RESUMO
Holoprosencephaly (HPE) is the most common developmental defect of the forebrain and midface in humans. sporadic and inherited mutations in the human sonic hedgehog (SHH) gene cause 37% of familial HPE. A couple was referred to our unit with a family history of two spontaneous first trimester miscarriages and a daughter with HPE who presented early neonatal death. The father had a repaired median cleft lip, absence of central incisors, facial medial hypoplasia, and cleft palate. Intelligence and a brain CT scan were normal. Direct paternal sequencing analysis showed a novel nonsense mutation (W127X). Facial characteristics are considered as HPE microforms, and the pedigree suggested autosomal dominant inheritance with a variable expression of the phenotype. This study reinforces the importance of an exhaustive evaluation of couples with a history of miscarriages and neonatal deaths with structural defects.
RESUMO
Satoyoshi syndrome (SS) (OMIM 600705) is a rare multisystemic disorder of unknown etiology characterized by progressive painful intermittent muscle spasm, alopecia universalis, diarrhea, short stature, amenorrhea, and secondary skeletal abnormalities mimicking a metaphyseal chondrodysplasia. To date all reported cases have been sporadic. We describe a 26-year-old Mexican woman, a product of consanguineous parents with clinical characteristics of SS. Our patient, also showed skeletal anomalies not previously reported that seems to be a coincidental finding.
Assuntos
Anormalidades Múltiplas/patologia , Osso e Ossos/anormalidades , Consanguinidade , Pais , Adolescente , Adulto , Alopecia/complicações , Osso e Ossos/diagnóstico por imagem , Criança , Pré-Escolar , Fácies , Feminino , Humanos , Masculino , Linhagem , Radiografia , SíndromeRESUMO
Ring chromosomes are present in 1 in 25,000 human fetuses; 99% arise de novo while less than 1% of rings are inherited. This chromosomal rearrangement may arise through a cytogenetic mechanism involving breaks in chromosome arms and fusion of the proximal broken ends, leading to a loss of distal material. Most patient Y ring chromosomes are present in a 45,X/46,X,r(Y) mosaic karyotype; molecular analyses of infertile men have shown that it is not rare to find r(Y) in these patients. However, the clinical spectrum in those cases with a 45,X cell line is broad and depends on the percentage of the monosomic cell line in different tissues. Y chromosome abnormalities and 45,X mosaic karyotypes are often associated with disorders of sex determination. Here, we report a male patient with hypospadias, cryptorchidism and a mosaic karyotype containing a low proportion of 45,X monosomic cells and multiple ring Y chromosomes in peripheral blood. Clinical, surgical, and molecular evidence was sufficient for a diagnosis of mixed gonadal dysgenesis. We suggest that a detailed cytogenetic and molecular analysis should be done in all males with bilateral descended testes and infertility.
Assuntos
Cromossomos Humanos Y/genética , Disgenesia Gonadal Mista/genética , Mosaicismo , Cromossomos em Anel , Núcleo Celular/metabolismo , Centrômero/metabolismo , Criança , Bandeamento Cromossômico , Humanos , Hibridização in Situ Fluorescente , Interfase , Cariotipagem , Masculino , Metáfase , Fenótipo , Proteína da Região Y Determinante do Sexo/metabolismoRESUMO
Ectrodactyly is a congenital limb malformation that involves a central reduction defect of the hands and/or feet which is frequently associated with other phenotypic abnormalities. The condition appears to be genetically heterogeneous and recently it has been demonstrated that mutations in the p63 gene, a homologue of the tumor suppressor gene p53, are the cause of at least four autosomal dominant genetic syndromes which feature ectrodactyly: ectrodactyly, ectodermal dysplasia, and facial clefting (EEC), split hand/split foot malformation (SHFM), limb-mammary syndrome (LMS), and acro-dermato-ungual-lacrimal-tooth syndrome (ADULT). In this study, genetic analysis of the p63 gene in a group of 13 patients with ectrodactyly (syndromic and isolated) was performed. Four patients with syndromic ectrodactyly had p63 heterozygous point mutations that affect the DNA binding domain of the protein. One of these subjects exhibited the typical features of EEC syndrome as well as ankyloblepharon being, to our knowledge, the first case combining these traits. This finding supports the view of a clinical overlap in this group of autosomal dominant syndromes caused by p63 mutations and demonstrates that there are exceptions in the previously established p63 genotype-phenotype correlation.
Assuntos
Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Fosfoproteínas/genética , Transativadores/genética , Adulto , Criança , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Feminino , Dedos/anormalidades , Genes Supressores de Tumor , Genótipo , Humanos , Masculino , México , Fenótipo , Dedos do Pé/anormalidades , Fatores de Transcrição , Proteínas Supressoras de TumorAssuntos
Síndrome de Goldenhar/diagnóstico , Ictiose Ligada ao Cromossomo X/diagnóstico , Anormalidades Múltiplas/diagnóstico , Adulto , Criança , Feminino , Seguimentos , Síndrome de Goldenhar/complicações , Humanos , Ictiose Ligada ao Cromossomo X/complicações , Masculino , México , Linhagem , Medição de RiscoRESUMO
Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder exhibiting a wide clinical spectrum ranging from minimal anomalies to classic CCD. Mutations scattered throughout the entire CBFA1 gene have been related to this disorder. However, it seems that most of them affect the highly conserved Runt domain, abolishing the DNA-binding ability of this transcription factor. Moreover, no systematic effect has been found to relate the type of mutation to the severity of the clinical features. In this paper, we studied two unrelated patients with classic CCD. DNA analysis revealed two novel mutations and three undescribed polymorphisms. One of the substitutions was a missense mutation in the Q/A domain leading to the replacement of a polar residue by a nonpolar one (158 A --> T [Q53L]). The second was an uncommon heterozygous stop codon mutation (1565 G --> C [X522S]) which theoretically results in a longer protein with 23 additional amino acids. This is the first report of this type of mutation in CBFA1. We discuss the possible consequences of these mutant sequences, although no phenotype-genotype correlation could be established. Our findings expand the existing number of allelic variants in this pathology.
Assuntos
Displasia Cleidocraniana/genética , Mutação , Proteínas de Neoplasias , Fatores de Transcrição/genética , Adolescente , Pré-Escolar , Subunidade alfa 1 de Fator de Ligação ao Core , Análise Mutacional de DNA , Feminino , Humanos , Masculino , México , Dados de Sequência Molecular , Polimorfismo GenéticoRESUMO
In humans, sexual differentiation is directed by SRY, a master regulatory gene located at the Y chromosome. This gene initiates the male pathway or represses the female pathway by regulating the transcription of downstream genes; however, the precise mechanisms by which SRY acts are largely unknown. Moreover, several genes have recently been implicated in the development of the bipotential gonad even before SRY is expressed. In some individuals, the normal process of sexual differentiation is altered and a sex reversal disorder is observed. These subjects present the chromosomes of one sex but the physical attributes of the other. Over the past years, considerable progress has been achieved in the molecular characterization of these disorders by using a combination of strategies including cell biology, animal models, and by studying patients with these pathologic entities.
Assuntos
Disgenesia Gonadal 46 XX/genética , Proteínas Nucleares , Doenças dos Animais/embriologia , Doenças dos Animais/genética , Animais , Proteínas de Ligação a DNA/fisiologia , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/patologia , Feminino , Genes sry , Genótipo , Disgenesia Gonadal 46 XX/embriologia , Disgenesia Gonadal 46 XX/epidemiologia , Disgenesia Gonadal 46 XX/patologia , Disgenesia Gonadal 46 XX/terapia , Disgenesia Gonadal 46 XX/veterinária , Gônadas/embriologia , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/fisiologia , Humanos , Cariotipagem , Camundongos , Camundongos Knockout , Mosaicismo , Mutação , Fenótipo , Fatores de Transcrição SOX9 , Processos de Determinação Sexual , Diferenciação Sexual/genética , Diferenciação Sexual/fisiologia , Proteína da Região Y Determinante do Sexo , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Translocação Genética/genética , Vertebrados/fisiologia , Cromossomo X/ultraestrutura , Cromossomo Y/genética , Cromossomo Y/ultraestruturaRESUMO
The androgen insensitivity syndrome (AIS) is an X-linked form of male pseudohermaphroditism caused by mutations in the androgen receptor (AR) gene. In the present study, we analyzed the AR gene in 8 patients, 4 sporadic and 2 familial cases with the syndrome, using exon-specific polymerase chain reaction, single-stranded conformational polymorphism and sequencing analysis and identified six new single base mutations, including one nonsense mutation at the hinge region of the receptor. These molecular lesions occurred in the steroid-binding domain (SBD) and all but one affected the first nucleotide of their respective codons. A nonsense mutation in exon 4, which converts a glutamine into a premature termination signal (Q657stop), a missense mutation changing arginine instead of glycine (G743R) and a conservative substitution of leucine with valine at amino acid 830 (L830V) were detected in patients with CAIS. Three other missense mutations located in exons 4 (L701I), 5 (A765S), and 6 (Q802R) were present in individuals bearing a partial form of AIS. These data allow us to reaffirm the view that nonsense mutations in the AR results almost invariably in a CAIS phenotype and underly the importance of the SBD for the AR functional activity.
Assuntos
Síndrome de Resistência a Andrógenos/genética , Receptores Androgênicos/genética , Adulto , Substituição de Aminoácidos , Sítios de Ligação/genética , Códon sem Sentido , DNA/análise , DNA/genética , Éxons , Humanos , Masculino , México , Mutação de Sentido IncorretoRESUMO
In several syndromes genetic males lack gonadal tissue. A range of phenotypes are seen, which varies from complete female external genitalia to anorchic subjects with sexual infantilism. Differences in phenotypic expression depend on the stage at which testes degenerated during intrauterine development. Although most cases of these syndromes are sporadic, several instances of familial recurrence suggest a genetic origin. To help elucidate the source, we performed molecular analysis of the complete SRY gene open reading frame in two subjects with true agonadism and in two with anorchia. Our results add to previous findings indicating that molecular defects in SRY are not readily identified as a cause of these syndromes.
Assuntos
Proteínas de Ligação a DNA/genética , Genitália/anormalidades , Proteínas Nucleares , Fatores de Transcrição , Adulto , Feminino , Humanos , Técnicas In Vitro , Cariotipagem , Fenótipo , Análise para Determinação do Sexo , Processos de Determinação Sexual , Proteína da Região Y Determinante do Sexo , Cromossomo X , Cromossomo YRESUMO
X-linked ichthyosis is an inherited disorder due to steroid sulfatase deficiency. It is clinically characterized by dark, adhesive, and regular scales of the skin. Most X-linked ichthyosis patients present large deletions of the STS gene and flanking markers; a minority show a point mutation or partial deletion of the STS gene. In this study we analyzed the STS gene in a family with simultaneous occurrence of X-linked ichthyosis and ichthyosis vulgaris. X-linked ichthyosis diagnosis was confirmed through steroid sulfatase assay in leukocytes using 7-[3H]-dehydroepiandrosterone sulfate as a substrate. Exons 1, 2, 5, and 6-10, and the 5' flanking markers DXS1130, DXS1139, and DXS996 of the STS gene were analyzed by polymerase chain reaction. X-linked ichthyosis patients of the family (n = 4 males) had undetectable levels of STS activity (0.00 pmol per mg protein per h). The DNA analysis showed that only exons 6-10 and the 5' flanking markers of the STS gene were present. We report the first partial deletion of the STS gene spanning exons 1-5 in X-linked ichthyosis patients.