Case Report: Unmanipulated Matched Sibling Donor Hematopoietic Cell Transplantation In TBX1 Congenital Athymia: A Lifesaving Therapeutic Approach When Facing a Systemic Viral Infection.

Congenital athymia can present with severe T cell lymphopenia (TCL) in the newborn period, which can be detected by decreased T cell receptor excision circles (TRECs) on newborn screening (NBS). The most common thymic stromal defect causing selective TCL is 22q11.2 deletion syndrome (22q11.2DS). T-box transcription factor 1 (TBX1), present on chromosome 22, is responsible for thymic epithelial development. Single variants in TBX1 causing haploinsufficiency cause a clinical syndrome that mimics 22q11.2DS. Definitive therapy for congenital athymia is allogeneic thymic transplantation. However, universal availability of such therapy is limited. We present a patient with early diagnosis of congenital athymia due to TBX1 haploinsufficiency. While evaluating for thymic transplantation, she developed Omenn Syndrome (OS) and life-threatening adenoviremia. Despite treatment with anti-virals and cytotoxic T lymphocytes (CTLs), life threatening adenoviremia persisted. Given the imminent need for rapid establishment of T cell immunity and viral clearance, the patient underwent an unmanipulated matched sibling donor (MSD) hematopoietic cell transplant (HCT), ultimately achieving post-thymic donor-derived engraftment, viral clearance, and immune reconstitution. This case illustrates that because of the slower immune recovery that occurs following thymus transplantation and the restricted availability of thymus transplantation globally, clinicians may consider CTL therapy and HCT to treat congenital athymia patients with severe infections.

Successful Salvage Haploidentical Alpha-Beta T Cell-Depleted Stem Cell Transplantation After Busulfan-Based Myeloablation in a Patient With IPEX Syndrome: A Case Report.

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/m2, and Grafalon (Neovii Pharmaceuticals, Rapperswil, Switzerland). The T-cell depletion product contained 15.06 x 106 CD34+ cells per kilogram body weight (BW) and 4.19 x 105 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.

Successful transcarotid transcatheter aortic valve replacement in a 34-kg patient with Schimke immuno-osseous dysplasia and severe biscuspid aortic stenosis.

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.

Characteristics of Good's Syndrome in China: A Systematic Review.

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.

Hematopoietic Stem Cell Transplant for Primary Immunodeficiency Diseases: A Single-Center Experience.

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.

Cartilage-hair hypoplasia associated with isolated hypoganglionosis: A case report.

Cartilage-hair hypoplasia is a rare metaphyseal chondrodysplasia characterized by diverse clinical manifestations and a high incidence of Hirschsprung disease. We present a male patient with cartilage-hair hypoplasia associated with severe intestinal obstruction. Genetic analysis of ribonuclease mitochondrial RNA-processing complex gene identified compound heterozygous mutations consisted with previously reported mutations: n.-14_3dupGAAGCTGAGGACGTGGT and n.183G > T. First, we considered that intestinal obstruction was due to an extensive type of Hirschsprung disease, but it was later confirmed as isolated hypoganglionosis. Isolated hypoganglionosis is rare and its therapeutic strategies are not well established. In cases of cartilage-hair hypoplasia associated with severe intestinal obstruction, the differential diagnosis of not only Hirschsprung disease, but also isolated hypoganglionosis, should be considered.

Rare Presentations of Epstein-Barr Virus--Associated Smooth Muscle Tumor in Children.

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.

Internal carotid artery surgical revascularization in a pediatric patient with Schimke immuno-osseous dysplasia.

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.

[Survival analysis of hematopoietic stem cell transplantation in children with primary immunodeficiency in Spain]. / Análisis de la supervivencia de los niños con inmunodeficiencias primarias que han recibido un trasplante de progenitores hematopoyéticos en España.

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.

Intestinal transplantation in children with multiple intestinal atresias and immunodeficiency.

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.

Alternative donor SCT for the treatment of MHC class II deficiency.

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.

Neutropenia in primary immunodeficiency.

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.