RESUMO
The PI3K-AKT signalling cascade has a highly conserved role in a variety of processes including cell growth and glucose homoeostasis. Variants affecting this pathway can lead to one of several segmental overgrowth disorders. These conditions are genetically heterogeneous and require tailored, multidisciplinary involvement throughout life. Hypoglycaemia is common in other overgrowth syndromes but has been described only sporadically in association with PIK3CA and CCND2 variants. We report a cohort of 6 children with megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes who developed clinically significant hypoglycaemia. Based on our findings, we suggest that segmental overgrowth patients should be screened for low blood glucose levels during childhood and there should be early specialist endocrine review in any children who develop hypoglycaemia.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Ciclina D2/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Hipoglicemia/diagnóstico , Hipoglicemia/genética , Fenótipo , Adolescente , Alelos , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Ciclina D2/metabolismo , Feminino , Estudos de Associação Genética/métodos , Variação Genética , Genótipo , Humanos , Lactente , Masculino , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Adulto JovemAssuntos
Repetições de Dinucleotídeos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo , Adulto , Alelos , Feminino , Frequência do Gene , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Fator de von Willebrand/imunologiaRESUMO
BACKGROUND: von Willebrand factor (VWF) variant c.2771G>A; p.R924Q has been described as a benign polymorphism or a possible marker for a null allele and been associated with mild bleeding phenotypes. It was identified in several patients in recent type 1 von Willebrand disease (VWD) studies. OBJECTIVES: To determine whether the p.R924Q allele contributes to reduced VWF levels and type 1 VWD. METHODS: One thousand one hundred and fifteen healthy controls and 148 index cases from the MCMDM-1VWD study were genotyped for c.2771G>A; VWF and FVIII levels were analyzed in ABO blood group stratified individuals and the p.R924Q variant was expressed in 293 EBNA cells. RESULTS: c.2771G>A was present in six index cases, five of whom had a second VWF variant which probably contributed to the phenotype. A common core haplotype identified in families, which included the rare G allele of c.5843-8C>G, was present in the majority of 35 c.2771G>A heterozygous controls. c.2771G>A contributed about 10% variance in VWF and FVIII levels in controls and 35% variance when co-inherited with blood group O. Recombinant p.R924Q VWF had no effect on in vitro expression and heterozygous family members had normal VWF-FVIII binding and normal clearance of VWF and FVIII. CONCLUSIONS: The allele bearing c.2771A leads to reductions in VWF and FVIII levels particularly in combination with blood group O. Its inheritance alone may be insufficient for VWD diagnosis, but it appears to be associated with a further VWF level reduction in individuals with a second VWF mutation and it contributes to population variance in VWF and FVIII levels.
Assuntos
Arginina/genética , Fator VIII/genética , Glutamina/genética , Doenças de von Willebrand/genética , Fator de von Willebrand/genética , Sistema ABO de Grupos Sanguíneos , Alelos , Estudos de Casos e Controles , Efeito Fundador , Variação Genética , Genótipo , Heterozigoto , Humanos , Mutação , Fenótipo , Proteínas Recombinantes/química , Fator de von Willebrand/químicaRESUMO
BACKGROUND: Many genetic defects with a chromosomal basis affect male reproduction via a range of different mechanisms. Chromosome position is a well-known marker of nuclear organization, and alterations in standard patterns can lead to disease phenotypes such as cancer, laminopathies and epilepsy. It has been demonstrated that normal mammalian sperm adopt a pattern with the centromeres aligning towards the nuclear centre. The purpose of this study was to test the hypothesis that altered chromosome position in the sperm head is associated with male infertility. METHODS: The average nuclear positions of fluorescence in-situ hybridization signals for three centromeric probes (for chromosomes X, Y and 18) were compared in normoozoospermic men and in men with compromised semen parameters. RESULTS: In controls, the centromeres of chromosomes X, Y and 18 all occupied a central nuclear location. In infertile men the sex chromosomes appeared more likely to be distributed in a pattern not distinguishable from a random model. CONCLUSIONS: Our findings cast doubt on the reliability of centromeric probes for aneuploidy screening. The analysis of chromosome position in sperm heads should be further investigated for the screening of infertile men.
Assuntos
Núcleo Celular , Cromossomos Humanos Par 18 , Infertilidade Masculina/etiologia , Cromossomos Sexuais , Espermatozoides/patologia , Adulto , Biomarcadores , Centrômero , Cromossomos Humanos X , Cromossomos Humanos Y , Humanos , Hibridização in Situ Fluorescente , Masculino , Oligospermia/metabolismoRESUMO
Back pain is a common problem with multiple aetiology. A thorough and systematic initial assessment of the patient will increase the specificity of diagnosis and set up a framework for management in which he will cooperate effectively.
