RESUMEN
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.
Asunto(s)
Ligando de CD40/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Hipergammaglobulinemia/genética , Inmunoglobulina M/sangre , Mutación , Secuencia de Aminoácidos , Ligando de CD40/análisis , Ligando de CD40/química , Humanos , Datos de Secuencia Molecular , Linfocitos T/químicaRESUMEN
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.
Asunto(s)
Trastornos del Crecimiento/genética , Hipergammaglobulinemia/genética , Inmunoglobulina M/sangre , Linfoma de Células B/genética , Pubertad Tardía/genética , Adolescente , Niño , Femenino , Humanos , Enfermedades Linfáticas/genéticaRESUMEN
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.
Asunto(s)
Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Ligando de CD40 , Hipergammaglobulinemia/genética , Inmunoglobulina M/genética , Mutación del Sistema de Lectura/genética , Ligando de CD40 , Asesoramiento Genético , Chile , Hipergammaglobulinemia/diagnóstico , Inmunoglobulina M/sangre , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral , SíndromeRESUMEN
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.
Asunto(s)
Ligando de CD40/genética , Mutación del Sistema de Lectura/genética , Hipergammaglobulinemia/genética , Inmunoglobulina M/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Ligando de CD40/sangre , Niño , Preescolar , Chile , Femenino , Asesoramiento Genético , Humanos , Hipergammaglobulinemia/diagnóstico , Inmunoglobulina M/sangre , Lactante , Masculino , Síndrome , Factor 3 Asociado a Receptor de TNF , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/sangreRESUMEN
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.
Asunto(s)
Adenocarcinoma/etiología , Colangitis Esclerosante/etiología , Neoplasias de la Vesícula Biliar/etiología , Hipergammaglobulinemia/complicaciones , Inmunoglobulina M/sangre , Síndromes de Inmunodeficiencia/complicaciones , Adolescente , Ligando de CD40/sangre , Ligando de CD40/genética , Cromosomas Humanos X , Exones , Humanos , Hipergammaglobulinemia/genética , Síndromes de Inmunodeficiencia/genética , Masculino , Mutación , Linfocitos TAsunto(s)
Fiebre Mediterránea Familiar/genética , Expresión Génica/genética , Síndromes de Inmunodeficiencia/genética , Biología Molecular/métodos , Mutación/genética , Análisis Mutacional de ADN/métodos , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Hipergammaglobulinemia/genética , Inmunoglobulina M/genética , Receptores del Factor de Necrosis Tumoral/genéticaRESUMEN
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.
Asunto(s)
Antígenos CD40/genética , Criptosporidiosis/etiología , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Hipergammaglobulinemia/complicaciones , Hipergammaglobulinemia/genética , Inmunoglobulina M/genética , Consanguinidad , Diagnóstico Diferencial , Femenino , Citometría de Flujo , Genes Recesivos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Trastornos del Crecimiento/etiología , Humanos , Hipergammaglobulinemia/diagnóstico , Hipergammaglobulinemia/terapia , Inmunofenotipificación , Lactante , Linaje , Insuficiencia Respiratoria/etiología , Tomografía Computarizada por Rayos X , TurquíaRESUMEN
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.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Antígenos CD40/inmunología , Infecciones por Enterovirus/etiología , Hipergammaglobulinemia/complicaciones , Hipergammaglobulinemia/genética , Inmunoglobulina M/sangre , Glicoproteínas de Membrana/genética , Meningoencefalitis/etiología , Mutación , Ligando de CD40 , Análisis Mutacional de ADN , Citometría de Flujo , Ligamiento Genético , Humanos , Hipergammaglobulinemia/terapia , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunoglobulinas Intravenosas/uso terapéutico , Lactante , Ligandos , Activación de Linfocitos , Masculino , Linaje , Neumonía por Pneumocystis/complicaciones , Reacción en Cadena de la Polimerasa , Síndrome , Cromosoma XAsunto(s)
Hipergammaglobulinemia/fisiopatología , Inmunoglobulina M , Síndromes de Inmunodeficiencia/fisiopatología , Linfocitos B/fisiología , Antígenos CD40/genética , Niño , Ligamiento Genético , Humanos , Hipergammaglobulinemia/diagnóstico , Hipergammaglobulinemia/genética , Deficiencia de IgG/diagnóstico , Deficiencia de IgG/genética , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Ligandos , Activación de Linfocitos/genética , Pronóstico , Linfocitos T/fisiología , Cromosoma X/genéticaRESUMEN
We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate.
Asunto(s)
Ligamiento Genético , Hipergammaglobulinemia/genética , Inmunoglobulina M , Síndromes de Inmunodeficiencia/genética , Cromosoma X , Trasplante de Médula Ósea , Antígenos CD40/genética , Causas de Muerte , Niño , Preescolar , Enfermedad Crónica , Criptosporidiosis/fisiopatología , Diarrea/fisiopatología , Humanos , Hipergammaglobulinemia/inmunología , Hipergammaglobulinemia/fisiopatología , Hipergammaglobulinemia/terapia , Inmunidad Celular/genética , Inmunidad Celular/fisiología , Inmunoglobulina M/administración & dosificación , Inmunoglobulina M/uso terapéutico , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/fisiopatología , Síndromes de Inmunodeficiencia/terapia , Lactante , Recién Nacido , Ligandos , Hepatopatías/fisiopatología , Trasplante de Hígado , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Mutación/genética , Neutropenia/fisiopatología , Infecciones Oportunistas/fisiopatología , Úlceras Bucales/fisiopatología , Neumonía por Pneumocystis/fisiopatología , Enfermedades del Recto/fisiopatología , Infecciones del Sistema Respiratorio/fisiopatología , Resultado del Tratamiento , Úlcera/fisiopatología , Cromosoma X/genéticaRESUMEN
We examined T-cell proliferation in five patients with X-linked hyper-IgM syndrome (XHIM), using a panel of antigens and lectins. All patients had impaired antigen-induced proliferation, whereas their lectin responses were normal. Thus, in addition to severely depressed antibody responses, patients with XHIM have a defect in antigen-specific T-cell proliferation, which may explain their susceptibility to pathogens such as Pneumocystis carinii.