RESUMO
Two related boys who died from fulminant infectious mononucleosis were diagnosed with X-linked lymphoproliferative disease type 1 (XLP-1). Family screening (n=17) identified 6 female mutation carriers and 2 more XLP-1 patients in whom, despite recurrent infections, agammaglobulinemia, and Hodgkin's Disease, the genetic basis had been unknown; demonstrating that awareness and early genetic testing are crucial to reveal underlying primary immunodeficiencies and improve outcome. Furthermore, XLP should be included routinely in the differential diagnosis of severe hypogammaglobulinemia and/or lymphoma in males.
Assuntos
Mononucleose Infecciosa/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfo-Histiocitose Hemofagocítica/genética , Transtornos Linfoproliferativos/genética , Adolescente , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Pré-Escolar , Análise Mutacional de DNA , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/genética , Éxons/genética , Evolução Fatal , Triagem de Portadores Genéticos , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Testes Genéticos , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/genética , Humanos , Lactente , Mononucleose Infecciosa/diagnóstico , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/mortalidade , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/mortalidade , Masculino , Meningoencefalite/complicações , Meningoencefalite/diagnóstico , Meningoencefalite/genética , Mutação de Sentido Incorreto , Linhagem , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Adulto JovemRESUMO
BACKGROUND: Li-Fraumeni syndrome greatly increases the risk of developing several types of cancer and is usually caused by TP53 germline mutations. Predictive testing of at-risk family members is only offered after a complex genetic counselling process. Recently the clinical implementation of array comparative genomic hybridisation (CGH) has revolutionised the diagnosis of patients with syndromic or non-syndromic mental retardation and has evolved to a routinely performed high resolution whole genome scan. METHODS AND RESULTS: When using array CGH to identify the cause for mental retardation in a 7-year-old child we found a submicroscopic de novo deletion of chromosome 17p13.1, which includes several genes likely to be causative for her phenotype, and also of TP53. CONCLUSION: Thus, array CGH resulted in an unintended predictive diagnosis of an increased tumour susceptibility as observed in Li-Fraumeni syndrome.
Assuntos
Deleção Cromossômica , Hibridização Genômica Comparativa/métodos , Síndrome de Li-Fraumeni/genética , Mutação , Proteína Supressora de Tumor p53/genética , Sequência de Bases , Criança , Quebra Cromossômica , Cromossomos Humanos Par 17/genética , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Hibridização in Situ Fluorescente , Síndrome de Li-Fraumeni/complicações , Síndrome de Li-Fraumeni/diagnóstico , Dados de Sequência Molecular , Neoplasias/etiologia , Neoplasias/genéticaRESUMO
A great number of syndromes and inborn errors of metabolism associated with impaired development have been observed, but the aetiology of mental retardation remains unclear in a considerable proportion of cases. Here, we present the clinical and molecular data from a patient with a new de novo subtelomeric deletion on chromosome 20 [46,XX.ish del(20)(qter-)]. For further refinement, bacterial artificial chromosome clones are used. The deletion spans exactly two genes called MYT1 and PCMTD2. Both genes play an important role in myelination and regulating neural differentiation. Loss of these two genes seems to be responsible for the severe mental retardation and mild facial dysmorphic features in our young patient. It might show the phenotypic picture of this specified deletion.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 20/genética , Deficiência Intelectual/genética , Telômero/genética , Pré-Escolar , Proteínas de Ligação a DNA/deficiência , Feminino , Humanos , Fatores de Transcrição/deficiênciaRESUMO
We report on a currently six-year-old patient with a de novo complex chromosome rearrangement (CCR) involving chromosomes 2 and 12. A translocation 2;12 that appeared to be reciprocal after standard banding turned out to be a complex event with seven breaks after molecular cytogenetic analyses. Array CGH analysis showed no imbalances at the breakpoints but revealed an additional microdeletion of about 80 kb on chromosome 11. The same deletion was also present in the phenotypically normal father. The patient showed relatively mild mental retardation, defined mainly as impaired speech development (orofacial dyspraxia) and psychomotor retardation. In addition, mild dysmorphic facial features like hypertelorism, a prominent philtrum and down-turned corners of the mouth were observed. We narrowed down all breakpoint regions to about 100 kb, using a panel of mapped bacterial artificial chromosome (BAC) clones for fluorescence in situ hybridization (FISH). BACs spanning or flanking all seven breakpoints were identified and no chromosomal imbalances were found consistent with the array CGH results. Our investigations resulted in the following karyotype: 46,XY,t(2;12)(2pter-->2p25.3::2p23.3-->2p25.2::2p23.3-->2p14::2q14.3-->2p14::2q14.3-->2q14.3::12q 12-->12qter;12pter-->12q12::2p25.3-->2p25.2::2q14.3-->2qter).