hyper-IgM Syndrome Research Articles

HYPER IGM SYNDROME: ABOUT 2 CASES

Hyper-IgM syndrome is a rare combined immune deficiency linked to a mutation most frequently found in CD40.The diagnosis is usually made in the presence of recurrent infections, particularly pulmonary, digestive and others. Through to the dosage of lymphocyte subpopulations and after elimination of other differential diagnoses, the diagnosis of hyper-IgM syndrome can be confirmed. The objective of this work is to emphasize the presence of the diagnosis of hyper-IgM syndrome, the interest to search for it to avoid the repercussions on the growth especially and the survival. Results: We reported the case of 2 patients the first one a 4 years old patient diagnosed at the stage of complication by a DDB which presented infections essentially pulmonary with repetition in front of this table a dosage of immunoglobulins was required which was in favor of syndrome of hyper-IgM. And a second one the 10 years old, this patient who had as history a brother who died of the same symptomatology, repeated ear infections, digestive infections such as gastritis with HP a zona the immunoglobulin dosage objectified a hyper-IgM syndrome. Both patients were put under immunoglobulins with good evolution. Conclusion: The hyper IgM syndrome is still rare but should be suspected as any immune deficiency in front of repeated infections. We have illustrated in this work two cases that have evolved well with treatment and how certain complications can be avoided by early diagnosis.

Hyper IgM Syndrome with a Novel Mutation in the AICDA Gene: Easy to Diagnose

Hyper IgM Syndrome with a Novel Mutation in the AICDA Gene: Easy to Diagnose

Autosomal Dominant Immune Dysfunction in Five Family Members with Truncating Variant in the Activation Induced Cytidine Deaminase (AICDA) Gene

Activation induced cytidine deaminase (AICDA) is an DNA editing enzyme specifically expressed in germinal center-like B-cells that is involved in somatic hypermutation and class-switch recombination. Bi-allelic defects in AICDA are a recognized cause of autosomal recessive hyper-IgM syndrome. However, truncating variants in AICDA have been rarely described as an autosomal dominant cause of hyper-IgM syndrome.

304 - A Case of Pneumocystis pneumonia in a patient with suspected hyper IGM syndrome

304 - A Case of Pneumocystis pneumonia in a patient with suspected hyper IGM syndrome

Respiratory infections in X-linked hyper-IgM syndrome with CD40LG mutation: a case series of seven children in China

BackgroundX-linked hyper-immunoglobulin M (XHIGM), a primary immunodeficiency syndrome caused by mutations in the CD40 ligand gene(CD40LG), presents with recurrent respiratory infections in pediatric patients. We aimed to evaluate the spectrum of clinical features and respiratory pathogens in pediatric patients with XHIGM in China.MethodsWe retrospectively reviewed seven pediatric patients who were diagnosed with XHIGM and received follow-up treatment at the Guangzhou Women and Children’s Medical Center between January 2010 and January 2021. We determined their clinical characteristics, causative pathogens, and prognosis by performing peripheral immunological and genetic tests.ResultsThere were seven boys with age ranging from 4–20 months (median age, 13 months). Four of the seven respiratory infections were caused by Talaromyces marneffei(T. marneffei). Two patients had viral infections caused by cytomegalovirus (CMV) and human adenovirus respectively. One patient had a mixed infection caused by Pneumocystis carinii and CMV. Except for one child who died of respiratory failure, one patient received hematopoietic stem cell transplantation (HSCT) and recovered well, the other five patients survived with regular infusions of intravenous immunoglobulin (IVIg) during the follow-up period. Six patients had reduced antibody levels, especially IgG, IgA, and IgE levels. Increased serum IgM levels were detected in four cases, and three cases presented normal IgM levels at onset. All children were diagnosed with XHIGM with CD40LG variation. Three novel mutations were identified in the present study.ConclusionsOur study suggests that respiratory infections usually begin within 2 years old, fungi and viruses are important pathogens causing respiratory infections in children with XHIGM. In endemic areas, T. marneffei is the common pathogen of respiratory tract infection in children with the disease.

HYPEREOSINOPHILIA LEADS TO PRIMARY IMMUNODEFICIENCY DIAGNOSIS

<h3>Introduction</h3> In the absence of prior infections, idiopathic hypereosinophilia should prompt consideration of a primary immunodeficiency (PID). <h3>Case Description</h3> We present an 8-month-old previously healthy male admitted for persistent hypoxia and suspected bronchiolitis. This patient did not present with fever, weight loss, adenopathy, chronic rash, GI symptoms, or medication use. There was no travel history, sick contacts, or pertinent family history. Laboratory results were significant for negative viral panel and absolute eosinophil count > 34,000. Chest CT showed scattered ground glass opacities without cavitation or bronchiectasis. Bone marrow biopsy was negative for malignancy. T cell (beta) and B cell gene rearrangement studies were negative, as well as FIP1L1-PDFGFRA, FISH studies, and myelodysplastic panels. Cardiac workup, infectious/parasitic tests, tryptase, and B12 levels were normal. The patient was started on systemic steroids with dramatically improved hypereosinophilia. Workup revealed low IgG/IgA levels, with normal IgM. Vaccine titers to tetanus, diphtheria and Hib were absent, despite up-to-date immunizations. Genetic testing revealed a pathogenic mutation in the CD40L gene, indicating X-linked hyper IgM syndrome (HIGM). Pneumocystic jirovecii was confirmed with bronchoscopy. TMP-SMX treatment allowed for weaning off steroids. The patient was started on IVIG and is awaiting bone marrow transplant. <h3>Discussion</h3> HIGM often presents in infancy with increased susceptibility to sinopulmonary infections. Unlike other PIDs with clinical manifestations of atopy, HIGM does not often present with eosinophilia. Opportunistic infections, including PJP, may drive eosinophil production through antigenic stimulation of TH2 cells. This case illustrates the importance of immunologic considerations in patients with unexplained hypereosinophilia, even without a significant infectious history.

PIK3CD, IMMUNODEFICIENCY, MUTATIONS, GAIN-OF-FUNCTION

<h3>Introduction</h3> PIK3CD-GOF is an inborn error of immunity (IEI) with variable phenotypic characteristics even with the same variant. Lymphoproliferation, autoimmunity, and dysgammaglobulinemia may lead to suspicion of the diagnosis. Here we present four unrelated Mexican patients from nonconsanguineous families with a diagnosis of PIK3CD-GOF: <h3>Case Description</h3> (1) A 2-year-old female with a history of very early-onset inflammatory bowel disease (VEO-IBD) at 8 months, late omphalorrhexis, hyper-IgA, hyperleukocytosis, and low B and NK cells. (2) A 12-year-old male with a family history of lymphoma. Sepsis due to Listeria, periodontal abscess, systemic lupus erythematosus, Sjögren's syndrome, bronchiectasis, hepatosplenomegaly, lymphadenopathy, autoimmune hemolytic anemia, chronic EBV/CMV infection; leukocytosis and hyper-IgM. (3) A 2-year-old male with chronic rhinosinusitis, chronic suppurative otitis media, diarrhea; enlarged lymph nodes, splenomegaly, thrombocytopenia, low IgG and IgA and normal IgM with poor antibody response to pneumococcal vaccine. Hyper-IgM syndrome was suspected so he underwent successful stem cell transplantation. (4) An 11-year-old male child whose both parents were HIV+. Presented at 4-months with episodic fever and recurrent respiratory infections, bronchiectasis, mild mental retardation elevated IgM, low IgG, lymphopenia, and decreased lymphocyte proliferation. HIV were suspected in this patient. <h3>Discussion</h3> We identified heterozygous pathogenic variants related to PIK3CD: 3 of them in exon 24 (p.Glu1021Lys); and a novel variant in exon 7 (p.Ile262Val). PIK3CD-GOF is a combined immunodeficiency disorder (CID) with variable phenotype characteristics even with the same variant. Lymphoproliferation, autoimmunity, and dysgammaglobulinemia may raise suspicion. By behaving like a great simulator, genetic diagnosis is necessary to identify the specific pathogenic variant.

Hematopoietic stem cell Transplantation in Children with very Early Onset Inflammatory Bowel Disease Secondary to Monogenic Disorders of immune-dysregulation.

Background: Very early-onset inflammatory bowel disease (VEOIBD) is defined as IBD in children under six years of age. We present outcome data of hematopoietic stem cell transplantation (HSCT) in the above children. Patients and methods: We performed a retrospective study in children under six years of age who underwent HSCT for VEOIBD with an identified monogenic disorder from December 2012 to December 2020. Results: Of the 25 children included, the underlying diagnosis was IL10R deficiency (n = 4), Wiskott-Aldrich syndrome (n = 4), Leukocyte adhesion defect (n = 4), Hyper IgM syndrome (n = 3), Chronic granulomatous disease (n = 2), and one each with XIAP deficiency, severe congenital neutropenia, Omenn syndrome, Hyper IgE syndrome, Griscelli syndrome, MHC Class II deficiency, LRBA deficiency, and IPEX syndrome. Donors included a matched family donor in 10(40%); a matched unrelated donor in 8 (32%), haploidentical in 7 (28%) (T depleted 16%, T replete with post-transplant cyclophosphamide12%). Conditioning was myeloablative in 84% ofHSCTs. We documented engraftment in 22 (88%) children, primary graft failure in 2 children (8%), mixed chimerism in 6 (24%) children with mortality in 4/6 children. Children with a sustained chimerism of > 95% did not have recurrence of any features of IBD. Overall survival was 64%, with a median follow-up of 55 months. Mixed chimerism was associated with a significantly increased risk of mortality (p-value = 0.001). Conclusions: VEOIBD caused by monogenic disorders can be offered HSCT. Early recognition, optimal supportive care, and complete chimerism are essential components to achieving survival.

A Novel De Novo NFKBIA Missense Mutation Associated to Ectodermal Dysplasia with Dysgammaglobulinemia.

Background: Inborn errors of immunity (IEIs) are comprised of heterogeneous groups of genetic disorders affecting immune function. In this report, a 17-month-old Malay patient suspected of having Hyper IgM syndrome, a type of IEIs, was described. However, the diagnosis of Hyper IgM syndrome was excluded by the normal functional studies and the mild features of ectodermal dysplasia observed from a further clinical phenotype inspection. Methods: Whole-exome sequencing (WES) was performed to unravel the causative mutation in this patient. Results: The variant analysis demonstrated a novel missense mutation in NFKBIA (NM_020529:c.94A > T,NP_065390:p.Ser32Cys) and was predicted as damaging by in silico prediction tools. The NFKBIA gene encodes for IκBα, a member of nuclear factor kappa B (NF-κB) inhibitors, playing an important role in regulating NF-κB activity. The mutation occurred at the six degrons (Asp31-Ser36) in IκBα which were evolutionarily conserved across several species. Prediction analysis suggested that the substitution of Ser32Cys may cause a loss of the phosphorylation site at residue 32 and a gain of the sumoylation site at residue 38, resulting in the alteration of post-translational modifications of IκBα required for NF-κB activation. Conclusion: Our analysis hints that the post-translational modification in the NFKBIA Ser32Cys mutant would alter the signaling pathway of NF-κB. Our findings support the usefulness of WES in diagnosing IEIs and suggest the role of post-translational modification of IκBα.

Exome sequencing contributes to identify comorbidities in a rare case of infant ARDS induced by the CD40LG mutation

BackgroundAcute respiratory distress syndrome (ARDS) causes significant mortality in young children with certain diseases. Early diagnosis and treatment can reduce infant mortality. Here, we report a rare case of exome sequencing in the early diagnosis of immunodeficiency in an infant.Case presentationA four-month-old full-term male infant presented with severe shortness of breath, hypoxemia, and unexplained parenchymal lung lesions. A series of examinations were performed to search for potential culprit viruses but negative results were obtained with the only exception being the rhinovirus that tested positive. The child’s family history revealed he had a brother who died of severe infection at the age of two years. We performed an exome sequencing analysis and a mutation analysis of CD40LG to obtain genetic data on the patient. Besides, we used flow cytometry to measure the CD40LG expression levels of activated T cells. A retrospective review of all the CD40LG mutant-induced X-linked hyper IgM syndromes (XHIGM) had been conducted to assess the differences between clinical and genetic molecular features. Finally, a regular intravenous immunoglobulin (IVIG) regimen led to steady breathing, the correction of hypoxemia, and a progressive improvement of lung CT scans. During follow-up, the patient received an IVIG regimen and his CT images improved. Moreover, his parents took advantage of pre-implantation genetic testing with in vitro fertilization to have a healthy twin offspring who did not carry such a mutation according to the early exome sequencing for the proband. Compared with other CD40LG mutant cases in our center, this proband displayed a normal plasma immunoglobulin level and he should be the youngest infant to have a molecular diagnosis of XHIGM.ConclusionUsually, XHIGM would not be suspected with a normal plasma immunoglobulin concentration. However, as we could not identify a potential comorbidity or risk factor, exome sequencing helps target this patient's real facts. Thus, this case report calls for exome sequencing to be performed in the case of unexplained infections when immunodeficiency is suspected after general immunological tests, especially for cases with a contributive family history among infants as the maternal transfused immunoglobulin might mask immune deficiency.

Targeted Gene Sanger Sequencing Should Remain the First-Tier Genetic Test for Children Suspected to Have the Five Common X-Linked Inborn Errors of Immunity.

To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott–Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.

Utility of targeted next generation sequencing for inborn errors of immunity at a tertiary care centre in North India

Inborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders that include primary immunodeficiency’s and other disorders affecting different aspects of the immune system. Next-Generation Sequencing (NGS) is an essential tool to diagnose IEI. We report our 3-year experience in setting up facilities for NGS for diagnosis of IEI in Chandigarh, North India. We used a targeted, customized gene panel of 44 genes known to result in IEI. Variant analysis was done using Ion Reporter software. The in-house NGS has enabled us to offer genetic diagnoses to patients with IEI at minimal costs. Of 121 patients who were included pathogenic variants were identified in 77 patients. These included patients with Chronic Granulomatous Disease, Severe Combined Immune Deficiency, leukocyte adhesion defect, X-linked agammaglobulinemia, Ataxia Telangiectasia, Hyper-IgE syndrome, Wiskott Aldrich syndrome, Mendelian susceptibility to mycobacterial diseases, Hyper-IgM syndrome, autoimmune lymphoproliferative syndrome, and GATA-2 deficiency. This manuscript discusses the challenges encountered while setting up and running targeted NGS for IEI in our unit. Genetic diagnosis has helped our patients with IEI in genetic counselling, prenatal diagnosis, and accessing appropriate therapeutic options.

Clinical effect of allogeneic hematopoietic stem cell transplantation in children with hyper-IgM syndrome

To evaluate the clinical effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with hyper-IgM syndrome (HIGM). A retrospective analysis was performed on the medical data of 17 children with HIGM who received allo-HSCT. The Kaplan Meier method was used for the survival analysis of the children with HIGM after allo-HSCT. After allo-HSCT, 16 children were diagnosed with sepsis; 14 tested positive for virus within 100 days after allo-HSCT, among whom 11 were positive for Epstein-Barr virus, 7 were positive for cytomegalovirus, and 2 were positive for JC virus; 9 children were found to have invasive fungal disease. There were 6 children with acute graft-versus-host disease and 3 children with chronic graft-versus-host disease. The median follow-up time was about 2 years, and 3 children died in the early stage after allo-HSCT. The children had an overall survival (OS) rate of 82.35%, an event-free survival (EFS) rate of 70.59%, and a disease-free survival (DFS) rate of 76.47%. The univariate analysis showed that the children receiving HLA-matched allo-HSCT had a significantly higher EFS rate than those receiving HLA-mismatched allo-HSCT (P=0.019) and that the children receiving HLA-matched unrelated allo-HSCT had significantly higher OS, EFS, and DFS rates than those receiving HLA-mismatched unrelated allo-HSCT (P<0.05). Compared with the children with fungal infection after allo-HSCT, the children without fungal infection had significantly higher EFS rate (P=0.02) and DFS rate (P=0.04). Allo-HSCT is an effective treatment method for children with HIGM. HLA-matched allo-HSCT and active prevention and treatment of fungal infection and opportunistic infection may help to improve the prognosis of such children.

Mobilization-based chemotherapy-free engraftment of gene-edited human hematopoietic stem cells

SummaryHematopoietic stem/progenitor cell gene therapy (HSPC-GT) is proving successful to treat several genetic diseases. HSPCs are mobilized, harvested, genetically corrected ex vivo, and infused, after the administration of toxic myeloablative conditioning to deplete the bone marrow (BM) for the modified cells. We show that mobilizers create an opportunity for seamless engraftment of exogenous cells, which effectively outcompete those mobilized, to repopulate the depleted BM. The competitive advantage results from the rescue during ex vivo culture of a detrimental impact of mobilization on HSPCs and can be further enhanced by the transient overexpression of engraftment effectors exploiting optimized mRNA-based delivery. We show the therapeutic efficacy in a mouse model of hyper IgM syndrome and further developed it in human hematochimeric mice, showing its applicability and versatility when coupled with gene transfer and editing strategies. Overall, our findings provide a potentially valuable strategy paving the way to broader and safer use of HSPC-GT.

SARS-CoV-2 symptomatic reinfection among patients with primary antibody deficiency

SARS-CoV-2 symptomatic reinfection among patients with primary antibody deficiency

Inborn Errors of Immunity among Egyptian Children with Recurrent Acute Otitis Media

Abstract Objective Our objective was to investigate the relative frequency and pattern of inborn errors of immunity (IEIs) among Egyptian children with recurrent acute otitis media (rAOM). Methods This was a cross-sectional study that included children from the age of 6 months to 16 years with rAOM. Those with structural, functional, and environmental risk factors were excluded. Enrolled children underwent thorough clinical, otorhinolaryngological, and immunological evaluation, including hematological counting, quantitative immunoglobulins assay, lymphocytic flow cytometric immunophenotyping, CH50, and phagocytic function tests. Results The study included 69 children with rAOM (44 boys and 25 girls; median age 30 months). IEIs were identified in 14 children, including transient hypogammaglobulinemia (three cases), selective IgA deficiency (three cases), agammaglobulinemia (two cases), common variable immunodeficiency (two cases), and one case for each of congenital neutropenia, Chediak–Higashi syndrome, hyper IgM syndrome, and Griscelli syndrome. Parental consanguinity and history of unexplained/infection-related siblings' deaths were significantly associated with IEIs (p = 0.018 and 0.003, respectively). AOM and related complications were more frequent among IEI cases (p = 0.018 and 0.032, respectively). IEI cases had lower levels of hemoglobin (10.7 ± 2.80 vs. 12.3 ± 1.64 g/dL; p = 0.002), IgG (203 [78–1,370] vs. 708 [42.3–1,509] mg/dL; p = 0.000), and IgA (24.3 [3–310] vs. 80 [15.6–305] mg/dL; p = 0.009) compared with non-IEI cases. Conclusion The current study identified IEIs in one-fifth of children with rAOM, most of which were predominately antibody deficiencies. An immunological workup for rAOM is particularly important in the presence of certain indicators for IEIs, provided that other more common risk factors are excluded.

CD40 is Required For Protective T Cell Responses Against Cryptosporidium

Abstract The apicomplexan intestinal parasite Cryptosporidium infects intestinal epithelial cells (IECs) and is a leading cause of life-threatening disease in infants, toddlers, and immunocompromised patients. No vaccine against Cryptosporidium exists, and current treatments are ineffective in immunocompromised individuals. A prominent immunodeficiency associated with susceptibility to Cryptosporidium is hyper-IgM syndrome, which is caused by defects in CD40 signaling. In a murine model of Cryptosporidiosis, mice deficient in CD154 (CD40L) are defective in parasite control and clearance, and complementation of CD40L restores protection. Therefore, characterizing CD40-mediated immune responses against Cryptosporidium may enhance progress toward effective therapy in at-risk individuals. CD40 engagement on dendritic cells (DCs) promotes IL-12 production that induces differentiation and proliferation of T helper type 1 (Th1) cells and their production of interferon-γ (IFN-γ), which is known to be essential for control and clearance of Cryptosporidium infection. Our findings suggest a defect in T cell responses in CD40−/− mice infected with Cryptosporidium. CD40 deletion on Xcr1+ DCs also resulted in increased susceptibility to Cryptosporidium along with a defect in CD8+ T cell expansion. Therefore, we conclude that CD8+ T cell responses against Cryptosporidium require CD40 on cDC1s. Supported by NIH grant U01AI163671

Bronchial inflammation biomarker patterns link humoral immunodeficiency with bronchiectasis-related small airway dysfunction.

The progression of chronic destructive lung disease in patients with humoral immunodeficiency (ID) and concomitant development of bronchiectasis is difficult to prevent. Lung function tests in these patients typically show bronchial obstruction of the small airways in combination with increased air trapping in the distal airways, which is consistent with small airway dysfunction. The objective was to assess the grade of chronic lower airway inflammation and small airway dysfunction from induced sputum and the corresponding local pro-inflammatory mediator pattern to discriminate patients affected by bronchiectasis-related Small Airway Dysfunction (SAD). In a prospective design, 22 patients with ID (14 CVID, 3 XLA, 3hyper-IgM syndrome, 1hyper-IgE syndrome and low IgG levels due to treatment with rituximab and 1 SCID after BMT and persistent humoral defect) and 21healthy controls were examined. Lung function, Fraction Expiratory Nitric Oxide (FeNO) and pro-inflammatory cytokine levels were compared in subsets of patients with (ID+BE) and without bronchiectasis (ID) pre-stratified using high-resolution computed tomography (HRCT) scans and control subjects. Analysis of induced sputum showed significantly increased total cell counts and severe neutrophilic inflammation in ID. The concomitant SAD revealed higher total cell numbers compared to ID. Bronchial inflammation in ID is clearly mirrored by pro-inflammatory mediators IL-1β, IL-6 and CXCL-8, whilst TNF-α revealed a correlation with lung function parameters altered in the context of bronchiectasis-related Small Airway Dysfunction. In spite of immunoglobulin substitution, bronchial inflammation was dominated by neutrophils and was highly increased in patients with ID+BE. Notably, the pro-inflammatory cytokines in patients with ID were significantly increased in induced sputum. The context-dependent cytokine pattern in relation to the presence of concomitant bronchiectasis associated with SAD in ID patients could be helpful in delimiting ID patient subgroups and individualizing therapeutic approaches.

X-linked hyper IgM syndrome with severe eosinophilia: a case report and review of the literature

BackgroundHyper IgM syndromes (HIGMS) are a group of rare primary immunodeficiency disorders. There are limited reports about HIGMS combined with severe eosinophilia.Case presentationIn this report, we described a 2-year-old boy with chronic cough and symptoms of hypoxia. Lung computed tomography (CT) scan showed that diffuse ground-glass changes and eosinophils in peripheral blood increased significantly. Subsequent tests revealed a notable decrease in serum IgG and IgA. The lymphocyte subgroup classification was basically normal. Pneumocystis jirovecii were detected from the bronchoalveolar lavage fluid (BALF) of the patient by metagenomic next-generation sequencing (mNGS). After treatments of caspofungin combined with sulfamethoxazole, intravenous immunoglobulin (IVIG) replacement and anti-inflammatory steroid, the clinical symptoms and pulmonary imaging noticeably improved. The absolute eosinophil count (AEC) also returned to normal range. X-linked hyper IgM syndrome was confirmed by gene test. Two months after the diagnosis, the patient underwent allogeneic stem cell transplantation (HSCT) and has recovered well.ConclusionsChildren with HIGMS are prone to opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP). Diffuse interstitial lung disease and hypoglobulinemia in a young child predict the diagnosis of a primary immunodeficiency (PID). mNGS has obvious advantages for obtaining etiological diagnosis of children with PIDs. Severe eosinophilia is rarely reported in this kind of PIDs. Considering literature review and the corresponding reaction to steroid, we proposed that eosinophilia in HIGMS might be related to infections. Steroid therapy can quickly relieve eosinophilia but is easy to rebound if the reduction is too fast. Once the diagnosis of HIGMS is confirmed, the earlier the HSCT, the better the prognosis.

A Novel AICDA Splice-Site Mutation in Two Siblings with HIGM2 Permits Somatic Hypermutation but Abrogates Mutational Targeting

Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients.