Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1

Hoyeraal-Hreidarsson (HH) syndrome is a multisystem disorder affecting boys characterized by aplastic anaemia (AA), immunodeficiency, microcephaly, cerebellar-hypoplasia and growth retardation. Its pathogenesis is unknown. X-linked dyskeratosis congenita (DC) is an inherited bone-marrow-failure syndrome characterized by skin pigmentation, nail dystrophy and leucoplakia which usually develop towards the end of the first decade of life. AA occurs in >90% of cases of DC. We speculated that mutations in the gene responsible for X-linked DC (DKC1) may account for the HH syndrome, due to the phenotypic similarities between the disease in respect of AA and gender bias. We therefore analysed the DKC1 gene in two HH families. In one family a nucleotide change at position 361(A --> G) in exon 5 was found in both affected brothers; in the other family a nucleotide change at position 146(C --> T) in exon 3 was found in the affected boys. The finding of these two novel missense DKC1 mutations demonstrates that HH is a severe variant of DC. They also show that mutations in DKC1 can give rise to a very wide clinical spectrum of manifestations. Boys with unexplained AA or immunodeficiency should be tested for mutations in DKC1 even though they may lack diagnostic features of DC.     

Molecular and biochemical characterization of JAK3 deficiency in a patient with severe combined immunodeficiency over 20 years after bone marrow transplantation: implications for treatment

Summary. Severe combined immunodeficiency (SCID) comprises a heterogenous group of disorders that are fatal unless treated by bone marrow transplantation (BMT). The most common form of SCID (T^?B⁺ SCID) is due to mutations of either the common gamma chain (γc) or of γc-coupled JAK3 kinase. We report an unusual JAK3 defect in a female who was successfully treated >20 years ago with a BMT using her HLA-identical father as the donor. Persistence of genetically and biochemically defective autologous B cells, associated with reconstitution of cellular and humoral immunity, suggests that integrity of the γc-JAK3 signalling pathway is not strictly required for immunoglobulin production.     

Successful bone marrow transplantation in children with severe aplastic anemia using HLA-partially matched family donors

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. © 1993 Wiley-Liss, Inc.     

Non-myeloablative bone marrow transplantation in an adult with Wiskott-Aldrich syndrome

Early bone marrow transplant is now standard treatment for infants with severe immunodeficiencies such as Wiskott-Aldrich Syndrome (WAS), but results in older children and adults are poor. Non-myeloablative transplant has shown promise in the treatment of older children, who are likely to have active infections and organ damage. We describe a non-myeloablative transplant of a 26-year-old man with WAS, undertaken because of severe infections and vasculitis. Partial engraftment and immunorestoration were achieved. The patient is well 1 year post transplantation.     

A patient with X‐linked dyskeratosis congenita presenting with bronchiolitis obliterans requiring lung transplantation and immunodeficiency

Dyskeratosis congenita (DKC) is a syndrome characterized by immunodeficiency, bone marrow (BM) failure, somatic abnormalities, and predisposition to malignancy, resulting from mutations in proteins involved in maintenance of telomeres. Pulmonary fibrosis resulting in respiratory failure is a serious complication affecting approximately 20% of DKC patients. Pediatric pulmonologists should consider this diagnosis in patients with lung fibrosis and concurrent immunodeficiency or BM failure. Pediatr Pulmonol. 2013; 48:91–93. © 2012 Wiley Periodicals, Inc.     

Hypereosinophilic syndrome with multiple organ dysfunction treated by allogeneic bone marrow transplantation

A 26-year-old man with hypereosinophilic syndrome who had initial neurologic, cardiac, and pulmonary dysfunction, high eosinophil count, thrombocytopenia, and bone marrow fibrosis had only a transient response to conventional treatment with corticosteroids and hydroxyurea. He therefore received human lymphocyte antigen-identical allogeneic bone marrow transplantation (BMT) after conditioning with cytoxan and fractionated total body irradiation. Hematologic recovery was prompt, with normalization of blood counts and bone marrow. The patient died less than 3 months after transplantation from diffuse cytomegalovirus infection. Potential interest of BMT in patients with resistant hypereosinophilic syndrome and features of poor prognosis is discussed.     

Allogeneic bone marrow transplantation in a patient with hypereosinophilic syndrome

We describe a 32-year-old man with idiopathic hypereosinophilic syndrome (HES) who presented with pulmonary dysfunction, thrombocytopenia, lymphadenopathy, and hepatosplenomegaly. The patient developed progressive disease on prednisone and hydroxyurea therapy, and he underwent a successful allogeneic bone marrow transplantation (BMT). The patient is asymptomatic with no evidence of eosinophilia 30 months after transplantation. There is currently no cure for patients with HES, and BMT should be considered in selected patients. © 1996 Wiley-Liss, Inc.     

Allogeneic bone marrow transplantation in a patieni with Shwachman-Diamond syndrome

Shwachman-Diamond syndrome (SDS) is a rare inherited disorder involving concomitant neutropenia and exocrine pancreatic insufficiency. About 25% of patients develop hematopoiesic malignancies. We describe a 24-year-old male patient with SDS who underwent allogeneic bone marrow transplantation (BMT) because of progression into acute myeloid leukemia (AML) following myelodysplastic syndrome (MDS). The BMT preparative regimen consisted of busulfan (16 mg/kg body wt.), followed by cyclophosphamide (120 mg/kg). Cyclosporin A and short methotrexate were used for graft-versus-host disease (GvHD) prophylaxis. The post-transplant period was complicated by staphylococcal septicemia, CMV infection, renal insufficiency, and acute GvHD grade III. Hematological recovery was delayed (post-transplant day +55). The patient was discharged at day +68 in complete remission without any evidence of MDS. RFLP fingerprint analysis showed complete engraftment of the donor's hematopoiesis. The patient's leukemia relapsed 9 months post-transplant, and death followed due to CMV infection and multiorgan failure. Despite the fatal course in this patient, allogeneic BMT could be an option for curative treatment of the hematopoietic failure in SDS. The interaction of BMT with pancreatic insufficiency still has to be ascertained.     

Toxoplasmosis with hemophagocytic syndrome after bone marrow transplantation: diagnosis at autopsy

Abstract: Toxoplasmosis is a rare but well recognized opportunistic infection that can occur after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Besides encephalitis, other common presentations of Toxoplasma gondii infection are interstitial pneumonitis and myocarditis. Because of its non‐specific clinical and biological signs and its lethal outcome, toxoplasmosis is often misdiagnosed and only revealed at autopsy. We report a case of a postmortem diagnosis of disseminated toxoplasmosis associated with hemophagocytic syndrome, which underlines the value of necropsy in cases of death after transplantation. We also discuss clinical presentations and risk factors that lead to toxoplasmosis in allo‐HSCT recipients.     

Pregnancy and delivery after bone marrow transplantation (BMT) for severe aplastic anemia (SAA)

Summary A 23 years old multiple pretransfused female with severe aplastic anemia (SAA) underwent bone marrow transplantation (BMT). Cyclophosphamide (200 mg/kg) was used for conditioning, donor buffy coat cells were given as rejection prophylaxis. Seven months after BMT regular menses started in the absence of exogenous hormonal manipulation and 21 months after BMT the patient became pregnant. Pregnancy was complicated by mumps in the 14th week. It was terminated at term by caesarean section. The normally developed newborn girl (3,450 gm) presented with a persistent fetal circulation syndrome. After surgical correction of the patent ductus arteriosus Botalli the girl baby recovered quickly.     

Allogeneic bone marrow transplantation with reduced conditioning (RC-BMT)

Allogeneic bone marrow transplantation with conventional conditioning (CC-BMT) has the potential of curing various malignant and non-malignant diseases. The curative mechanisms encompass 1) stem cell support for myeloablative radio-chemotherapy, 2) the graft-versus-tumor (GVT) effect, 3) gene replacement for genetic diseases and 4) immunoablation for autoimmune diseases. CC-BMT is characterized by high intensity conditioning, the requirement of prolonged and expensive hospital treatment and a treatment related mortality (TRM) of 10-50% depending on diagnosis, disease stage, patient age and donor type. Recent preclinical and clinical progress has resulted in the emergence of new concepts and procedures that allow replacement of patient bone marrow and immune system with that of the donor by a transplant procedure with markedly reduced conditioning (RC-BMT). This type of transplant, sometimes referred to as mini-BMT, activates curative mechanisms 2-4, which for a number of diseases seems sufficient for cure. It avoids the severe organ toxicity of myeloablative radio-chemotherapy and the complications of profound neutropenia. Patients beyond the age limit of conventional BMT (50-60 yr) may therefore be candidates for this type of transplant as well as patients which because of other medical conditions or the type of disease for which the transplant is needed are poor candidates for CC-BMT. The procedure can be performed in an outpatient setting. The resulting cost reduction should contribute to making allogenic BMT more readily available. This review describes basic concepts and procedures involved in RC-BMT and summarizes preliminary results obtained with RC-BMT in different transplant centers.     

骨髓间充质干细胞移植对大鼠重症急性胰腺炎的治疗作用观察

目的探讨骨髓间充质干细胞（MSCs）移植对重症胰腺炎（SAP）的治疗作用及相关机制。方法将雄性SD大鼠120只随机分为假手术组、模型组及移植组各40只。模型组和移植组采用5%牛磺胆酸钠逆行胰胆管注射方法制作SAP模型,假手术组开腹后翻动肠壁即关腹。造模成功后移植组经门静脉植入MSCs;模型组及假手术组采用同样方法给予等量生理盐水。于24、48、72 h每组分别处死10只大鼠,对胰腺和肾脏损伤进行大体形态和光镜下观察,测定血清淀粉酶（AMY）、BUN、Cr、TNF-α和IL-6水平。结果模型组胰腺和肾脏组织损伤明显,各时间点血清AMY、BUN、Cr、TNF-α和IL-6水平均高于假手术组,P均〈0.05。移植组胰腺和肾脏组织损伤有所减轻;各时间点血清中AMY、BUN、Cr、TNF-α和IL-6水平均低于模型组及假手术组,P均〈0.05。结论经门静脉移植MSCs治疗SAP效果确切,可降低多器官功能障碍的发生率。     

Donor leucocyte transfusions for relapse in myelodysplastic syndrome after allogeneic bone marrow transplantation

A 31-year-old man with refractory anaemia of excess blasts, which had karyotypic abnormalities, received an allogeneic bone marrow transplant (BMT). At time of relapse, 3 months after BMT, he was treated with donor leucocyte transfusions (DLT). Grade III acute GVHD (graft-versus-host disease) occurred 35 d after DLT which was fully reversed with cyclosporin and prednisolone. His condition was complicated by a herpes zoster infection. 2 months after DLT, neutrophil and platelet count were increased and karyotypic abnormalities disappeared. This observation demonstrates that DLT is an effective treatment for relapse of myelodysplastic syndrome (MDS) after BMT.     

A successful pregnancy after bone marrow transplantation for severe aplastic anaemia with pre-transplant conditioning of total lymph-node irradiation and cyclophosphamide

Summary. Pregnancy after bone marrow transplantation (BMT) for severe aplastic anaemia (SAA) is now an encouraging reality. We present a successful pregnancy, 4 years after BMT for SAA, in a woman being immunosuppressed before transplantation with cyclophosphamide and total lymphnode irradiation (TLI). No fetal complication was diagnosed.     

Regeneration of CALLA (CD10+), TdT+ and double-positive cells in the bone marrow and blood after autologous bone marrow transplantation.

In this prospective study we investigated the frequency of CD10+, TdT+ and CD10+TdT+ mononuclear cells in the bone marrow (BM) and peripheral blood (PB) before and after autologous bone marrow transplantation (ABMT). 49 patients treated for acute lymphoblastic or myeloblastic leukaemia, malignant lymphoma or multiple myeloma were included. A significant increase in CD10+ cells occurred in BM in both children and adults after ABMT. In children, we also found a significant increase in CD10+ cells in PB. In individual patients remaining in remission, up to 34% CD10+ cells having a normal Ig kappa/lambda light chain ratio were recorded after ABMT. In children, the percentage of TdT+ and CD10+ TdT+ cells increased significantly in BM. In most cases the CD10/TdT-ratio was greater than 1.0, but during early regeneration after ABMT this ratio was less than 1.0 in several patients remaining in complete remission. In patients remaining in remission, CD10+TdT+ cells were detected in the blood in only 2 out of 140 samples tested, and the proportion of these cells never exceeded 0.03%. We conclude that quantitation of CD10+TdT+ cells in peripheral blood is helpful in the evaluation of complete remission in patients treated for pre-B-ALL.     

A prospective study of screening upper gastrointestinal (GI) endoscopy prior to and after bone marrow transplantation (BMT)

Background: Upper gastrointestinal (GI) endoscopic abnormalities are common in symptomatic bone marrow transplant (BMT) recipients but the incidence of occult gastrointestinal disease in these patients is unknown.
Aims: To examine the role of screening upper GI endoscopy before and after BMT.
Methods: Endoscopy was performed routinely on allogeneic (n = 24) and autologous (n = 17) BMT patients before transplant and at 30 and 120 days after transplant.
Results: Twenty-one of 41 patients (51%) had an endoscopic abnormality on one or more occasions which necessitated a change in treatment. These abnormalities were present in ten of 41 (24%) pre-transplant endoscopies, ten of 32 (31%) endoscopies at day 30 after BMT, and in seven of 22 (32%) day 120 endoscopies. Abnormalities included mucosal erosions or ulcers (n = 22 endoscopies), infections (n = 5) or previously undiagnosed GI graft-versus-host disease (n = 3). Mucosal erosions or ulcers were present in eight of 28 endoscopies despite regular anti ulcer drug therapy.
Conclusions: Screening upper GI endoscopy before and after BMT is generally safe and detects a high yield of significant GI abnormalities. However, it remains to be demonstrated that treatment of these lesions will improve the clinical outcome in BMT recipients without GI symptoms.     

Role of reduced intensity conditioning in T-cell and B-cell immune reconstitution after HLA-identical bone marrow transplantation in ADA-SCID

The treatment of choice for severe combined immunodeficiency is bone marrow transplantation from an HLA-identical donor sibling without conditioning. However, this may result in low donor stem cell chimerism, leading to reduced long-term immune reconstitution. We compared engraftment, metabolic, and T-cell and B-cell immune reconstitution of HLA-identical sibling bone marrow transplantation performed in 2 severe combined immunodeficiency infants with adenosine deaminase deficiency from the same family treated with or without a reduced intensity conditioning regimen (busulfan/fludarabine). Only the patient who received conditioning showed a stable mixed chimerism in all lineages, including bone marrow myeloid and B cells. The use of conditioning resulted in higher thymus-derived naïve T cells and T-cell receptor excision circles, normalization of the T-cell repertoire, and faster and complete B-cell and metabolic reconstitution. These results suggest the utility of exploring the use of reduced intensity conditioning in bone marrow transplantation from HLA-identical donor in severe combined immunodeficiency to improve long-term immune reconstitution.