Haematopoietic stem cell transplant for hyper-IgM syndrome due to CD40 defects: a single-centre experience.

Hyper-IgM syndrome due to CD40 deficiency (HIGM3) is a rare disease with only a few reported cases of haematopoietic stem cell transplantation (HSCT). In retrospective study, we reviewed all patients with HIGM3 who underwent HSCT at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, between 2008 and 2013. Six patients were identified. Three male and three female patients from three families. The median age of diagnosis was 13 months (range, 1-28 months). All lacked CD40 expression on B cells by flow cytometry. The median time from diagnosis to transplantation was 8.5 months (range, 1-17 months). For all patients, the donors were HLA-identical siblings, with the exception of one patient for whom the donor was a sibling with one antigen mismatch. The conditioning regimen was busulfan and cyclophosphamide in five patients and busulfan, cyclophosphamide and antithymocyte globulin in one patient. For GVHD prophylaxis, cyclosporine and methotrexate was used. All patients engrafted. The survival rate was 100%, with a median follow-up of 54 months (range, 30-116 months). One patient developed acute GVHD. All patients showed complete immune recovery with positive CD40 expression on B cells and discontinued IVIG replacement. Our study shows that HSCT is potentially effective at curing the disease.

The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management.

Hyper Immunoglobulin M syndrome (HIGM) is a rare primary immunodeficiency disorder characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM. Various X-linked and autosomal recessive/dominant mutations have been reported as the underlying cause of the disease. Based on the underlying genetic defect, the affected patients present a variety of clinical manifestations including pulmonary and gastrointestinal complications, autoimmune disorders, hematologic abnormalities, lymphoproliferation and malignancies which could be controlled by multiple relevant therapeutic approaches. Herein, the epidemiology, pathogenesis, clinical manifestations, diagnosis, management, prognosis and treatment in patients with HIGM syndrome have been reviewed.

Prospects for modulating the CD40/CD40L pathway in the therapy of the hyper-IgM syndrome.

The critical role of the CD40/CD40L pathway in B-cell proliferation, immunoglobulin (Ig) isotype switching and germinal center formation has been studied and described extensively in previous literature. Interruption of the CD40/CD40L signal causes hyper-IgM (HIGM) syndrome, which has been classified and recognized as a group of rare inherited immune deficiency disorders. Defects in CD40 and CD40L interactions or in downstream signaling molecules, including activation-induced cytidine deaminase, uracyl-DNA-glycosylase, NF-κB and DNA repair enzymes, result in an increased level of serum IgM and a significantly decreased or absent level of IgA, IgG and IgE that is accompanied by severe recurrent infections and autoimmune diseases. Many genetic defects in HIGM have been identified and, as a result, it is possible for patients to be definitively diagnosed by gene sequencing and to delineate the immunological features of the patients. Modifying the CD40/CD40L signaling pathway may offer the possibility of restoring the normal serum Ab production and curing the immunodeficiency. Hematopoietic stem cell transplantation has achieved a high rate of success using a sibling donor. In addition, successful examples of treating other immunodeficiencies using gene therapy indicated that there was a possibility of eradicating HIGM with this approach. In this review, we summarize the current drugs and a variety of therapeutic approaches for the treatment of the HIGM syndrome by interfering with the defective CD40/CD40L pathway.

Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

Hyper IgM Syndrome with low IgM and thrombocytosis: an unusual case of immunodeficiency.

We report a 5 years old male child with low serum IgG, IgA and IgM levels, who presented with recurrent perianal and oral ulcers, intermittent fever, and protracted diarrhea. Despite the lack of typical respiratory symptoms, low serum IgM level and persistent thrombocytosis, an X-linked hyper-IgM syndrome (X-HIGM) was considered. Laboratory investigations revealed a diagnosis of hyper-IgM syndrome caused by CD40L deficiency.

Hyper IgM Syndrome: a Report from the USIDNET Registry.

PURPOSE: The United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM). METHODS: The USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality. RESULTS: Fifty-two physicians entered data from 145 patients of ages 2 months to 62 years (median 12 years); 131 were males. Using patients' age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40 % had a normal serum IgM and 15 %, normal IgA. Infections were reported for 91 %, with pulmonary, ear, and sinus infections being the most common. 42 % had Pneumocystis jirovecii pneumonia; 6 % had Cryptosporidium. 41 % had neutropenia. 78 % experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14 years). CONCLUSIONS: Analysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.

First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes.

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.

Successful haploidentical PBSCT with subsequent T-cell addbacks in a boy with HyperIgM syndrome presenting as severe congenital neutropenia.

HIGM syndrome is a group of primary immunodeficiency disorders characterized by recurrent bacterial and opportunistic infections; it is also associated with normal to elevated serum IgM levels and a concomitant deficiency of IgG, IgA, and IgE. In this report, we give account of a boy with X-linked HIGM and a novel Y172C mutation within his CD40LG gene. He presented with severe neutropenia as the dominating symptom. His bone marrow showed maturation arrest at the promyelocyte/myelocyte stage, typical of congenital neutropenia. This boy suffered from life-threatening infections and required high doses of rhG-CSF, and a haploidentical PBSCT was also successfully performed, thus leading to reconstitution of CD40L expression on activated CD4+ T cells (as assessed with flow cytometry six months after the procedure). Two low-dose T-cell addbacks were required to re-establish full donor chimerism and clear CMV reactivation. The report demonstrates that in select cases, alternative donor allogeneic HSCT supported by DLI may be effective in correcting the defect in X-linked HIGM, and HSCT in HIGM children is not necessarily limited to matched sibling donor transplantation.

Hyper IgM syndrome presenting as chronic suppurative lung disease.

The Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders resulting in defects of immunoglobulin class switch recombination. Affected patients show humoral immunodeficiency and high susceptibility to opportunistic infections. Elevated serum IgM levels are the hallmark of the disease, even though in few rare cases they may be in the normal range. Hyper IgM is associated with low to undetectable levels of serum IgG, IgA, and IgE. In some cases, alterations in different genes may be identified. Mutations in five genes have so far been associated to the disease, which can be inherited with an X-linked (CD40 ligand, and nuclear factor-kB essential modulator defects) or an autosomal recessive (CD40, activation-induced cytidine deaminase, and uracil-DNA glycosylase mutation) pattern. The patient herein described presented with recurrent upper and lower respiratory infections and evidence of suppurative lung disease at the conventional chest imaging. The presence of low serum IgG and IgA levels, elevated IgM levels, and a marked reduction of in vivo switched memory B cells led to a clinical and functional diagnosis of HIGM although the genetic cause was not identified.

Generalized verrucosis: a review of the associated diseases, evaluation, and treatments.

Generalized verrucosis has been described in the past as synonymous with epidermodysplasia verruciformis. It has been shown, however, that epidermodysplasia verruciformis and other genetic or immunodeficiency diseases are just a subset of diffuse infections with human papillomavirus termed "generalized verrucosis." This article defines generalized verrucosis and distinct diseases associated with generalized warts. The indications for histopathologic testing, human papillomavirus typing, and other laboratory analyses and potential treatment options are discussed.

Update on the hyper immunoglobulin M syndromes.

The Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders resulting in defects of immunoglobulin class switch recombination (CSR), with or without defects of somatic hypermutation (SHM). They can be classified as defects of signalling through CD40 causing both a humoral immunodeficiency and a susceptibility to opportunistic infections, or intrinsic defects in B cells of the mechanism of CSR resulting in a pure humoral immunodeficiency. A HIGM picture can also be seen as part of generalized defects of DNA repair and in antibody deficiency syndromes, such as common variable immunodeficiency. CD40 signalling defects may require corrective therapy with bone marrow transplantation. Gene therapy, a potential curative approach in the future, currently remains a distant prospect. Those with a defective CSR mechanism generally do well on immunoglobulin replacement therapy. Complications may include autoimmunity, lymphoid hyperplasia and, in some cases, a predisposition to lymphoid malignancy.

Cryptosporidium infection in patients with primary immunodeficiencies.

BACKGROUND: Cryptosporidium species infection is usually self-limited in immunocompetent populations, but can be severe and life-threatening among immunocompromised individuals, particularly in patients with AIDS and in these patients with primary immunodeficiencies (PIDs). PATIENTS AND METHODS: A group of 5 patients with genetically confirmed hyper-IgM syndrome type 1 (XHIM) and one patient with primary CD4 lymphopenia were enrolled in the study. At least 2 stool samples and a bile sample in one patient were examined for Cryptosporidium oocysts by a modified Ziehl-Neelsen technique, by immunofluorescence assay using a commercial kit, as well as by molecular analysis followed by genotyping. Immunological status at the time of PID diagnosis and the complex picture of disease are presented. RESULTS: Chronic cryptosporidiosis was confirmed in 3 patients with XHIM and in one patient with primary CD4 lymphopenia. Molecular diagnosis showed the presence of C parvum, C hominis, and C meleagridis in analyzed specimens. CONCLUSIONS: Cryptosporidium infection with serious clinical symptoms observed in patients with hyper-IgM syndrome calls for regular, repeated screening in this group of patients.

Nonmyeloablative stem cell transplantation for nonmalignant diseases in children with severe organ dysfunction.

Allogeneic stem cell transplantation (SCT) can cure several nonmalignant diseases in children. However, patients frequently have significant morbidity before transplantation and there is a high transplant-related mortality. Nonmyeloablative SCT might achieve the same goals but with less toxicity. Six pediatric patients with nonmalignant diseases underwent nonmyeloablative SCT from different stem cell sources. All patients were conditioned with fludarabine/melphalan with additional anti-thymocyte globulin for haploidentical grafts and prophylaxis for graft-versus-host disease (GVHD) consisting of tacrolimus and methotrexate with additional prednisolone for haploidentical grafts. Hematopoietic stem cells were neither T-cell depleted nor purged. All patients had severe organ dysfunction that precluded transplantation with conventional conditioning. Five of the six are alive and in complete disease resolution at a median of 19 months (range, 7-53 months) after SCT. One patient died of bacteremia before engraftment. Three patients achieved complete donor chimerism. Two patients remained stable mixed chimerism. Short-term toxicities were minimal. Acute and chronic GVHD were not seen. In summary, the fludarabine-based nonmyeloablative regimen followed by SCT provides a good approach for children with nonmalignant diseases. Even patients with severe organ dysfunctions had adequate engraftment with acceptable toxicities.