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Background: X-linked immunodysregulation syndrome with polyendocrinopathy and enteropathy (IPEX) is caused by FOXP3 gene mutations that block the generation of regulatory T lymphocytes. We report an 18-month-old boy with classic IPEX who underwent 2 hematopoietic stem cell transplantations (HSCTs)., Methods: The first HSCT from an unrelated 8/10 HLA-matched umbilical cord blood donor (UCB) was performed after a conditioning regimen consisting of treosulfan, fludarabine, thiotepa, and thymoglobulin. Due to complete rejection of the UCB transplant, a second transplantation from a 6/10 HLA-matched mother was performed after alpha-beta T-cell depletion. The second conditioning regimen consisted of busulfan, fludarabine, a single dose of cyclophosphamide 1 g/m 2 , and Grafalon (Neovii Pharmaceuticals, Rapperswil, Switzerland). The T-cell depletion product contained 15.06 x 10 6 CD34+ cells per kilogram body weight (BW) and 4.19 x 10 5 alpha-beta T lymphocytes per kilogram BW. Due to acute graft rejection, the boy was treated with thymoglobulin, and full donor chimerism in both T lymphocytes and mononuclear cells was achieved. The immunosuppressive therapy was stopped 1 year after transplantation. To date, the patient remains free from graft-vs-host disease (GVHD) and immunosuppression., Conclusions: HSCT after busulfan-based reduced-toxicity conditioning in patients with IPEX syndrome is feasible and well tolerated and can result in full donor engraftment. Monitoring of chimerism and aggressive therapy in cases of graft rejection are warranted due to the high reactivity of residual autologous T lymphocytes. T-cell depletion reduces the risk of GVHD and the need for steroid therapy, which is especially challenging in patients with diabetes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We present the case of transcatheter aortic valve replacement in a 20-year-old woman with severe bicuspid aortic stenosis and Schmike immuno-osseous dysplasia who was unfit for surgical aortic valve replacement. Meticulous pre-procedural planning and a multidisciplinary team approach can enable successful transcatheter aortic valve replacement in complex patients with genetic syndromes.

This article presents a case study of a female patient with primary immunodeficiency, who underwent percutaneous nephrolithotripsy. The presence of a serious concomitant disease affects different aspects of preoperative and postoperative management of the patient. The choice of percutaneous nephrolithotripsy is necessitated by the need to render the patient stone free using a one-stage and the most effective surgical modality. The article describes the choice of antibacterial therapy to treat inflammatory complications in this category of patients. Broad-spectrum antibiotics should be used to prevent the onset of pyelonephritis, while pyelonephritis exacerbation requires administration of reserve antibiotics in combination with human immunoglobulin.

Background: Good's syndrome (GS) is a rare disease characterized by thymoma, hypogammaglobulinemia, low or absent B-cells, decreased T-cells, an inverted CD4+/CD8+ T-cell ratio and reduced T-cell mitogen proliferative responses. GS is difficult to diagnose preoperatively due to its rarity and lack of typical symptoms, the characteristics of Chinese GS patients are still lacking. This study aimed to systematically review all the clinical, laboratory, and immunologic findings of reported cases of Chinese patients with GS., Methods: We searched for case reports and articles up to January 2017 using PubMed, China National Knowledge Infrastructure, Wangfang database and China Science and Technology Journal Database with the following words in combinations as key words: "thymoma," "hypogammaglobulinemia," and "Good's syndrome." The text words and MeSH terms were entered depending on the databases characteristics. The reference lists from retrieved articles were also screened for additional applicable studies. The authors were restricted to Chinese. There was no language restriction., Results: Forty-seven patients were reported in 27 studies. We found that GS has a nationwide distribution and that most cases (83%) have been described on the mainland of China. The initial clinical presentation is varied, ranging from symptoms related to the thymoma to infections resulting from immunodeficiency. Type AB (50%) is the most common histologic type of thymomas in Chinese GS patients according to the World Health Organization classification of thymomas. With respect to infection, sinopulmonary infection (74%) is the most common type, followed by skin infection (10%) and intestinal tract infection (10%). Diarrhea was presented in 36% of patients, and autoimmune manifestations were presented in 36% of patients., Conclusions: GS is a rare association of thymoma and immunodeficiency with a poor prognosis. Astute clinical acumen and increased awareness of the clinical and immunological profile of GS are needed to increase early diagnosis, that would benefit improved therapeutic effects.

Objectives: The only curative treatment for many patients with primary immunodeficiency disease is hematopoietic stem cell transplant. In this study, we report the transplant outcomes of patients with primary immunodeficiency diseases., Materials and Methods: Herein, we present the transplant outcomes of 20 patients with primary immunodeficiency disease seen at our center in Kayseri, Turkey, from 2010 to 2015., Results: The disease distribution of the 20 patients were as follows: 6 patients with severe combined immunodeficiency, 4 patients with hemophagocytic lymphohistiocytosis, 2 patients with chronic granulomatous disease, 2 patients with type 2 Griscelli syndrome, 2 patients with B-cell deficiency plus bone marrow failure, 1 patient with severe congenital neutropenia, 1 patient with X-linked lymphoproliferative disease, 1 patient with T-cell deficiency plus relapsed non-Hodgkin lymphoma, and 1 patient with type 1 leukocyte adhesion deficiency. Of the 20 patients, 11 received related HLA-matched, 6 received haploidentical, 2 received unrelated HLA-matched, and 1 received HLA-mismatched transplant. The median age at transplant was 21 months, and median follow-up was 5 months. Overall survival rate was 65%. Mean engraftment times for neutrophils and platelets were 14.25 ± 3.08 and 24.7 ± 11.4 days. Graft-versus-host disease was observed in 30% of patients., Conclusions: Patients with primary immunodeficiency disease treated at our center had acceptable transplant outcomes. This study supports the use of hematopoietic stem cell transplant in patients with primary immunodeficiency disease.

Epstein-Barr virus (EBV) has oncogenic potential and has been implicated in the etiology of a wide range of malignancies. Certain EBV-driven neoplasms, such as smooth muscle tumors (SMTs), manifest typically in immunocompromised patients. In children, these neoplasms have been encountered in the setting of primary immune disorders, specifically severe combined and common variable immunodeficiency syndromes. Human immunodeficiency virus infection and posttransplant immunosuppression, in particular liver and kidney transplantation, likewise increase the risk in the pediatric population. The location of these neoplasms appears related to the type of immunodeficiency: in acquired immunodeficiency syndrome they are frequently located intracranially or intraspinally, whereas after transplant they usually involve the liver or lung. We report 2 distinct cases of EBV-related SMT, unique through their coassociated immunosuppressive state or location: the 1st occurred in a patient with immunodeficiency secondary to NEMO gene mutation following hematopoietic stem cell transplantation; the 2nd developed in the orbit after heart transplant.

Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, episodic lymphopenia, renal failure, and cerebrovascular disease secondary to arteriosclerosis and myointimal hyperplasia. In this paper the authors report the first known application of internal carotid artery (ICA) surgical revascularization to relieve a high-grade focal stenosis of the ICA in a pediatric patient, a 6-year-old boy with SIOD. The clinical presentation, imaging features, operative technique, and postoperative course are described and the molecular genetics, pathophysiology, and treatment considerations in SIOD are discussed.

Introduction: Children with primary immunodeficiency have severe life-threatening infections and a higher prevalence of autoimmune problems, allergy and lymphoproliferative disorders. Allogenic hematopoietic stem cell transplantation has been the only potentially curative option., Patients and Methods: Patients with primary immunodeficiency underwent allogenic stem cell transplantation in the period 1985-2011, and registered in the Spanish Working Party for Bone Marrow Transplantation in Children., Results: One hundred and fifty nine patients underwent 173 allogenic stem cell transplantations, of whom 97 had severe combined immunodeficiency, 30 with immune dysregulation disorders, 25 Wiskott-Aldrich syndrome, and 21 phagocyte disorders. The median patient age at diagnosis was 6 months (range: 17 days - 168 months) and the median patient age at transplant was 12 months (range: 1 month - 189 months). The donors were 30 (19%) identical siblings, 40 (25%) alternative family donors, and 89 (56%) unrelated donors. The source of stem cells was bone marrow in 68 (43%), cord blood in 52 (33%), and peripheral blood in 39 (24%). Ninety eight (61.6%) are alive, 57 (35.9%) died. Event-free survival at 10 years was 63%, with 90% for children transplanted from identical siblings, 36% for those transplanted from alternative family donors, and 66% for those transplanted from unrelated donors., Conclusions: The best results have been obtained with identical siblings, but other options may be considered., (Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

GVHD has been reported in 8-10% of children after small bowel transplant (SBTx). Immunodeficient children may be predisposed to aggressive, steroid-resistant GVHD. There exists a unique association of immunodeficiency in children with MIA (MIAI). We report on our SBTx experience in patients with the diagnosis of MIAI, their high incidence of GVHD, and the possible role of stem cell transplantation in these patients. We performed a review of records from children that underwent SBTx or that we evaluated for SBTx at our institution. We focused on the diagnoses of atresia, multiple intestinal atresia, immunodeficiency, and GVHD in our patient population. Children with MIAI are likely to experience severe GVHD following SBTx. MIAI correlated with a 100% incidence of GVHD in these patients. Of the five patients with MIAI that underwent SBTx, three succumbed to severe GVHD within 1-6 months after SBTx. One patient received stem cell transplant prior to SBTx and did not develop severe GVHD, but died from influenza nine months after SBTx. Our unique patient survives long-term, with engraftment of donor γ δ T cells. He has mild, persistent chronic GVHD. Atresia is a common referral diagnosis for SBTx. Patients with multiple atresias, especially MIAI, are at significant risk for the complication of GVHD following SBTx. We recommend careful immunologic assessment and antecedent stem cell transplant in children with MIAI prior to SBTx., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

MHC Class II deficiency is a rare primary immunodeficiency disease characterized by absent HLA Class II expression resulting in CD4 lymphopenia, lack of Ag-specific responses and recurrent infection. Without successful allogeneic SCT, most children succumb to infection within the first decade of life. To date, alternative donor transplants for this disorder have been inferior to SCT for other forms of combined immunodeficiency disease due to an increased incidence of graft rejection, GVHD and death from infections generally acquired before haematopoietic cell transplantation. This study details the transplant outcome of 16 affected children consecutively transplanted at four centers since 1990, 8 of whom required mechanical ventilation pretransplant. Stem cells were derived from an HLA-mismatched family member (n=10), an HLA-matched unrelated adult donor (n=4), or an unrelated cord blood donor (n=2). Graft failure occurred in five children, all of whom underwent a second SCT. Six patients developed acute GVHD although no patient developed chronic GVHD after primary transplantation. CD4 T-cell reconstitution remained below the normal range for age, suggesting defective thymopoiesis after allo-SCT. Nonetheless, 69% of children survive without GVHD at a median follow-up of 5.7 years, indicating improved outcomes compared with previous studies.

Purpose of Review: Neutropenia is a feature of several primary immunodeficiency diseases (PIDDs). Because of the diverse pathophysiologies of the PIDDs and the rarity of each disorder, data are often lacking, leading to the necessity of empiric treatment. Recent developments in the understanding of neutropenia in several of the PIDDs make a review of the data timely., Recent Findings: The category of severe congenital neutropenia continues to expand. Mutations in G6PC3 have been identified as the cause of neutropenia in a minority of previously molecularly undefined cases. Recent advances have broadened our understanding of the pathophysiology and the clinical expression of this disorder. A possible function of the C16orf57 gene has been hypothesized that may explain the clinical overlap between Clerucuzio-type poikiloderma with neutropenia and other marrow diseases. Plerixafor has been shown to be a potentially useful treatment in the warts, hypogammaglobulinemia, infection, and myelokathexis syndrome. Investigations of patients with adenosine deaminase deficient severe combined immunodeficiency have identified neutropenia, and particularly susceptibility to myelotoxins, as a feature of this disorder. Granulocyte-colony stimulating factor is the treatment of choice for neutropenia in PIDD, whereas hematopoietic cell transplantation is the only curative option., Summary: The number of PIDDs associated with neutropenia has increased, as has our understanding of the range of phenotypes. Additional data and hypotheses have been generated helping to explain the diversity of presentations of neutropenia in PIDDs., Competing Interests: There are no conflicts of interest.

Background: Foxn1 transcription factor deficit leads to immune deficiency, with hair and nail abnormalities. We report the case of a patient also presenting localized leucoderma., Case Report: A 3-year-old boy underwent thymus transplantation at the age of 9 months for Foxn1 deficiency. He had developed urticaria and autoimmune hypothyroidism after thymus grafting. On examination, he had universal non-scarring alopecia, nail changes (atrophy, partial onycholysis and longitudinal grooves) and leucoderma on both big toes., Discussion: This is the first description of leucoderma occurring in a patient with Foxn1 deficiency, as well as the first report of this pigment abnormality following thymus transplantation. The pathogenic hypotheses discussed were post-graft vitiligo and leucoderma induced by Foxn1 deficiency., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

A single-center experience of catheter-related blood stream infections in children undergoing hematopoietic stem cell transplant for primary immunodeficiency is described. The rate of definite central venous catheter infections was 5.31/1000 line days. Staphylococcus epidermidis was the most commonly identified organism. Teicoplanin resistance occurred in 17% of S. epidermidis infections. The central catheter was removed in 21% of infections.

We describe the incidence of malignancy in patients with primary immunodeficiency disorders (PIDD) following hematopoietic cell transplantation (HCT). From the Center for International Blood and Marrow Transplant Research, 2266 PIDD patients who had undergone allogeneic HCT between 1968 and 2003 were identified. Patient, disease, and transplant factors for development of malignancy were examined and pathology reports for reported malignancies reviewed independently by a pathologist for confirmation. The incidence of malignancy was highest for Wiskott-Aldrich syndrome (3.3%), with an overall incidence of 2.3% for PIDD. Post-HCT malignancy was confirmed for 52 of 63 reported cases. Forty-five of 52 patients developed posttransplant lymphoproliferative disorders (PTLD) at a median of 3 months post-HCT. Of these, 26 had received T cell-depleted (TCD) bone marrow. Three patients who developed myelodysplastic syndrome had received TCD marrow and total body irradiation. Three patients developed a solid tumor. Patients with PIDD are at a relatively low risk of developing malignancies post-HCT compared with their historic risk of cancer. The most frequent malignancy or lymphoproliferative disorder was early-onset PTLD. As in other HCT recipients, TCD appears to correlate with PTLD development. Our results lend support to the hypothesis that immune reconstitution in PIDD following HCT leads to a decrease in cancer risk., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

FOXP3 is critical for the development and function of CD4(+)CD25(bright) natural regulatory T cells (nTreg). Individuals harboring mutations in FOXP3 develop immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). We describe a child diagnosed with IPEX who underwent a reduced intensity, T and B cell depleted, matched unrelated donor bone marrow transplant followed by clinical resolution. Using lineage-specific donor chimerism studies, we demonstrate that non-myeloablative HSCT resolves disease in the context of low level donor hematopoietic stem cell (HSC) engraftment. Despite low-levels of donor HSC, thymically-derived nTreg and to a lesser extent CD4(+) and CD8(+) T cells, exhibit a selective in vivo growth advantage for populations containing a functional FOXP3 gene. Moreover, nTreg from this patient show regulatory function directly ex vivo. These results have implications for improving clinical therapy for patients with IPEX and provide mechanistic insight into the in vivo development of human nTreg and unexpectedly, non-regulatory T cells., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Previous studies have reported increased rates of social difficulties in children treated by haematopoietic cell transplant (HCT). This study assessed social functioning in children with congenital immunodeficiency treated by HCT and investigated two potential underlying mechanisms that may explain social difficulties: executive function skills and physical appearance. In total, 31 children (8-16 years of age) were assessed on measures of social functioning and peer relationships, executive function and physical appearance. Results were compared with a control group of 31 healthy children, matched for age, gender, ethnicity and cognitive ability. Parent, teacher and self-report data were collected. HCT survivors were described by parents and teachers, but not by themselves, as experiencing more difficulties with social functioning than the control group. Executive function was not associated with social functioning. However, an objective measure of physical appearance was significantly associated with social functioning. Results suggest that children treated by HCT for congenital immunodeficiency do experience significant difficulties in social functioning, not solely accounted for by below average intelligence. These difficulties are associated with physical appearance, but not with executive functional skills. This has clinical implications for identifying and treating children at increased risk of difficulties with social functioning.

Deficient thymopoiesis is a pivotal determinant of impaired immune competence following hematopoietic stem cell transplantation (HSCT). Stem cell factor (SCF) is essentially involved in early thymopoiesis. We evaluated whether SCF administration would improve recovery of thymopoiesis following HSCT in immunodeficient mice receiving: 1) bone marrow (BM) transplantation of congenic mice; or 2) human fetal liver HSCT in the human immune system mouse model. Following murine BM transplantation, SCF significantly enhanced thymopoiesis and peripheral T cell recovery in lymph nodes and spleen. SCF did not affect BM lymphoid progenitor recovery and/or expansion. Median thymic cellularity increased from 0.9 in PBS- to 266 × 10(4)/thymus in SCF-treated mice (p = 0.05). Following human HSCT in human immune system mice, higher thymic cellularity was observed in SCF-treated mice. Double-negative and early double-positive thymocyte subsets increased, but especially late double-positive, CD4 single-positive, and CD8 single-positive thymocyte subsets were significantly enhanced (p < 0.05). These results show that exogenous supply of SCF may significantly improve murine and human posttransplant thymopoiesis, for which the effect is probably exerted by directly promoting T cell development intrathymically rather than by enhanced entry of prethymically expanded lymphoid progenitors.

Analyzing the phenotypic characterization of the immune system cells involved in the pathogenesis of immunodeficiency with thymoma (Good's syndrome) is difficult due to the low number of studies on that subject. We describe the immunological alterations observed in a case of Good's syndrome, and we summarize the pathogenic explanations found in the literature., (Copyright © 2011 International Clinical Cytometry Society.)

Objective: To understand the clinical characteristics and outcome associated with respiratory syncytial virus (RSV) infection in hematopoietic stem cell transplantation (HSCT) recipients with primary immunodeficiencies (PIDs)., Method: Nasopharyngeal aspirate samples were collected consecutively before and after HSCT from 9 recipients from Apr. 2009 to Sep. 2010 and analyzed for the presence of RSV using real-time polymerase chain reaction assay. To further verify the presence of the virus, positive samples for PCR were isolated for RSV. RSV G gene was amplified, sequenced and used for phylogenetic analysis., Result: The presence of RSV was detected in 3 out of 9 children. The viral replication in all the patients was prolonged for months. All the 3 patients with RSV infection were treated with intravenous immune globulin (IVIG) and one was treated with antiviral medication. All patients survived and achieved successful immune reconstitution., Conclusion: This study indicates that the HSCT recipients with PID are at increased risk for RSV infection. RSV can shed for months after the initial infection and the patients recover with the course of immune reconstitution.

MHC class II deficiency is a rare and fatal form of primary combined immunodeficiency caused by a lack of T-cell-dependent humoral and cellular immune response to foreign antigens, which can only be cured by allogenic stem cell transplantation. In the literature search, we identified 68 cases of HSCT in MHC class II deficiency in the last 14 yr. Pre- and post-transplant MHC class II deficiency is complicated by overwhelming viral infections, a high incidence of GvHD, and graft failure with a poor overall survival rate below 50%. We report an eight-month-old boy presenting with severe respiratory infections and chronic diarrhea, whose sister died at the age of four yr from septicemia. MHC II deficiency was caused by an RFXANK-mutation and treated successfully by 4/6 mismatched unrelated CBT after a myeloablative conditioning regimen based on anti-thymocyte globulin, busulfane, fludarabine, and cyclophosphamide. At present, our patient is well with full immune reconstitution 3(4/12) yr after CBT. CB may represent an alternative source of stem cells for children with MHC class II deficiency without a suitable donor., (© 2010 John Wiley & Sons A/S.)

Children with primary immunodeficiency diseases, particularly those less than 1 year of age, experience significant toxicity after hematopoietic stem cell transplantation, with busulfan- or melphalan-based conditioning. Treosulfan causes less veno-occlusive disease than busulfan and does not require pharmacokinetic monitoring. We report its use in 70 children. Children received 42 g/m(2) or 36 g/m(2) with cyclophosphamide 200 mg/kg (n = 30) or fludarabine 150 mg/m(2) (n = 40), with alemtuzumab in most. Median age at transplantation was 8.5 months (range, 1.2-175 months); 46 (66%) patients were 12 months of age or younger. Donors were as follows: matched sibling donor, 8; matched family donor, 13; haploidentical, 4; and unrelated, 45. Median follow-up was 19 months (range, 1-47 months). Overall survival was 81%, equivalent in those age less or greater than 1 year. Skin toxicity was common. Veno-occlusive disease occurred twice with cyclophosphamide. Eighteen patients (26%) had graft-versus-host disease, and only 7 (10%) greater than grade 2. Two patients rejected; 24 of 42 more than 1 year after transplantation had 100% donor chimerism. The remainder had stable mixed chimerism. T-cell chimerism was significantly better with fludarabine. Long-term follow-up is required, but in combination with fludarabine, treosulfan is a good choice of conditioning for hematopoietic stem cell transplantation in primary immunodeficiency disease.

Background: Second stem cell transplantation (SCT) is usually associated with high morbidity and mortality and the data on its outcome in pediatric patients with non-malignant disorders are scarce., Patients and Methods: We present 30 children with non-malignant conditions who underwent second SCT at our institution for graft failure after the first SCT; 20 had a non-malignant hematological disorder and 10 had an immune deficiency disorder. Median age at the second SCT was 6.1 years (range, 0.4-13 years) and median time from the first SCT to the second SCT was 6.2 months (range, 1.2-96 months)., Results: Twenty patients (70%) engrafted; severe acute GVHD developed in four patients (13%), and chronic GVHD developed in two patients of those at risk (10%). Thirteen deaths occurred and nine were considered treatment related. The 5-year overall (OS) and event free survival (EFS) for all patients were 53% and 47% respectively. The interval between the two transplants seemed to affect the outcome; patients who had the second SCT ≥ 6 months from the first SCT had better survival; the 5-year OS for the two groups (<6 months and ≥ 6 months) respectively were 30% and 74% (P = 0.004), and the 5-year EFS were 27% and 66% (P = 0.004). The underlying disease did not affect the outcome nor did the use of radiation in the conditioning regimen for the second SCT., Conclusions: Second SCT for graft failure should be considered for children with non-malignant hematological and immune deficiency disorders., (Copyright © 2010 Wiley-Liss, Inc.)

Patients with some hereditary nephropathies-including autosomal dominant polycystic kidney disease (ADPKD), Fabry disease and Alport syndrome-can progress to end-stage renal disease (ESRD) and are candidates for kidney transplantation. When considering whether a potential living donor is appropriate for a particular patient, clinicians should be aware of the increased risk of adverse outcomes for the donor and the recipient. Renal transplantation from a living related donor is not contraindicated in most nephropathies that have an autosomal recessive mode of inheritance (for example, autosomal recessive polycystic kidney disease and cystinosis). Renal transplant recipients with ADPKD, however, should only receive a kidney from a related donor if the disease has been excluded in the donor by imaging and/or genetic testing. Potential living related donors for patients with Alport syndrome should be evaluated carefully for the presence of microhematuria and microalbuminuria before a decision is made to perform transplantation, and mothers or heterozygous sisters of affected male recipients with X-linked Alport syndrome should be informed about the possible long-term increased risk of renal dysfunction associated with donation. Most patients with atypical hemolytic uremic syndrome should not receive a kidney transplant from a living donor because there is a high risk of disease recurrence and graft loss.

Major histocompatibility complex class II (MHC II) deficiency is a rare combined immunodeficiency disease. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Between June 1994 and February 2007, 30 children with MHC II deficiency underwent a total of 33 HSCT procedures. Median age at HSCT was 27 months. The stem cell source was unmanipulated bone marrow from HLA-identical related donors in 26 patients, one HLA antigen-mismatched bone marrow in 3 patients, and unrelated umbilical cord blood in 1 patient. Conditioning was with one of 3 myeloablative regimens--regimen A (18 patients): busulfan (Bu), cyclophosphamide (Cy), and etoposide; regimen B (2 patients): Bu, Cy, and antithymocyte globulin (ATG); or regimen C (1 patient): CY and total body irradiation (TBI)--or with a reduced-intensity regimen (12 patients): fludarabine, melphalan, and ATG. The median CD34 cell dose was 8.3 x 10(6)/kg. Twenty patients experienced immune reconstitution and had sustained engraftment ranging from 9% to 100% for lymphoid lines and from 5% to 100% for myeloid lines that were significant to cure the disease. The overall disease-free survival rate was 66% and 76% after HLA-identical HSCT, with a median follow-up of 6.3 years, which is higher than previously reported. In HLA-identical transplant recipients, reliable donor stem cell engraftment and immune reconstitution were achieved through myeloablative or reduced-intensity conditioning. Further studies and long-term follow-up are needed to determine the appropriate conditioning regimen., (Copyright 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Primary immune deficiencies (PIDs) are rare diseases, and most are lethal without appropriate intervention. Hematopoietic cell transplantation (HCT) can cure the majority of patients, but most lack a suitable matched related donor. Alternative donor stem cells (mismatched related donor bone marrow, unrelated donor bone marrow, and unrelated donor umbilical cord blood [UCB]) are therefore frequently required. Published data comparing outcomes after alternative donor transplant for PID are scarce. The outcomes and potential advantage and disadvantages of each alternative stem cell source are discussed in this chapter. Although there are insufficient prospective data to make meaningful comparisons between the alternative stem cell sources, the results presented here demonstrate clearly that the use of UCB transplantation for PID is a viable option and may be advantageous in many situations., ((c) 2010 Elsevier Inc. All rights reserved.)

More than 20 North American academic centers account for the majority of hematopoietic stem cell transplantation (HCT) procedures for primary immunodeficiency diseases (PIDs), with smaller numbers performed at additional sites. Given the importance of a timely diagnosis of these rare diseases and the diversity of practice sites, there is a need for guidance as to best practices in management of patients with PIDs before, during, and in follow-up for definitive treatment. In this conference report of immune deficiency experts and HCT physicians who care for patients with PIDs, we present expert guidance for (1) PID diagnoses that are indications for HCT, including severe combined immunodeficiency disease (SCID), combined immunodeficiency disease, and other non-SCID diseases; (2) the critical importance of a high degree of suspicion of the primary care physician and timeliness of diagnosis for PIDs; (3) the need for rapid referral to an immune deficiency expert, center with experience in HCT, or both for patients with PIDs; (4) medical management of a child with suspicion of SCID/combined immunodeficiency disease while confirming the diagnosis, including infectious disease management and workup; (5) the posttransplantation follow-up visit schedule; (6) antimicrobial prophylaxis after transplantation, including gamma globulin administration; and (7) important indications for return to the transplantation center after discharge. Finally, we discuss the role of high-quality databases in treatment of PIDs and HCT as an element of the infrastructure that will be needed for productive multicenter clinical trials in these rare diseases.

We reported that complement (C) becomes activated and cleaved in bone marrow during preconditioning for hematopoietic transplantation and the third C component (C3) cleavage fragments, C3a and (desArg)C3a, increase responsiveness of hematopoietic stem/progenitor cells (HSPCs) to stromal-derived factor-1 (SDF-1). We also showed that this homing-promoting effect is not C3a receptor (C3aR) dependent. Herein, we report our new observation that transplantation of C3aR(-/-) HSPCs into lethally irradiated recipients results in: (1) approximately 5-7 day delay in recovery of platelets and leukocytes; (2) decrease in formation of day 12 colony-forming units-spleen; and (3) decrease in the number of donor-derived CFU-granulocyte-macrophage progenitors detectable in the bone marrow cavities at day 16 after transplantation. In agreement with the murine data, blockage of C3aR on human umbilical cord blood CD34(+) cells by C3aR antagonist SB290157 impairs their engraftment in non-obese diabetic/severe combined immunodeficient mice. However, HSPCs from C3aR(-/-) mice stimulated by C3a still better responded to SDF-1 gradient, after exposure to C3a, they secrete less matrix metalloprotease-9 and show impaired adhesion to stroma cells. We conclude that C3a, in addition to enhancing responsiveness of HSPCs to SDF-1 gradient in a C3aR independent manner, may also directly modulate HSPC homing by augmenting C3aR-mediated secretion of matrix metalloprotease-9 and cell adhesion.

T-cell development follows a defined set of stage-specific differentiation steps. However, molecular and cellular events occurring at early stages of human T-cell development remain to be fully elucidated. To address this, human umbilical cord blood (UCB) hematopoietic stem cells (HSCs) were induced to differentiate to the T lineage in OP9-DL1 cocultures. A developmental program involving a sequential and temporally discrete expression of key differentiation markers was revealed. Quantitative clonal analyses demonstrated that CD34(+)CD38(-) and CD34(+)CD38(lo) subsets of UCB contain a similarly high T-lineage progenitor frequency, whereas the frequency in CD34(+)CD38(+/hi) cells was 5-fold lower. Delta-like/Notch-induced signals increased the T-cell progenitor frequency of CD34(+)CD38(-/lo) cells differentiated on OP9-DL1, and 2 distinct progenitor subsets, CD34(+)CD45RA(+)CD7(++)CD5(-)CD1a(-) (proT1) and CD34(+)CD45RA(+)CD7(++)CD5(+)CD1a(-) (proT2), were identified and their thymus engrafting capacity was examined, with proT2 cells showing a 3-fold enhanced reconstituting capacity compared with the proT1 subset. Furthermore, in vitro-generated CD34(+)CD7(++) progenitors effectively engrafted the thymus of immunodeficient mice, which was enhanced by the addition of an IL-7/IL-7 antibody complex. Taken together, the identification of T-progenitor subsets readily generated in vitro may offer important avenues to improve cellular-based immune-reconstitution approaches.

Hypomorphic mutations in nuclear factor kappa B essential modulator (NEMO) cause X-linked ectodermal dysplasia with immunodeficiency (X-ED-ID). Clinical manifestations in boys with X-ED-ID apart from ectodermal dysplasia and immunodeficiency include osteopetrosis, lymphedema, and colitis. Further description of atypical findings in this disorder is needed. Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is in its infancy, and how or whether non-immune manifestations of defective NEMO function are impacted by HSCT is poorly described. We report an interesting case of a boy with NEMO mutation who had symptoms reminiscent of Omenn's syndrome and small intestinal villous atrophy with features reminiscent of tufting enteropathy. We describe his treatment course as well as reconstitution of immune function and correction of osteopetrosis post-HSCT, and review the cases of allogeneic HSCT reported to date in the literature.

We retrospectively analyzed the transplantation outcomes of 31 patients with primary immunodeficiency diseases treated at our center (All Children's Hospital, University of South Florida) since its inception in 1986. The primary immune diseases included severe combined immunodeficiency, Wiscott-Aldrich syndrome, X-linked hyper-IgM syndrome, and chronic granulomatous disease. The age of the patient's at the time of transplant ranged from 1 month to 19 years, and conditioning regimens varied based on the patients underlying disease. In 23 patients, the graft source was bone marrow, 4 patients received umbilical cord blood grafts and 4 patients received peripheral blood stem cell grafts. Better survival rates were observed in those patients transplanted at a younger age and free of infections, demonstrating that transplantation at an early age before significant infections, autoimmune manifestation and malignant transformation have occurred is beneficial.

Gene therapy with hematopoietic stem cells (HSC) is an attractive therapeutic strategy for several forms of primary immunodeficiencies. Current approaches are based on ex vivo gene transfer of the therapeutic gene into autologous HSC by vector-mediated gene transfer. In the past decade, substantial progress has been achieved in the treatment of severe combined immundeficiencies (SCID)-X1, adenosine deaminase (ADA)-deficient SCID, and chronic granulomatous disease (CGD). Results of the SCID gene therapy trials have shown long-term restoration of immune competence and clinical benefit in over 30 patients. The inclusion of reduced-dose conditioning in the ADA-SCID has allowed the engraftment of multipotent gene-corrected HSC at substantial level. In the CGD trial significant engraftment and transgene expression were observed, but the therapeutic effect was transient. The occurrence of adverse events related to insertional mutagenesis in the SCID-X1 and CGD trial has highlighted the limitations of current retroviral vector technology. For future applications the risk-benefit evaluation should include the type of vector employed, the disease background and the nature of the transgene. The use of self-inactivating lentiviral vectors will provide significant advantages in terms of natural gene regulation and reduction in the potential for adverse mutagenic events. Following recent advances in preclinical studies, lentiviral vectors are now being translated into new clinical approaches, such as Wiskott-Aldrich Syndrome.

Autoimmune manifestations are increasingly being recognized as a component of several forms of primary immunodeficiencies (PID). Defects in purging of self-reactive T and B cells, impaired Fas-mediated apoptosis, abnormalities in development and/or function of regulatory T cells, and persistence of immune activation as a result of inability to clear infections have been shown to account for this association. Among autoimmune manifestations in patients with PID, cytopenias are particularly common. Up to 80% of patients with autoimmune lymphoproliferative syndrome (ALPS) have autoantibodies, and autoimmune hemolytic anemia and immune thrombocytopenia have been reported in 23% and 51% of ALPS patients, and may even mark the onset of the disease. ALPS-associated cytopenias are often refractory to conventional treatment and represent a therapeutic challenge. Autoimmune manifestations occur in 22% to 48% of patients with common variable immunodeficiencies (CVIDs), and are more frequent among CVID patients with splenomegaly and granulomatous disease. Finally, autoimmune cytopenias have been reported also in patients with combined immunodeficiency. In particular, autoimmune hemolytic anemia is very common among infants with nucleoside phosphorylase deficiency. While immune suppression may be beneficial in these cases, full resolution of the autoimmune manifestations ultimately depends on immune reconstitution, which is typically provided by hematopoietic cell transplantation.

Objective: To study the diagnosis and treatment of pulmonary aspergillosis in patients without immunodeficiency., Method: Pulmonary aspergillosis in 15 patients without immunodeficiency was reviewed., Results: Twelve of the patients had underlying lung diseases (lung cancer), 2 showed masses in the lung by radiography and CT halo, and 1 had aspergilloma within the left main bronchus. The diagnosis of intra-cavitary aspergilloma had been made in all the patients with lung cancer before surgery. Only 3 cases were confirmed by fungal examination before surgery. Thirteen patients received surgical removal of the lesions, and the post-operative recovery was uneventful. Antifungal therapy and open drainage were administered in 1 patient with pleural residual cavity infection, but the treatment failed. Anti-cancer therapy alone was given in 1 patient. Sudden death occurred in another patient., Conclusion: In suspected cases of aspergillosis, CT halo sign, histology examination are helpful for the diagnosis. Aspergilloma complicated with underlying lung diseases and mass lesions can be cured by surgery.

The sensory nerve is highly involved in lower extremity wound healing. In diabetic and vascular diseases, impaired nerve function and blood flow delay wound healing. Tissue regeneration using adult stem cells is a targeted therapeutic modality in disorders of nerve and blood supply. Effective delivery using an autologous vascularized fascial flap as a vehicle of stem cells leads to severed sensory nerve recovery, local tissue blood flow, and wound healing. Human MSCs (hMSCs) were transfected with green fluorescent protein (GFP) cDNA and tested for efficiency and proliferation in vitro. The nude rat model with femoral vessel and saphenous nerve severance and ligation was wrapped with a vascularized epigastric flap for GFP-hMSC, fibroblast growth factor-2 (FGF-2), or a combination of both after 2 weeks. Maximum nerve conduction velocity recovered to 70% of the presurgical level in the GFP-hMSC- and FGF-2-treated group at 2 weeks. Blood flow and nerve conduction velocity were positively correlated at 1 week. Wound healing in the ipsilateral paw had significantly improved by 1 week. Histologically, blood vessels and nerves are very organized, and regenerated neuron immunoreactivity of GAP-43 and a nerve regrowth marker of S-100 were remarkable in the human GFP (hGFP)-hMSC and FGF-2-treated group at 2 weeks; therefore, sensory nerve regeneration, blood flow, and wound healing were improved by the administration of stem cells and FGF-2 via a vascularized flap. This may be implicated in clinical denervated and reduced circulation tissue wound healing.

Immunodeficiency-centromeric instability-facial dysmorphism syndrome, characterized by variable immunodeficiency, centromeric instability, and facial anomalies caused by epigenetic dysregulation resulting in hypomethylation, is caused in many patients by mutations in DNMT3B, a DNA methyltransferase gene; associated infections are a major cause of serious sequelae and death. Hematopoietic stem cell transplantation may improve the clinical course in immunodeficiency-centromeric instability-facial dysmorphism syndrome. We report 3 unrelated patients with persistent infections and intestinal complications who successfully underwent hematopoietic stem cell transplantation after nonmyeloablative or myeloablative conditioning regimens using HLA-matched donors. In all cases, donor chimerism led to resolution of intestinal complications and infections, growth improvement, and correction of the immunodeficiency.

GS is an uncommon autosomal recessive disorder characterized by pigmentary dilution of the skin and hair and in most patients by abnormal regulation of the immune system. Childhood melanoma is rare in the pediatric population. The best prognosis is achieved with early diagnosis and definitive surgical excision of melanoma. We report a case of a patient with GS type II and melanoma who was successfully treated by allogeneic bone marrow transplantation and surgical excision of the melanoma.