RESUMO
Type 1, X-linked Hyper-IgM syndrome (HIGM1) is caused by mutations in the gene encoding the CD154 protein, also known as CD40 ligand (CD40LG). CD40L is expressed in activated T cells and interacts with CD40 receptor expressed on B lymphocytes and dendritic cells. Affected patients present cellular and humoral immune defects, with infections by intracellular, opportunistic and extracellular pathogens. In the present study we investigated the molecular defects underlying disease in four patients with HIGM1. We identified four distinct CD40L mutations, two of them which have not been previously described. P1 harboured the novel p.G227X mutation which abolished CD40L expression. P2 had a previously described frame shift deletion in exon 2 (p.I53fsX65) which also prevented protein expression. P3 demonstrated the previously known p.V126D change in exon 4, affecting the TNF homology (TNFH) domain. Finally, P4 evidenced the novel p.F229L mutation also located in the TNFH domain. In silico analysis of F229L predicted the change to be pathological, affecting the many hydrophobic interactions of this residue. Precise molecular diagnosis in HIGM syndrome allows reliable detection of carriers, making genetic counselling and prenatal diagnosis possible.
Assuntos
Ligante de CD40/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hipergamaglobulinemia/genética , Imunoglobulina M/sangue , Mutação , Sequência de Aminoácidos , Ligante de CD40/análise , Ligante de CD40/química , Humanos , Dados de Sequência Molecular , Linfócitos T/químicaRESUMO
HyperIgM syndrome is a heterogenous immunodeficiency characterized by impaired class-switch recombination due to different molecular abnormalities. We report on two female patients affected by a novel syndrome associating HIGM, growth and pubertal disturbances, and severe lymphoid hyperplasia with eventual development into lymphomas, suggesting a DNA repair defect.
Assuntos
Transtornos do Crescimento/genética , Hipergamaglobulinemia/genética , Imunoglobulina M/sangue , Linfoma de Células B/genética , Puberdade Tardia/genética , Adolescente , Criança , Feminino , Humanos , Doenças Linfáticas/genéticaRESUMO
BACKGROUND: Hyper-IgM syndronie (HIGM) is a rare primary immunodeficiency used to describe a heterogeneous group of disorders characterized by recurrey bacterial infrctions, normal or elevated serum IgM levels and low or absent serum IgG, IgA and IgE. AIM: To make definitive diagnosis, detect mutations in carriers and perform genetic counseling in patients with HIGM. PATIENTS AND METHODS: We studied the expression of CD40L, CD40 and made a mutation analysis of the CD40L gene in 3 males of 2 unrelated Chilean families diagnosed as a possible syndrome of hyper-IgM and 3 relatives. RESULTS: We identified a deletion frameshift in the exon 2 (delA225) of the extracellular domain of GD40L gene in one patient and verified the carrier stains of his mother and sister. The other patients showed a low expression of GD40L in activated T cells (65.3% ammd 65.5%) and a normal expressiomi of CD40. No alterations were found in the single strand conformation polymorphism analysis of the CD40L. CONCLUSIONS: These result allowed us to make a definite diagnosis of HIGM1 of a patient, detect female carriers and suggest a HIGM of recessive inheritance with normal CD40 expression in the patients of the second family.
Assuntos
Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Ligante de CD40 , Hipergamaglobulinemia/genética , Imunoglobulina M/genética , Mutação da Fase de Leitura/genética , Ligante de CD40 , Aconselhamento Genético , Chile , Hipergamaglobulinemia/diagnóstico , Imunoglobulina M/sangue , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral , SíndromeRESUMO
BACKGROUND: Hyper-IgM syndronie (HIGM) is a rare primary immunodeficiency used to describe a heterogeneous group of disorders characterized by recurrey bacterial infrctions, normal or elevated serum IgM levels and low or absent serum IgG, IgA and IgE. AIM: To make definitive diagnosis, detect mutations in carriers and perform genetic counseling in patients with HIGM. PATIENTS AND METHODS: We studied the expression of CD40L, CD40 and made a mutation analysis of the CD40L gene in 3 males of 2 unrelated Chilean families diagnosed as a possible syndrome of hyper-IgM and 3 relatives. RESULTS: We identified a deletion frameshift in the exon 2 (delA225) of the extracellular domain of GD40L gene in one patient and verified the carrier stains of his mother and sister. The other patients showed a low expression of GD40L in activated T cells (65.3% ammd 65.5%) and a normal expressiomi of CD40. No alterations were found in the single strand conformation polymorphism analysis of the CD40L. CONCLUSIONS: These result allowed us to make a definite diagnosis of HIGM1 of a patient, detect female carriers and suggest a HIGM of recessive inheritance with normal CD40 expression in the patients of the second family.
Assuntos
Ligante de CD40/genética , Mutação da Fase de Leitura/genética , Hipergamaglobulinemia/genética , Imunoglobulina M/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Ligante de CD40/sangue , Criança , Pré-Escolar , Chile , Feminino , Aconselhamento Genético , Humanos , Hipergamaglobulinemia/diagnóstico , Imunoglobulina M/sangue , Lactente , Masculino , Síndrome , Fator 3 Associado a Receptor de TNF , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/sangueRESUMO
We report a 11 years old male diagnosed as a X-linked hyper-IgM syndrome that presented with recurrent infections and sclerosing cholangitis and later developed a gallbladder cancer. Immunological evaluation showed decreased levels of serum IgG and IgA with elevated levels of IgM. Study of CD40 ligand expression on mitogen activated peripheral blood mononuclear cells revealed total absence of this marker on T lymphocytes. Molecular analysis detected, in the patient and his mother, a nonsense mutation in exon 1 of the transmembrane segment of the CD40 ligand. He also presented elevation of alkaline phosphatases and mild elevation of liver enzymes. Liver biopsy demonstrated the presence of idiopathic sclerosing cholangitis. The patient was started on monthly IVIG therapy at 400 mg/kg, as well as ursodeoxycholic acid and vitamin E, with normalization of his IgG and IgM levels a decrease in the incidence of infections and normalization of liver function. Three years after diagnosis, we detected the presence of polyps inside the gallbladder that were reported at biopsy as adenocarcinoma. He underwent hepatic bisegmentectomy (VI B-V) and local lymphadenectomy.
Assuntos
Adenocarcinoma/etiologia , Colangite Esclerosante/etiologia , Neoplasias da Vesícula Biliar/etiologia , Hipergamaglobulinemia/complicações , Imunoglobulina M/sangue , Síndromes de Imunodeficiência/complicações , Adolescente , Ligante de CD40/sangue , Ligante de CD40/genética , Cromossomos Humanos X , Éxons , Humanos , Hipergamaglobulinemia/genética , Síndromes de Imunodeficiência/genética , Masculino , Mutação , Linfócitos TAssuntos
Febre Familiar do Mediterrâneo/genética , Expressão Gênica/genética , Síndromes de Imunodeficiência/genética , Biologia Molecular/métodos , Mutação/genética , Análise Mutacional de DNA/métodos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Hipergamaglobulinemia/genética , Imunoglobulina M/genética , Receptores do Fator de Necrose Tumoral/genéticaRESUMO
We report the case of an infant with severe respiratory infections, chronic diarrhea, failure to thrive, and disseminated Cryptosporidium parvum infection. Laboratory investigations disclosed a diagnosis of hyper-IgM syndrome caused by CD40 deficiency.
Assuntos
Antígenos CD40/genética , Criptosporidiose/etiologia , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hipergamaglobulinemia/complicações , Hipergamaglobulinemia/genética , Imunoglobulina M/genética , Consanguinidade , Diagnóstico Diferencial , Feminino , Citometria de Fluxo , Genes Recessivos/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Transtornos do Crescimento/etiologia , Humanos , Hipergamaglobulinemia/diagnóstico , Hipergamaglobulinemia/terapia , Imunofenotipagem , Lactente , Linhagem , Insuficiência Respiratória/etiologia , Tomografia Computadorizada por Raios X , TurquiaRESUMO
We describe 5 children from 2 families with mutations in the CD40 ligand (CD40L) gene leading to absent expression of CD40L on activated CD4 cells. All subjects presented with interstitial pneumonia with low serum IgG and normal serum IgM. One child had normal and one child had elevated serum IgA. Four had confirmed Pneumocystis carinii pneumonia. In spite of intravenous immunoglobulin treatment yielding therapeutic serum immunoglobulin levels, 3 children had enteroviral encephalitis. When assessed by flow cytometry, the 3 surviving affected male children had absent CD40L expression on activated CD4(+) T cells. The affected children from both families were shown to have the same single nucleotide insertion (codon 131) resulting in frameshift and early termination within exon 4 (extracellular domain). This observation demonstrates that persistent enteroviral infection is not only observed in X-linked agammaglobulinemia but may also occur in patients with X-linked hyper IgM syndrome.