction, impaired hematopoiesis, and leukemia predisposition. Other clinical features include skeletal, immunologic, hepatic, and cardiac disorders. Treatment for these BM failure syndromes, including stem cell transplantation (SCT), will be discussed in this review.

Congenital cytopenias and bone marrow failure syndromes.

Congenital bone marrow failure syndromes (CBMFS) are extremely uncommon diseases that can present in the neonate. The objective of this article is to review the presentation, diagnosis, pathophysiology, and management of CBMFS in relation to neonatology. CBMFS should be considered when a single or multiple blood cell lineages are low secondary to failure of production. Diagnosis in the neonatal period requires a high index of suspicion. In this particular age group, CBMFS should be considered when the neonate has a family history of CBMFS, is small for gestational age, or has other physical abnormalities. History and physical examination can lead to the diagnosis. CBMFS are often associated with a predisposition to cancer later in life.

Aplasia medular grave adquirida: evolución histórica de los resultados obtenidos con trasplante de progenitores hematopoyéticos de donante familiar. Estudio del Grupo Español para el Trasplante de Médula Ósea en Niños (GETMON) / Severe acquired aplastic anemia: historical outcome of patients treated by allogeneic bone marrow transplantation from matched sibling donors. A study by the Spanish Group for Bone Marrow Transplantation in Children (GETMON)

Introducción: El trasplante de progenitores hematopoyéticos (TPH) de donante familiar compatible es el tratamiento de elección en la aplasia medular adquirida (AMA) grave en la infancia. Se presenta la experiencia de Grupo Español para el Trasplante de Médula Ósea en Niños en esta enfermedad a lo largo del período cronológico 1982-2004. Pacientes y métodos: Recibieron un trasplante 62 pacientes con una mediana de edad de 10 años. En el período 1982-1990 lo recibieron 18 pacientes y en el período 1991-2004, 44. El régimen de acondicionamiento varió según el período cronológico; en el primero se utilizó preferentemente la asociación de radioterapia y ciclofosfamida (72 % de los casos) y en el segundo ciclofosfamida con o sin globulina antitimocitaria (62 %). La profilaxis de enfermedad injerto contra huésped más utilizada fue la ciclosporina (57/62 pacientes). Resultados: Un total de 51 pacientes están vivos y en remisión completa de su aplasia con períodos de observación de entre 24 y 289 meses (mediana de 127 meses). La probabilidad de supervivencia actuarial libre de eventos a 5 años es del 82 %. Dicha supervivencia se incrementó del 61 al 90 % entre los dos períodos analizados. Un total de 11 pacientes fallecieron por fracaso o pérdida del injerto (3), enfermedad injerto contra huésped aguda o crónica asociada a infecciones (4) o fallo multiorgánico (4). El análisis univariante evidenció dos factores con valor predictivo para la supervivencia: el intervalo diagnóstico/trasplante y el período cronológico en que se efectuó (en ambos, p = 0,03). Conclusiones: Esta experiencia confirma que el trasplante de progenitores hematopoyéticos de donante familiar compatible es el tratamiento de elección para la aplasia medular grave adquirida, con un porcentaje de supervivencia libre de episodios del 90 % en la actualidad (AU)

Allogeneic haematopoietic stem-cell transplantation is the treatment of choice for acquired aplastic anaemia in children. Experience with this approach from Spanish Working Party for Bone Marrow Transplantation in Children in two sequential time periods (1982-1990 and 1991-2004) is reported. Patients and methods: Sixty two consecutive patients with a median age of 10 years were transplanted; 18 in the 1982-1990 period and 44 in the 1991-2004 period. Conditioning regimen consisted mainly of irradiation and cyclophosphamide in the first period (72 % of patients) and cyclophosphamide ± anti-thymocyte globulin (62 %) in the second. Graft versus host disease prophylaxis consisted of cyclosporine in most patients (57/62). Results: Fifty one patients are alive and disease-free at a median follow-up of 127 months. Five years probability of event-free survival is 82 %. The survival increased from 61 % to 91 % during the two time periods. Eleven patients died from graft failure or rejection (3), acute or chronic graft versus host disease and infection (4) or multi-organ failure (4). Univariate analysis identified two significant prognostic factors: interval diagnostic/transplant and time period of transplant (for both p = 0.03). Conclusions: This experience corroborates that allogeneic haematopoietic stem-cell transplantation is the best treatment for severe acquired aplastic anaemia, with a current disease - free survival of 90 % of patients (AU)

[Congenital bone marrow failure syndromes. The last 20 years by the example of congenital neutropenia]. / Angeborene Störungen der Blutbildung. Die Entwicklung der letzten 20 Jahre am Beispiel der kongenitalen Neutropenie.

Congenital bone marrow failure syndromes are rare diseases characterised by a reduction of mature blood cells (erythrocytes, platelets, neutrophils). Examples of such disorders include congenital aplastic anemia (Fanconi anemia), congenital hypoplastic anemia (Diamond-Blackfan anemia), congenital neutropenias (Kostmann syndrome, cyclic neutropenia, Shwachman-Diamond syndrome and others), and congenital thrombocytopenias (TAR syndrome, amegacaryocytic thrombocytopenia). In Germany the prevalence of congenital bone marrow failure syndromes can be estimated to be 10/1,000,000 children and adolescents. Although rare, these diseases contributed significantly to the current knowledge on normal haematopoiesis. The documentation of rare diseases by patient registries and the cooperation of clinical centres within networks are most important for the resolution of such disorders. In the following, congenital neutropenia will be presented as an example: Until the 1980s congenital neutropenia could only be classified clinically. Few cases had been reported in the literature. All subtypes were therefore collected under the general term "congenital neutropenia". The establishment of an international network of experts and the long-term documentation of the courses of disease in a common database allowed for statistically workable data in response to therapy, secondary diagnoses and the long-term prognosis. A close cooperation with scientists finally led to the characterisation of genetically different disorders with common pathomechanisms.

Disease progression in recently diagnosed patients with inherited marrow failure syndromes: a Canadian Inherited Marrow Failure Registry (CIMFR) report.

BACKGROUND: Inherited bone marrow failure syndromes (IMFSs) are genetic disorders characterized by defective single-lineage or multi-lineage hematopoiesis. IMFS patients are at risk for severe cytopenias, development of marrow cytogenetic abnormalities (MCA), myelodysplasia (MDS), and malignancy. The rate of disease progression and proportion of patients at risk for these complications is currently unclear. We examined recently diagnosed IMFS patients to determine distribution of diagnoses, disease progression and development of significant outcomes. METHODS: The CIMFR is a prospective multi-center study established in 2001 to register all IMFS patients in Canada. Analysis was restricted to patients diagnosed after November 30, 1997. Summary statistics were used to depict the study population while survival was described using the Kaplan-Meier method. RESULTS: 74 CIMFR patients were considered recently diagnosed. Median age at diagnosis was 2.7 years (range, birth to 40.6). Annual follow-up data were available for 53 (72%) patients. The five most prevalent diagnoses were Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), Diamond-Blackfan anemia (DBA), dyskeratosis congenita (DKC), and Kostmann's neutropenia (KS). Eighteen (24%) patients were unclassifiable. Twenty-eight (53%) follow-up patients had disease progression as indicated by new or worsening cytopenias, new marrow changes, or initiation of transfusion support and/or medical therapy. Fourteen (19%) fulfilled minimal diagnostic criteria for myelodysplasia. Eleven patients had hematopoietic stem cell transplantation (HSCT) by first follow-up. Five patients have died. Survival at 36 months is 89.8 +/- 5.7%. CONCLUSIONS: IMFS patients are often diagnosed at a young age. The relative distribution of diagnoses is similar to previous reviews of published cases; however, 25% of patients are currently unclassifiable. Disease progression has occurred in approximately 50% of follow-up patients. Early mortality is noted. Continued prospective observation of these patients is warranted.

Hematopoietic transplantation for bone marrow failure syndromes and thalassemia.

Several genetic diseases, generally considered as congenital diseases, are characterized by bone marrow failure during early childhood. Hematopoietic stem cell transplantation is the only curative treatment for syndromes involving bone marrow failure and thalassemia. In this slate-of-the-art review, we wish to focus on the results of hematopoietic transplantation in treating some of these diseases, with a special emphasis on congenital bone marrow failure and thalassemia. The results of this procedure have improved over the previous years, mainly when performed by experienced teams. New conditioning regimes based on fludarabine and the use of HLA-identical donors have been related with better survivals. In the previous years, donors other than HLA-identical siblings have been increasingly used in patients not responding to conventional measures, but this approach needs to be evaluated in larger studies.

Hematopoietic cell transplantation for congenital bone marrow failure.

PURPOSE OF REVIEW: Congenital bone marrow failure is rare and multifactorial. This review focuses on the outcome after allogeneic hematopoietic cell transplantation for the treatment of these disorders, with particular emphasis on recent discoveries and the challenges. RECENT FINDINGS: In the treatment of congenital bone marrow failure disorders, the goals are to eliminate or reduce early and late toxicities and the risk of graft-versus-host disease. Novel nonmyeloablative fludarabine-based preparative regimens have demonstrated low risks of toxicity and acceptable engraftment rates for several congenital bone marrow failure disorders. Although there seems to be less early toxicity, longer follow-up is needed to determine late effects, especially the development of malignancy. T cell depletion of the bone marrow or peripheral blood, or the use of umbilical cord blood, has decreased the risk of graft-versus-host disease. Together, reduced toxicity and low rates of graft-versus-host disease have at least minimized the morbidity early after transplantation, with promising early survival. SUMMARY: With marked improvement in rates of survival after allogeneic hematopoietic cell transplantation for selected congenital bone marrow failure disorders, emphasis is now being placed on improving quality of life and reducing late effects. Multicenter collaborative trials will determine the best treatment for these rare disorders.

[Congenital inborn diseases with disorders of neutrophil count]. / Wrodzone schorzenia przebiegajace z zaburzeniami liczby granulocytów obojetnochlonnych.

In the research we showed some inborn syndromes with disturbances of the neutrophils' number. The diseases were divided in the following categories: disturbed proliferation of myeloid stem cells, phenotypic anomalies, panmyelophtisis, neutropenia caused of marrow infiltration, neutropenia caused of agammaglobulinemia or dysgammaglobulinemia, metabolic disorders. The nowadays diagnostic possibilities and treatment in these cases were showed.

Congenital bone marrow failure syndromes associated with protean developmental defects and leukemia.

Congenital bone marrow failure syndromes are associated with a number of congenital abnormalities affecting a wide range of organ systems. The underlying molecular abnormalities that cause these disorders affect normal embryonic development during the critical organogenesis phase (weeks 4 to 8). These syndromes predispose patients to leukemia and other malignancies, and these genetic disorders may represent the first hit of at least two hits necessary for malignant transformation. The molecular defects underlying these diseases are just beginning to be understood; mechanisms suggested by recent research include DNA repair (FA-A, FA-G); abnormalities of the ribosomes (DBA, DC); to disorders of electron transport (FA-C, Pearson's syndrome, Barth's syndrome). Understanding these molecular mechanisms provides the knowledge necessary to develop better therapy, possibly including gene therapy, offering for the first time the potential for curing the hematologic manifestations of these illnesses.

Long-term proliferation in vitro of hematopoietic progenitor cells from children with congenital bone marrow failure: effect of rhGM-CSF and rhEPO.

We have characterized the proliferation kinetics of hematopoietic cells in long-term marrow cultures (LTMC) from five normal children and seven children with congenital bone marrow failure (four with Fanconi anemia [FA] and three with congenital pure red cell aplasia [PRCA]). Total nonadherent and adherent cells, as well as nonadherent progenitors, were determined weekly in the presence or in the absence of rhGM-CSF (10 ng/ml) or rhEPO (3 U/ml). As compared to normal LTMC, hematopoiesis was drastically reduced in cultures from FA patients. Myeloid and erythroid progenitor cells reached undetectable levels after only 3 and 1 weeks of culture, respectively. This was observed even in cultures supplemented with rhGM-CSF, in which no response to this cytokine occurred. In LTMC from PRCA children, the growth of erythroid and multipotent progenitors was also drastically reduced. Myelopoiesis, on the other hand, showed normal levels during the first three weeks of culture; however, from week 4, there was a significant decrease in the levels of both progenitor and mature cells, reaching undetectable levels several weeks before normal cells did. Response to rhGM-CSF and rhEPO was transient and deficient. Our results suggest that in FA, alterations at the level of primitive progenitor cells are so severe that myeloid, erythroid and multipotent progenitors are unable to proliferate in LTMC, even in the presence of rhGM-CSF. In patients with PRCA the erythroid arm of hematopoiesis is preferentially affected and addition of rhGM-CSF and/or rhEPO to these cultures had little or no effect on erythroid cell production. Interestingly, myelopoiesis in this culture system was deficient as well and response to rhGM-CSF was defective, suggesting that the myeloid lineage is also altered in congenital PRCA.

[Congenital amegakaryocytic thrombocytopenia: indication for allogeneic stem cell transplantation]. / Congenitale amegakaryocytaire trombocytopenie: indicatie voor allogene stamceltransplantatie.

In two neonates, girls, persistent thrombocytopenia was found, which afterwards proved to be caused by a megakaryocytosis. Congenital amegakaryocytic thrombocytopenia is a rare bone marrow failure in young children that is defined as thrombocytopenia with absent or markedly decreased megakaryocytes in the bone marrow. Untreated, amegakaryocytic thrombocytopenia progresses to marrow failure with pancytopenia. Allogeneic stem cell transplantation offers the only possibility for cure, and is successful in approximately half of the patients. Both patients were treated by stem cell transplantation, the one with a matched unrelated donor, the second with stem cells from her HLA-identical sister. The first patient died, the second recovered with a normal number of circulating thrombocytes of donor origin.