ABSTRACT
A girl with coloboma of the iris, sensorineural deafness, growth delay, distinctive face, and cranial nerve dysfunction was diagnosed of CHARGE association in the first year of life. She presented with repeated otitis. At 3 yr of age, the patient suffered a septicemia (Streptococcus pneumoniae, Corynebacterium sp.). The immunoglobulin G (IgG) and IgA serum levels were decreased, IgM increased and cellular immunity parameters were normal, supporting the diagnosis of hyper-IgM (HIM) syndrome. The sequence of CD40 ligand and cytidine deaminase genes were normal. From then on, she was receiving immunoglobulin intravenously with an excellent outcome. Here, we report the first case of CHARGE association and HIM syndrome in the same patient. Although the cause could not be identified, a non-random link is likely.
Subject(s)
Choanal Atresia/etiology , Coloboma/etiology , Genitalia, Female/abnormalities , Growth Disorders/etiology , Hearing Loss, Sensorineural/etiology , Heart Defects, Congenital/etiology , Hypergammaglobulinemia/diagnosis , Hypergammaglobulinemia/etiology , Immunoglobulin M/blood , Iris/abnormalities , Abnormalities, Multiple/etiology , Child, Preschool , Choanal Atresia/immunology , Cranial Nerve Diseases/etiology , Face/abnormalities , Female , Growth Disorders/immunology , Hearing Loss, Sensorineural/immunology , Heart Defects, Congenital/immunology , Humans , Hypergammaglobulinemia/blood , Immunoglobulin A/blood , Immunoglobulin A/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Otitis/etiology , SyndromeABSTRACT
BACKGROUND AND OBJECTIVE: The autoimmune lymphoproliferative syndrome (ALPS) is a disorder caused by a defect in lymphocytes' apoptosis and characterized by non malignant lymphoproliferation, autoimmune features and increased TCR alpha + CD4CD8 cells. Most patients have a mutation in the TNFRSF6 gene, which encodes the Fas protein. Our aim was to identify mutations in this gene in two families with possible ALPS cases. PATIENTS AND METHOD: Two patients with suspicion of ALPS, belonging to two unrelated families, were studied. To confirm such a diagnosis, immunoglobulin quantification, cellular phenotypic analysis by flow cytometry, IL-10 quantification, an apoptosis study, and molecular analysis were performed. RESULTS: Both patients showed hypergammaglobulinemia and an increased percentage of TCR alpha + CD4CD8 cells (family A patient: 14%; family B patient: 4.25%). In family A, in vitro Fas-mediated apoptosis was absent in the patient and markedly reduced in his father. In this family, both the patient and his father were heterozygous for the Fas mutation T1045C (Leu 268 Pro). The family B patient and her mother showed the Fas mutation G943T (Arg 234 Leu), both being heterozygous for it too. Both mutations are located in exon 9 of TNFRSF6 gene, affecting the death domain of the Fas protein. CONCLUSIONS: The molecular study of these families confirms a diagnosis of ALPS and suggests that the causing defect of this syndrome is compatible with an autosomal dominant inheritance with incomplete penetrance.
Subject(s)
Autoimmune Diseases/diagnosis , Lymphoproliferative Disorders/diagnosis , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Base Sequence , Child , Child, Preschool , Family Health , Female , Genes, T-Cell Receptor alpha/genetics , Humans , Immunoglobulin E/metabolism , Immunoglobulin G/metabolism , Immunohistochemistry , Lymphocytes/immunology , Lymphocytes/pathology , Lymphoma, Non-Hodgkin/diagnosis , Lymphoma, Non-Hodgkin/genetics , Lymphoproliferative Disorders/genetics , Lymphoproliferative Disorders/immunology , Male , Molecular Sequence Data , Mutation , Pedigree , Sequence Homology, Nucleic Acid , Splenomegaly/diagnosis , Splenomegaly/genetics , SyndromeABSTRACT
FUNDAMENTO Y OBJETIVO: El síndrome linfoproliferativo autoinmune (SLPA) es una enfermedad debida a un defecto en la apoptosis de los linfocitos, que cursa con linfoproliferación crónica no maligna, manifestaciones autoinmunes e incremento de los linfocitos TCRalfa beta+CD4-CD8-. La mayoría de los casos se deben a mutaciones en el gen TNFRSF6 que codifica para la proteína Fas. Nuestro objetivo fue identificar mutaciones en este gen en dos familias, algunos de miembros presentaban una clínica y una analítica compatibles con SLPA. PACIENTES Y MÉTODO: Estudiamos a dos enfermos con sospecha de SLPA. Para confirmar este diagnóstico realizamos cuantificación de inmunoglobulinas, fenotipado celular por citometría de flujo, cuantificación de interleucina (IL) 10, estudio de apoptosis y análisis molecular. RESULTADOS: Ambos enfermos presentaron hipergammaglobulinemia y un aumento de las células TCRalfa beta+CD4-CD8- (paciente de la familia A: 14 por ciento; enferma de la familia B: 4,25 por ciento). En la familia A se efectuó un estudio de apoptosis, ausente en los linfocitos del paciente y muy disminuida en los linfocitos del padre. Ambos fueron heterocigotos para la mutación T1045C (Leu 268 Pro). La paciente de la familia B y su madre presentaron la mutación G943T (Arg 234 Leu), también en heterocigosis. Las dos mutaciones descritas se localizan en el exón 9 del gen TNFRSF6, que afecta al dominio de muerte de la proteína Fas. CONCLUSIONES: Los resultados del estudio molecular en estas dos familias apoyaron el diagnóstico de SLPA y apuntan a que el defecto causante del síndrome es compatible con un patrón de herencia autosómico dominante con penetrancia incompleta (AU)
