Advances in the diagnosis and treatment of hyper-IgM syndrome in children / 国际儿科学杂志

The hyper immunoglobulin M syndrome(hyper-IgM syndrome, HIGM)is a rare X-linked inherited primary immunodeficiency disease(PID)characterized by defective class switch recombination(CSR)with or without somatic hyper mutation(SHM), resulting in normal or increased levels of serum IgM associated with deficiency of immunoglobulin G(IgG), immunoglobulin A(IgA), and immunoglobulin E(IgE)and antibody dysfunction.Most cases have X-linked recessive inheritance, and a few are autosomal-recessive forms.The clinical manifestations include recurrent infections in early age, tumors and autoimmune diseases.The prognosis is poor, especially for HIGM with X-linked recessive inheritance.And if these patients do not be treated timely after birth, most of them will die early.In order to improve pediatricians′ understanding of the disease, and to timely identify and treat HIGM for an improved prognosis, this paper reviews the pathogenesis, clinical manifestations, diagnosis and treatment of HIGM.

Clinical effect of allogeneic hematopoietic stem cell transplantation in children with hyper-IgM syndrome / 中国当代儿科杂志

OBJECTIVES@#To evaluate the clinical effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with hyper-IgM syndrome (HIGM).@*METHODS@#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.@*RESULTS@#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).@*CONCLUSIONS@#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.

Human Inborn Errors of Immunity (HIEI): predominantly antibody deficiencies (PADs): if you suspect it, you can detect it

Abstract Objective: This minireview gathers the scientific foundations of the literature on genetic errors in the development of the humoral immune system to help pediatricians suspect these defects. Sources: A systemic search using the PubMed MEDLINE database was performed for all Predominantly Antibody Deficiencies (PADs) described in the 2020 IUIS Expert Committee for PID classification system, combined with terms for hypogammaglobulinemia. Search terms for PADs were based on the listed names and affected genes as classified by the IUIS 2020. Abstracts of the results were reviewed to find relevant case series, review articles of PADs associated with infection, opportunistic infection, autoimmunity, cytopenias, malignancies, inflammatory diseases, neurological and respiratory diseases. References from relevant articles were further reviewed for additional references. Relevant findings were grouped in accordance with the IUIS 2020 classification system. Clinical and genetic features, if known, were described. Data synthesis: PADs refer to impaired antibody production due to molecular defects intrinsic to B cells or a failure of interaction between B and T cells. The patients develop recurrent or chronic infection or respond to the antigens with dysregulation of the immune function, causing severe allergy, autoimmunity, inflammation, lymphoproliferation and malignancy. The diagnosis is a combined exercise of clinical and laboratory investigation similar to that performed by Bruton (1952). In the context of SARS-CoV-2 infection, the experience of XLA and CVID patients has been surprising. Variants in 39 genes were reported as causing PADs, but the clinical heterogeneity within each variant is not clear. Conclusion: Bruton (1952) used clinical expertise and protein electrophoresis to identify XLA. The IUIS (2020) committee used immunoglobulins and B lymphocyte to characterize PADs. Pediatricians should suspect it to detect it and prevent morbidities that can have an astonishing and irreversible impact on the child's life.

A case of X-linked hyper IgM syndrome with a novel CD 40LG mutation / 中华实用儿科临床杂志

A retrospective analysis was performed on the clinical data of a child with X-linked hyper IgM syndrome (XHIGM) with cholangiectasis as a major manifestation in Children′s Hospital of Fudan University in March 2017.The patient was a 4-year-old boy who was admitted to the hospital due to repeated diarrhea for half a year and yellow skin for 5 days.No abnormalities were found in his fetal period and birth history; The patient had 2 severe pneumonias and suppurative infection of the left axillary lymph node in infancy.Physical examination revealed delayed physical development, severe malnutrition, moderately stained yellow, lymphadenopathy and hepatomegaly.Laboratory examinations showed elevated leukocyte, eosinophils and C-reactive protein, low hemoglobin and albumin, high gamma-glutamyl transpeptidase (GGT), low IgG and normal IgM.Imaging examination revealed diffuse expansion of intrahepatic and extrahepatic bile ducts.Hepatic pathology showed hyperplasia in the bile canaliculus and some fibrous tissues around the large bile ducts.High-throughput sequencing identified a pathogenic mutation in the XHIGM gene CD 40LG (exon5 c. 506A>G, p.Y169C), with his mother as a carrier.After admission, the patient was given anti-infection, diet adjustment, albumin, intravenous immunoglobulin and ursodeoxycholic acid.The patient was discharged after the improvement in his condition.This case suggested that in addition to the common infection characteristics, XHIGM can also be manifested as diffuse intrahepatic, extrahepatic cholangiectasis and significantly elevated eosinophil.c.506A>G mutation in CD 40LG was the pathogenic mutation of this disease.

Progress of allogeneic hematopoietic stem cell transplantation for hyper IgM syndrome / 国际儿科学杂志

Hyper immunoglobulin M syndrome(HIGM)is a group of rare primary immunodeficiency disease(PID)caused by single gene mutation.Allogeneic hematopoietic stem cell transplantation(allo-HSCT)is the only treatment to cure the disease, and patients should receive allo-HSCT if possible.Younger patients who can keep in good pre-transplant state, obtain matching sibling donor and tolerate to myeloablative conditioning may get better outcome after early transplantation, and the overall survival rate can reach 80%.The progress in the timing of transplantation, donor and graft, conditioning regimen, prevention and treatment of complications of allo-HSCT for HIGM is reviewed in this paper.

A case of primary immunodeficiency: hyper IgM syndrome

Hyper IgM syndrome are group to disorders characterized by elevated serum level of IgM and low or absent serum levels of IgG, IgA and IgE the mechanism of HIGM is immunoglobulin Class-Switch Recombination (CSR) failure and Somatic Hyper Mutation (SHM). This diagnosis should be considered in any patient presenting with hypogammaglobulinemia, with low or absent IgG and IgA and normal or elevated IgM level. In the present case report, this was a 6-year-old male child who had history of recurrent respiratory tract infections who presented with otitis media and persistent fever spikes. Immunoglobulin studies revealed a pattern consistent with hyper IgM.

Update on the pathogenesis of hyper IgM syndrome / 国际儿科学杂志

The hyper immunoglobulin M syndromes(HIGM) are a heterogeneous group of genetic disorders resulting in defects of immunoglobulin class switch recombination,with or without defects of somatic hypermutation.They can be classified as defects of signalling through CD40 causing combined immunodeficiency,or intrinsic defects in B cells of the mechanism of class switch recombination resulting in a pure humoral immunodeficiency.This review summarizes the molecular pathogenesis of HIGM.

A Case of Neuroendocrine Carcinoma and Childhood Myelodysplastic Syndrome in Hyper-IgM Syndrome / 대한혈액학회지

Congenital immunodeficiency is one or combined immune defect in immunoglobulin, leukocyte, and complement. These patients have increased susceptibility to respiratory infection. Hence, their infection must be taken care of, tried to gene therapy and stem cell transplantation. We present here a case of hyper-IgM syndrome in an 11-year-old male patient who complained of abdominal distension and abdominal pain. Multiple abdominal masses were detected by abdominal computed tomography (CT) and he was diagnosed with neuroendocrine carcinoma by mass biopsy. There was no evidence of metastasis of cancer cells to the bone marrow, but a dysgranulopoietic feature was noted and he was diagnosed with childhood myelodysplastic syndrome. This is the first report that neuroendocrine carcinoma is associated with childhood myelodysplastic syndrome in hyper-IgM syndrome.

A Clinical Study of Primary Immunodeficiency Disease in a Single Center in Seoul from 1996 to 2004 / 소아알레르기및호흡기학회지

PURPOSE: Although primary immunodeficiency disorders are relatively rare, early diagnosis provides the opportunity to reduce morbidity and mortality. The aim of this study was to investigate disease distribution, clinical manifestations, genetic mutation, treatment and prognosis of primary immunodeficiency disorders of childhood. METHODS: We retrospectively reviewed the medical records of 15 cases with primary immunodeficiency disorders between 1996 and 2004 in Samsung Seoul Hospital, Seoul, Korea. RESULTS: The most common primary immunodeficiency was common variable immunodeficiency (CVID) (n=7), followed by X-linked agammaglobulinemia (XLA) (n=3), severe combined immunodeficiency (SCID) (n=2), hyper IgM syndrome (n=1), selective IgA deficiency (n=1), and chronic granulomatous disease (CGD) (n=1). Most cases had recurrent infections such as otitis media, bacterial pneumonia, sinusitis and other respiratory infections during infancy. The age at diagnosis ranged from 4 months to 17 years with a median age of 5 years. The male to female ratio was 11 to 4. Eleven patients were diagnosed with primary immunodeficiency diseases following respiratory infection, while the other 4 patients had pulmonary tuberculosis, perianal abscess, bacterial meningitis, septic arthritis. All the patients with XLA and CVID were regularly treated with IVIG. Two cases of SCID underwent successful bone marrow transplantation without complications. The patients with hyper IgM syndrome died due to severe infection even after bone marrow transplantation. CONCLUSION: Fifteen variable cases of primary immunodeficiency were diagnosed during 9 years. A high index of suspicion is required in children with recurrent or severe infections for the diagnosis of primary immunodeficiency, because early diagnosis and treatment can reduce mortality and morbidity.

Characterization of B Cells of Lymph Nodes and Peripheral Blood in a Patient with Hyper IgM Syndrome

PURPOSE: Hyper IgM syndrome(HIGM) is characterized by severe recurrent bacterial infections with decreased serum levels of IgG, IgA, and IgE but elevated IgM levels. Recently, it has been classified into three groups; HIGM1, HIGM2 and a rare form of HIGM. HIGM1 is a X-linked form of HIGM and has now been identified as a T-cell deficiency in which mutations occur in the gene that encodes the CD40 ligand molecule. HIGM2 is an autosomal recessive form of HIGM. Molecular studies have shown that the mutation of HIGM2 is in the gene that encodes activation-induced cytidine deaminase(AID). Recently, another rare form of X-linked HIGM syndrome associated with hypohydrotic ectodermal dysplasia has been identified. We encountered a patient with a varient form of HIGM2. To clarify the cause of this form of HIGM, we evaluated the peripheral B cells of this patient. METHODS: The lymphocytes of the patient were prepared from peripheral blood. B cells were immortalized with the infection of EBV. Cell cycle analysis was done with the immortalized B cells of the patient. Peripheral mononuclear cells were stained with monoclonal anti-CD40L antibody. Total RNA was extracted from the peripheral mononuclear cells. After RT-PCR, direct sequencing for CD40L gene and HuAID gene were done. Immunostainings of a lymph node for CD3, CD23, CD40, Fas-L, bcl-2, BAX were done. RESULTS: The peripheral B cells of this patient showed normal expression of CD40L molecule and normal sequencing of CD40L gene, and also normal sequencing of AID gene. Interestingly, the peripheral B cells of this patient showed a decreased population of G2/mitosis phase in cell cycles which recovered to normal with the stimulation of IL-4. CONCLUSION: We suspect that the cause of increased serum IgM in this patient may be from a decrease of G2/mitosis phase of the peripheral B cells, which may be from the decreased production or secretion of IL-4. Therefore, this may be a new form of HIGM.

Hyper IgM Syndrome - An Immunodeficiency Disorder

A seven-year male child presented with history of recurrent life threatening infections associated with low IgA and IgG levels and significant elevation of IgM levels. He was diagnosed to have Hyper IgM syndrome. There was significant improvement after the immunoglobulin therapy. The child is now on regular immunoglobulin therapy and is free from recurrent infections. An index of suspicion to consider a possible diagnosis of immunodeficiency is stressed.