RESUMO
Copy number variations of several genes involved in the process of gonadal determination have been identified as a cause of 46,XY differences of sex development. We report a non-syndromic 14-year-old female patient who was referred with primary amenorrhea, absence of breast development, and atypical genitalia. Her karyotype was 47,XY,+mar/46,XY, and FISH analysis revealed the X chromosome origin of the marker chromosome. Array-CGH data identified a pathogenic 2.0-Mb gain of an Xp21.2 segment containing NR0B1/DAX1 and a 1.9-Mb variant of unknown significance from the Xp11.21p11.1 region. This is the first report of a chromosomal microarray analysis to reveal the genetic content of a small supernumerary marker chromosome detected in a 47,XY,+der(X)/46,XY karyotype in a non-syndromic girl with partial gonadal dysgenesis and gonadoblastoma. Our findings indicate that the mosaic presence of the small supernumerary Xp marker, encompassing the NR0B1/DAX1 gene, may have been the main cause of dysgenetic testes development, although the role of MAGEB and other genes mapped to the Xp21 segment could not be completely ruled out.
Assuntos
Disgenesia Gonadal 46 XY , Gonadoblastoma , Neoplasias Ovarianas , Adolescente , Receptor Nuclear Órfão DAX-1/genética , Variações do Número de Cópias de DNA , Feminino , Disgenesia Gonadal 46 XY/genética , Gonadoblastoma/genética , Humanos , CariótipoRESUMO
BACKGROUND: Adrenal hypoplasia congenita (AHC) is an X-linked disorder that affects the adrenal cortex and hypothalamus-pituitary-gonadal axis (HPG), leading to primary adrenocortical insufficiency (PAI) and hypogonadotropic hypogonadism. AHC is caused by a mutation in the DAX-1 gene (NR0B1). More commonly, this disease is characterized by early-onset PAI, with symptoms in the first months of life. However, a less severe phenotype termed late-onset AHC has been described, as PAI signs and symptoms may begin in adolescence and adulthood. Here we describe a family report of a novel mutation within NR0B1 gene and variable reproductive phenotypes, including spontaneous fertility, in a very late-onset X-linked AHC kindred. CASE PRESENTATION: Three affected maternal male relatives had confirmed PAI diagnosis between 30 y and at late 64 y. The X-linked pattern has made the endocrinology team to AHC suspicion. Regarding the HPG axis, all males presented a distinct degree of testosterone deficiency and fertility phenotypes, varying from a variable degree of hypogonadism, oligoasthenoteratozoospermia to spontaneous fertility. Interestingly, the other five maternal male relatives unexpectedly died during early adulthood, most likely due to undiagnosed PAI/adrenal crisis as the probable cause of their premature deaths. Sequencing analysis of the NR0B1 gene has shown a novel NR0B1 mutation (p.Tyr378Cys) that segregated in three AHC family members. CONCLUSIONS: NR0B1 p.Tyr378Cys segregates in an AHC family with a variable degree of adrenal and gonadal phenotypes, and its hemizygous trait explains the disease in affected family members. We recommend that NR0B1 mutation carriers, even those that are allegedly asymptomatic, be carefully monitored while reinforcing education to prevent PAI and consider early sperm banking when spermatogenesis still viable.
Assuntos
Insuficiência Adrenal/genética , Insuficiência Adrenal/patologia , Receptor Nuclear Órfão DAX-1/genética , Fertilidade , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Reprodução , Adulto , Idade de Início , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , PrognósticoRESUMO
INTRODUCTION: In Brazil, driver aggressiveness in road traffic is a critical issue and could be an important contributing factor to the high number of traffic accidents. Because no instruments are available in Portuguese to register driving aggressiveness or driving anger in Brazil, we adapted English instruments into the Brazilian context. The aims of this study were to provide a Brazilian adaptation of the Driving Anger Expression Inventory (DAX) and to try to validate it by testing its psychometric properties and investigating its relationships with risky driving behaviors (DBQ), road accidents, driving sensation seeking, and hostility. METHOD: The Brazilian adaptations of the DAX, DBQ, the Driving Sensation Seeking Scale (DSSS) and the hostility Scale were administered to a sample of 512 undergraduate students (with a mean age of 23.7 years, 52.1% men). RESULTS: Confirmatory factor analysis of the Brazilian DAX (DAX-BR) items yielded a four-factor solution with 43 items, which obtained the best goodness-of-fit to the data. Cronbach's alpha for the DAX-BR factors ranged from 0.69 to 0.88. Other results on validity were a positive correlation (range 0.39-0.59) between the factors of the DAX-BR, DSSS, and DBQ. CONCLUSION: DAX-BR as the same structure as the original and is a reliable instrument for use with young drivers. Other studies should be conducted to further validate the DAX-BR in different types of populations such as older and more experienced drivers, professional drivers, and traffic regulation offenders whose driver's license has been taken away. Practical applications: This Brazilian version can be recommended for the assessment of driving anger expression in Brazil among young drivers in view of helping them driver more safely, and in particular to reduce traffic violations.
Assuntos
Acidentes de Trânsito/psicologia , Agressão/psicologia , Ira , Condução de Veículo/psicologia , Hostilidade , Assunção de Riscos , Inquéritos e Questionários/normas , Acidentes de Trânsito/prevenção & controle , Adolescente , Adulto , Brasil , Análise Fatorial , Feminino , Humanos , Idioma , Licenciamento , Masculino , Ocupações , Psicometria , Reprodutibilidade dos Testes , Fatores de Risco , Sensação , Estudantes , Adulto JovemRESUMO
Two sisters phenotypically normal females, presenting with tumor abdominal mass with histopathological findings of teratoma and gonadoblastoma associated to 46,XY male-to-female sex reversal syndrome, secondary to a duplication in DAX-1, possibly inherited of maternal gonadal mosaicism. Copy number variation and functional effects of the duplication were done by MLPA multiplex ligation-dependent probe amplification and real time PCR. DAX-1, also known as dosage sensitive sex reversal gene (DSS), is considered the most likely candidate gene involved in XY gonadal dysgenesis when overexpressed. The excess of DAX-1 gene disturbs testicular development by down regulation of SF-1, WT1, and SOX9. This is the first report of 46,XY sex reversal in two siblings who have a maternally inherited duplication of DAX-1 associated with reduced levels of expression of downstream genes as SOX9-SF1.
Assuntos
Receptor Nuclear Órfão DAX-1/genética , Disgenesia Gonadal/genética , Processos de Determinação Sexual/genética , Adolescente , Criança , Receptor Nuclear Órfão DAX-1/metabolismo , Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA/genética , Feminino , Dosagem de Genes/genética , Duplicação Gênica , Disgenesia Gonadal 46 XY/genética , Gonadoblastoma/genética , Humanos , Linhagem , Análise para Determinação do Sexo/métodos , Diferenciação Sexual , Maturidade Sexual/genética , Irmãos , Teratoma , Testículo/anormalidadesRESUMO
Adrenal hypoplasia congenita (AHC) is a rare disease that can be caused by many abnormalities, including an X-linked form. Mutations in the DAX1 gene have been assigned as the genetic cause of AHC. We describe here three siblings with AHC, clinically presented at different ages, two in the neonatal period and one oligosymptomatic during infancy. Molecular analysis was able to detect a novel mutation in exon 1 of the DAX1 gene, consisting of a transition of C to T at position 359, determining a stop codon at position 359 (Q359X). The mutated gene encodes a truncated protein missing a large portion of the ligand-binding domain (C-terminal domain). The recognition of the disease in the index case suggested the diagnosis in the other siblings. Interestingly, the same mutation is presented with different phenotypes, suggesting that first-degree family members of patients with DAX1 mutations should be carefully evaluated routinely.