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.
B-Lymphocytes* ; Bacterial Infections ; CD40 Ligand ; Cell Cycle ; Cytidine ; Ectodermal Dysplasia ; Herpesvirus 4, Human ; Humans ; Hyper-IgM Immunodeficiency Syndrome* ; Hyper-IgM Immunodeficiency Syndrome, Type 1 ; Immunoglobulin A ; Immunoglobulin E ; Immunoglobulin G ; Immunoglobulin M ; Interleukin-4 ; Lymph Nodes* ; Lymphocytes ; RNA ; T-Lymphocytes

OBJECTIVE: To detect variant of the CD40L gene and infection of Jamestown Canyon virus (JCV) in a 7-year-and-9-month-old boy with co-commitment progressive multifocal leukoencephalopathy (PML) and X-linked hyper IgM syndrome (XHIGM). METHODS: Peripheral blood samples of the child and his parents were collected for the extraction of genomic DNA. The 5 exons and exon/intronic boundaries of the CD40L gene were subjected to PCR amplification and sequencing. Suspected variants were analyzed by using bioinformatic software. The JCV gene was amplified from genomic DNA by nested PCR and sequenced. RESULTS: The child was found to harbor a hemizygous c.506 A>C (p.Y169S) missense variant in exon 5 of the CD40L gene. The variant may affect the TNFH domain of the CD40L protein and result in structural instability and loss of hydrophobic interaction between CD40L and CD40. As predicted by PolyPhen2 and SIFT software, the variant was probably damaging (score = 1.00) and deleterious (score= -8.868). His mother was found to be a heterozygous carrier, while the same variant was not found in his father. Gel electrophoresis of the nested PCR product revealed presence of target JCV band, which was confirmed to be 99% identical with the JCV gene by sequencing. CONCLUSION The patient was diagnosed with co-commitment XHIGM and PML based on the testing of the CD40L gene and JCV infection.
Adult ; CD40 Ligand/genetics* ; Child ; Exons/genetics* ; Female ; Humans ; Hyper-IgM Immunodeficiency Syndrome, Type 1/genetics* ; Leukoencephalopathy, Progressive Multifocal/genetics* ; Male ; Mutation, Missense ; Polymerase Chain Reaction

A 2-year-old boy was admitted into the hospital because of cough and fever. Lymph node tuberculosis was noted when he was 2 months old and he was subsequently hospitalized several times because of cough and fever. After hospitalization the laboratory examination showed an increased eosinophia level in blood. The immune function tests shows decreased levels of IgG, IgA, and IgM. The patient had no response to anti-tuberculosis, anti-bacterial, and anti-fungal treatment, resulting in recurrent fever and progressive enlargement of the liver and spleen. Jam-like stools were noted 35 days after admission. B ultrasonography showed suspected intussusception. Laparotomy, reduction of intussusception and ileocecum angioplasty, biopsies of intestinal wall nodules and lymphoglandulae mesentericae, and hepatic biopsy were then performed under general anesthesia. The patient eventually died because of postoperative severe liver damage, disseminated intravascular coagulation and electrolyte disorder. Both the blood culture and hepatic biopsy tests showed Penicillium marneffei infecton. Immunodeficiency gene test was performed on the patient, his bother and their parents. T→G base substitution mutation (IVS1-3 T→G) in the CD40L gene was found in the patient. X-linked hyper-IgM syndrome was thus diagnosed in the patient. His mother was a carrier of the mutated CD40L gene, but his father was normal in the gene test. Hemizygous mutation in the CD40L gene was found in both the patient and his bother.
CD40 Ligand ; genetics ; Child, Preschool ; Eosinophilia ; etiology ; Fever ; etiology ; Hepatomegaly ; etiology ; Humans ; Hyper-IgM Immunodeficiency Syndrome ; diagnosis ; genetics ; Male ; Mutation ; Recurrence ; Splenomegaly ; etiology

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.
Abdominal Pain ; Biopsy ; Bone Marrow ; Carcinoma, Neuroendocrine ; Child ; Complement System Proteins ; Genetic Therapy ; Humans ; Hyper-IgM Immunodeficiency Syndrome ; Immunoglobulins ; Leukocytes ; Male ; Myelodysplastic Syndromes ; Neoplasm Metastasis ; Stem Cell Transplantation

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.
Child ; Epstein-Barr Virus Infections ; Graft vs Host Disease/prevention & control* ; Hematopoietic Stem Cell Transplantation/methods* ; Herpesvirus 4, Human ; Humans ; Hyper-IgM Immunodeficiency Syndrome ; Retrospective Studies

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.
Abscess ; Agammaglobulinemia ; Arthritis, Infectious ; Bone Marrow Transplantation ; Child ; Common Variable Immunodeficiency ; Diagnosis ; Early Diagnosis ; Female ; Granulomatous Disease, Chronic ; Hospital Distribution Systems ; Humans ; Hyper-IgM Immunodeficiency Syndrome ; IgA Deficiency ; Immunoglobulins, Intravenous ; Korea ; Male ; Medical Records ; Meningitis, Bacterial ; Mortality ; Otitis Media ; Pneumonia, Bacterial ; Prognosis ; Respiratory Tract Infections ; Retrospective Studies ; Seoul* ; Severe Combined Immunodeficiency ; Sinusitis ; Tuberculosis, Pulmonary