RESUMO
We report two similarly affected cousins (children of monozygotic twin sisters) with phenotypic features consistent with 9p deletion syndrome, including dysmorphic craniofacial features (trigonocephaly, midface hypoplasia, upward-slanting palpebral fissures and long philtrum), intellectual disability and disorders of sex development. Initial cytogenetic examination showed normal karyotypes in the probands and their respective parents, though multiplex ligation probe amplification revealed a 1q terminal duplication and a 9p terminal deletion in both affected children. Further analysis by fluorescence in situ hybridization, identified a familial balanced cryptic translocation t(1;9)(q44;p23) in the mothers, showing the importance of the association of molecular cytogenetic techniques in clinical genetics, given the implications for the care of patients and for genetic counseling.
Assuntos
Hibridização in Situ Fluorescente/métodos , Translocação Genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 9/genética , Feminino , Humanos , MasculinoRESUMO
Monosomy 1p36 is the most common subtelomeric microdeletion syndrome with an incidence rate estimated to be 1 in 5000 births. A hypothesis of a similarity between patients with 1p36 deletion and those with Prader-Willi syndrome and the existence of two different phenotypes for 1p36 microdeletion has been suggested. The main objective of the present study was to determine the existence of 1p36 microdeletion in a sample of patients with mental retardation, obesity and hyperphagia who tested negative by the methylation test for Prader-Willi syndrome. Sixteen patients (7 females, 9 males), 16-26 years old, were evaluated with high-resolution cytogenetic analysis at 550-850 band levels and with 11 polymorphic microsatellite markers located in the 1p36 region. All patients had normal cytogenetic and molecular results. The results obtained by high-resolution cytogenetic methodology were confirmed by the molecular analyses. We did not detect a 1p36 microdeletion in 16 subjects with the Prader-Willi-like phenotype, which reinforces that no correlation seems to exist between Prader-Willi-like phenotype and the 1p36 microdeletion syndrome.
Assuntos
Metilação de DNA , Monossomia/genética , Síndrome de Prader-Willi/genética , Adolescente , Adulto , Feminino , Deleção de Genes , Marcadores Genéticos , Humanos , Masculino , Repetições de Microssatélites/genética , Fenótipo , Polimorfismo Genético , Adulto JovemRESUMO
Monosomy 1p36 is the most common subtelomeric microdeletion syndrome with an incidence rate estimated to be 1 in 5000 births. A hypothesis of a similarity between patients with 1p36 deletion and those with Prader-Willi syndrome and the existence of two different phenotypes for 1p36 microdeletion has been suggested. The main objective of the present study was to determine the existence of 1p36 microdeletion in a sample of patients with mental retardation, obesity and hyperphagia who tested negative by the methylation test for Prader-Willi syndrome. Sixteen patients (7 females, 9 males), 16-26 years old, were evaluated with high-resolution cytogenetic analysis at 550-850 band levels and with 11 polymorphic microsatellite markers located in the 1p36 region. All patients had normal cytogenetic and molecular results. The results obtained by high-resolution cytogenetic methodology were confirmed by the molecular analyses. We did not detect a 1p36 microdeletion in 16 subjects with the Prader-Willi-like phenotype, which reinforces that no correlation seems to exist between Prader-Willi-like phenotype and the 1p36 microdeletion syndrome.
Assuntos
Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Metilação de DNA , Monossomia/genética , Síndrome de Prader-Willi/genética , Deleção de Genes , Marcadores Genéticos , Repetições de Microssatélites/genética , Fenótipo , Polimorfismo Genético , Adulto JovemRESUMO
Atretic cephalocele is a clinicopathological entity, which is different from the common form of cephalocele. Its etiopathogenesis has not been completely explained and there are only two previous reports of familial recurrence. We report a Brazilian family with autosomal dominant inheritance with variable expressivity.
Assuntos
Encefalocele/genética , Genes Dominantes , Couro Cabeludo/anormalidades , Adulto , Idoso , Alopecia/complicações , Brasil , Criança , Pré-Escolar , Encefalocele/complicações , Encefalocele/diagnóstico , Características da Família , Feminino , Variação Genética , Humanos , Cariotipagem , Masculino , Meningocele/patologia , Pessoa de Meia-Idade , Linhagem , Fenótipo , Estrabismo/complicaçõesRESUMO
The objective of the present study was to determine the frequency of somatic chromosomal anomalies and Y chromosomal microdeletions (azoospermia factor genes, AZF) in infertile males who seek assisted reproduction. These studies are very important because the assisted reproduction techniques (mainly intracytoplasmic sperm injection) bypass the natural selection process and some classical chromosomal abnormalities, microdeletions of AZF genes or some deleterious genic mutations could pass through generations. These genetic abnormalities can cause in the offspring of these patients male infertility, ambiguous external genitalia, mental retardation, and other birth defects. We studied 165 infertile men whose infertility was attributable to testicular problems (60 were azoospermic, 100 were oligospermic and 5 were asthenospermic). We studied 100 metaphases per patient with GTG banding obtained from temporary lymphocyte culture for chromosomal abnormality detection and performed a genomic DNA analysis using 28 Y chromosome-specific sequence-tagged sites for Y AZF microdeletion detection. Karyotyping revealed somatic anomalies in 16 subjects (16/165 = 9.6%). Of these 16, 12 were in the azoospermic group (12/60 = 20%) and 4 were in the oligospermic group (4/100 = 4%). The most common chromosomal anomaly was Klinefelter syndrome (10/165 = 6%). Microdeletions of AZF genes were detected in 12 subjects (12/160 = 7.5%). The frequencies detected are similar to those described previously. These results show the importance of genetic evaluation of infertile males prior to assisted reproduction. Such evaluation can lead to genetic counseling and, consequently, to primary and secondary prevention of mental retardation and birth defects.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Y/genética , Deleção de Genes , Infertilidade Masculina/genética , Humanos , Cariotipagem , Masculino , Oligospermia/genética , Reação em Cadeia da PolimeraseRESUMO
The objective of the present study was to determine the frequency of somatic chromosomal anomalies and Y chromosomal microdeletions (azoospermia factor genes, AZF) in infertile males who seek assisted reproduction. These studies are very important because the assisted reproduction techniques (mainly intracytoplasmic sperm injection) bypass the natural selection process and some classical chromosomal abnormalities, microdeletions of AZF genes or some deleterious genic mutations could pass through generations. These genetic abnormalities can cause in the offspring of these patients male infertility, ambiguous external genitalia, mental retardation, and other birth defects. We studied 165 infertile men whose infertility was attributable to testicular problems (60 were azoospermic, 100 were oligospermic and 5 were asthenospermic). We studied 100 metaphases per patient with GTG banding obtained from temporary lymphocyte culture for chromosomal abnormality detection and performed a genomic DNA analysis using 28 Y chromosome-specific sequence-tagged sites for Y AZF microdeletion detection. Karyotyping revealed somatic anomalies in 16 subjects (16/165 = 9.6 percent). Of these 16, 12 were in the azoospermic group (12/60 = 20 percent) and 4 were in the oligospermic group (4/100 = 4 percent). The most common chromosomal anomaly was Klinefelter syndrome (10/165 = 6 percent). Microdeletions of AZF genes were detected in 12 subjects (12/160 = 7.5 percent). The frequencies detected are similar to those described previously. These results show the importance of genetic evaluation of infertile males prior to assisted reproduction. Such evaluation can lead to genetic counseling and, consequently, to primary and secondary prevention of mental retardation and birth defects.
Assuntos
Humanos , Masculino , Deleção Cromossômica , Cromossomos Humanos Y/genética , Deleção de Genes , Infertilidade Masculina/genética , Cariotipagem , Oligospermia/genética , Reação em Cadeia da PolimeraseRESUMO
Complex chromosome rearrangements (CCR) involving multiple breaks in two or more chromosomes are rare. We describe a girl with development delay and overgrowth who presents a nine-break apparently balanced de novo rearrangement involving chromosomes 1, 2, 3, 4 and 12, and a boy with developmental delay and seizures with a complex three-chromosome apparently balanced de novo rearrangement involving chromosomes 2, 7 and 13. The relationship between clinical abnormalities and apparently balanced rearrangements is discussed.
Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Translocação Genética , Adolescente , Bandeamento Cromossômico , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 7/genética , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Microcefalia/complicações , Hipotonia Muscular/complicaçõesRESUMO
Mutations have been found in the UBE3A gene (E6-AP ubiquitin protein ligase gene) in many Angelman syndrome (AS) patients with no deletion, no uniparental disomy, and no imprinting defect. UBE3A mutations are more frequent in familial than in sporadic patients and the mutations described so far seem to cause similar phenotypes in the familial affected cases. Here we describe two first cousins who have inherited the same UBE3A frameshift mutation (duplication of GAGG in exon 10) from their asymptomatic mothers but present discordant phenotypes. The proband shows typical AS features. Her affected cousin shows a more severe phenotype, with asymmetric spasticity that led originally to a diagnosis of cerebral palsy. Proband's brain MRI shows mild cerebral atrophy while her cousin's brain MRI shows severe brain malformation. This family demonstrates that, although brain malformation is unusual in AS, presence of a brain malformation does not exclude the diagnosis of AS. Also, this UBE3A mutation was transmitted from the cousin's grandfather to only two sisters among eight full siblings, raising the hypothesis of mosaicism for this mutation.
Assuntos
Mutação da Fase de Leitura , Ubiquitina-Proteína Ligases/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , SíndromeRESUMO
The objective of the present study was to develop a simplified low cost method for the collection and fixation of pediatric autopsy cells and to determine the quantitative and qualitative adequacy of extracted DNA. Touch and scrape preparations of pediatric liver cells were obtained from 15 cadavers at autopsy and fixed in 95 percent ethanol or 3:1 methanol:acetic acid. Material prepared by each fixation procedure was submitted to DNA extraction with the Wizard© genomic DNA purification kit for DNA quantification and five of the preparations were amplified by multiplex PCR (azoospermia factor genes). The amount of DNA extracted varied from 20 to 8,640 æg, with significant differences between fixation methods. Scrape preparation fixed in 95 percent ethanol provided larger amount of extracted DNA. However, the mean for all groups was higher than the quantity needed for PCR (50 ng) or Southern blot (500 ng). There were no qualitative differences among the different material and fixatives. The same results were also obtained for glass slides stored at room temperature for 6, 12, 18 and 24 months. We conclude that touch and scrape preparations fixed in 95 percent ethanol are a good source of DNA and present fewer limitations than cell culture, tissue paraffin embedding or freezing that require sterile material, culture medium, laboratory equipment and trained technicians. In addition, they are more practical and less labor intensive and can be obtained and stored for a long time at low cost.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Anormalidades Congênitas , DNA , Hepatócitos , Manejo de Espécimes , Fixação de Tecidos , Autopsia , Reação em Cadeia da PolimeraseRESUMO
The objective of the present study was to develop a simplified low cost method for the collection and fixation of pediatric autopsy cells and to determine the quantitative and qualitative adequacy of extracted DNA. Touch and scrape preparations of pediatric liver cells were obtained from 15 cadavers at autopsy and fixed in 95% ethanol or 3:1 methanol:acetic acid. Material prepared by each fixation procedure was submitted to DNA extraction with the Wizard genomic DNA purification kit for DNA quantification and five of the preparations were amplified by multiplex PCR (azoospermia factor genes). The amount of DNA extracted varied from 20 to 8,640 microg, with significant differences between fixation methods. Scrape preparation fixed in 95% ethanol provided larger amount of extracted DNA. However, the mean for all groups was higher than the quantity needed for PCR (50 ng) or Southern blot (500 ng). There were no qualitative differences among the different material and fixatives. The same results were also obtained for glass slides stored at room temperature for 6, 12, 18 and 24 months. We conclude that touch and scrape preparations fixed in 95% ethanol are a good source of DNA and present fewer limitations than cell culture, tissue paraffin embedding or freezing that require sterile material, culture medium, laboratory equipment and trained technicians. In addition, they are more practical and less labor intensive and can be obtained and stored for a long time at low cost.
Assuntos
Anormalidades Congênitas/diagnóstico , DNA/isolamento & purificação , Hepatócitos , Manejo de Espécimes/métodos , Fixação de Tecidos/métodos , Autopsia , Pré-Escolar , DNA/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase , Manejo de Espécimes/economia , Fixação de Tecidos/economiaRESUMO
A total of 95 patients suspected with the clinical diagnosis of AS were evaluated and 37 cases (39%) were confirmed by cytogenetic or molecular studies as affected by Angelman syndrome. The clinical analysis was performed according to a specific clinical protocol for the diagnosis of AS. Cytogenetical analysis was used to detect chromosome rearrangements by determining the karyotype in lymphocytes by GTG banding and revealed an abnormal karyotype in two cases (5.4%), both of them presenting a new pericentromeric inversion in chromosome 15. Molecular analyses included determination of DNA methylation within the 15q11-13 region by Southern blotting and microsattelite analysis within the 15q11-13 region by PCR and the UBE3A gene was also studied by mutational screening. In 16 cases (43.2%) a de novo deletion was detected in the maternal chromosome 15:3 cases (8.1%) presented imprinting defect at the 15q11-13 region; one case is due to a paternal uniparental dissomy (2.7%) and another two cases showed a inherited mutation at the UBE3A gene (5.4%). Thirteen cases (35.1%) showed no deletion, no UPD, no imprinting defect, no UBE3A mutation and the diagnosis of AS could be ruled out in 58 patients. The objective of the present work was to describe the clinical and laboratory protocols employed at our laboratory in order to establish the AS study. We conclude that the protocols employed here were efficient for the diagnosis of AS, a frequently underdiagnosed pathology.
Assuntos
Síndrome de Angelman/genética , Aberrações Cromossômicas , Análise Mutacional de DNA , Cariotipagem , Ligases/genética , Adolescente , Adulto , Síndrome de Angelman/diagnóstico , Southern Blotting , Brasil , Criança , Pré-Escolar , Inversão Cromossômica , Cromossomos Humanos Par 15 , Metilação de DNA , Diagnóstico Diferencial , Feminino , Impressão Genômica/genética , Humanos , Lactente , Masculino , Análise de Sequência de DNA , Ubiquitina-Proteína LigasesRESUMO
OBJECTIVE: To investigate whether increased age alters the frequency and type of chromosomal anomalies in human spermatozoa. DESIGN: Semen specimens were collected from donors via masturbation; cytogenetic studies were performed on sperm chromosomes after heterologous (human-hamster) in vitro fertilization. SETTING: Cytogenetics Laboratory, Genetics Department, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil. PATIENT(S): Seven men ages 59-74 (older group) and five men ages 23-39 (control group). MAIN OUTCOME MEASURE(S): Frequency and types of chromosomal anomalies in older and control group donors. RESULT(S): The frequency of numerical and structural aberrations (acentric fragments and complex radial figures) was significantly greater in chromosomes of older donors when compared with those of the control group. CONCLUSION(S): The higher frequency of sperm chromosome aberrations in older men was mainly a result of increased nondisjunction, acentric fragments, and complex radial figures.
Assuntos
Aberrações Cromossômicas , Idade Paterna , Interações Espermatozoide-Óvulo/fisiologia , Espermatozoides/ultraestrutura , Adulto , Fatores Etários , Idoso , Animais , Cricetinae , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Sêmen/citologia , Sêmen/fisiologia , Espermatozoides/citologia , Espermatozoides/fisiologiaRESUMO
Among the various types of pigmentary disturbances associated with mosaicism, the phylloid pattern (Greek phyllon = leaf, eidos = form) is characterized by multiple leaf-like patches reminiscent of an art nouveau painting. The number of cases displaying this unusual pattern is so far limited. We describe a phylloid pattern of hypomelanosis in a 3-year-old girl with multiple congenital anomalies including microcephaly, midfacial hypoplasia, cleft lip, coloboma, posteriorly rotated ears, pectus carinatum, and pronounced mental and physical retardation. In addition, this child had oval or oblong patches of hyperpigmentation involving the trunk in a horizontal arrangement dissimilar from the phylloid hypomelanotic pattern. In peripheral blood lymphocytes a karyotype 46,XX,-13,+t(13q;13q) was consistently found, whereas cultured skin fibroblasts showed a complex form of mosaicism comprising three different abnormal cell lines (46,XX,-13,+t(13q;13q)/45,XX,-13/45,XX,-13,+frag). This case provides further evidence that the phylloid pattern represents a separate category of pigmentary disturbance to be distinguished from other types of cutaneous mosaicism such as the lines of Blaschko or the checkerboard arrangement.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 13 , Hipopigmentação/genética , Melaninas/deficiência , Melanose/genética , Mosaicismo/genética , Adulto , Pré-Escolar , Citogenética , Feminino , Humanos , Hipopigmentação/patologia , Pele/patologia , Cromossomo XRESUMO
Ablepharon-macrostomia syndrome (AMS) is a rare condition comprising severe deficiency of the anterior lamella of both eyelids, abnormal ears, macrostomia, anomalous genitalia, redundant skin, and absence of lanugo. There is no agreement about cause; some authors suggest autosomal recessive inheritance. We describe familial occurrence of AMS in a girl, sister of a previously reported patient. The father has facial anomalies that suggest autosomal dominant inheritance. Am. J. Med. Genet. 94:281-283, 2000.
Assuntos
Anormalidades Múltiplas/genética , Pálpebras/anormalidades , Transtornos do Crescimento/genética , Macrostomia/genética , Adulto , Pré-Escolar , Pálpebras/crescimento & desenvolvimento , Feminino , Genes Dominantes , Genitália Feminina/anormalidades , Genitália Feminina/crescimento & desenvolvimento , Transtornos do Crescimento/diagnóstico , Cabelo/anormalidades , Cabelo/crescimento & desenvolvimento , Humanos , Lactente , Recém-Nascido , Masculino , Núcleo Familiar , Gravidez , SíndromeRESUMO
We report a preterm male infant, the first child of a young consanguineous couple, whose physical examination revealed craniofacial disproportion with microcephaly, wide fontanelles, exophthalmos, low nasal root and hypoplastic nose, long philtrum, small mouth, high arched and narrow palate, micrognathia, dysplastic, low-set and rounded ears, short neck and, arthrogryposis. Postmortem findings included hypoplastic lungs. Radiological examinations showed mild and localized increased of bone density in the cranial vault and skull base and facial bones and undermodelled in the long bones. The above findings are characteristics of Raine dysplasia but the case reported here presents a mild bone involvement with only a localized bone sclerosis and absence of prenatal fractures. We discuss the possibility that this case represents an allelic mutation of the Raine gene. The consanguinity of the parents reinforces the hypothesis of autosomal recessive inheritance for this entity.
Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Ossos Faciais/anormalidades , Microcefalia/diagnóstico por imagem , Osteosclerose/diagnóstico por imagem , Anormalidades Múltiplas/genética , Artrogripose/diagnóstico por imagem , Artrogripose/genética , Brasil , Exoftalmia/diagnóstico por imagem , Exoftalmia/genética , Evolução Fatal , Genes Dominantes , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Microcefalia/genética , Osteosclerose/genética , Radiografia , Crânio/anormalidadesRESUMO
A new case of Hernandez syndrome is described in a 16-year-old Brazilian girl. The syndrome consists mainly of psychomotor retardation, epilepsy, a bulbous nose and obesity.
Assuntos
Deficiências do Desenvolvimento , Epilepsia , Nariz/anormalidades , Desempenho Psicomotor , Adolescente , Feminino , Humanos , Obesidade , SíndromeRESUMO
A triploidia é uma anomalia cromossômica comum encontrada em 1 a 2 por cento das gestaçöes clinicamente reconhecidas e em cerca de 15 a 20 por cento dos abortos espontâneos de causa cromossômica. Em aproximadamente 5 por cento dos casos, uma aneuploidia pode estar também associada (Boué et al., 1985). Descrevemos um recém-nascido do sexo feminino, prematuro (30 semanas de idade gestacional), com microcefalia, dismorfias faciais e alteraçöes de membros, que foi a óbito com 1 dia de vida por insuficiência respiratória. O exame anátomo-patológico da placenta revelou alteraçöes compatíveis com degeneraçäo molar. A necrópsia da criança näo evidenciou malformaçöes internas. A análise citogenética de 100 metástases, obtidas a partir de cultura de tecido renal, evidenciou cariótipo 68,XX[73]/69,XXX[27]. Apenas 9 casos de triploidia 68,XX foram descritos anteriormente, sendo 7 em abortos, 1 em feto de 21 semanas e 1 em recém-nascido a termo. Consideramos que este estudo seja o primeiro da literatura relatando a ocorrência de mosaicismo 69,XXX/68,XX em um recém-nascido vivo. Os autores discutem os achados clínicos e os possíveis mecanismos envolvidos nesta aberraçäo cromossômica.
Assuntos
Humanos , Feminino , Gravidez , Recém-Nascido , Adulto , Anormalidades Múltiplas , Aberrações Cromossômicas , Cromossomo X/genética , Aberrações dos Cromossomos SexuaisRESUMO
Three families with the fragile X syndrome were studied with the aim to establish the most frequent clinical signs in the affected individuals and heterozygous women. The clinical evaluation, IQ level measurements and cytogenetic studies were performed in 40 subjects, 20 males and 20 females. The fragile X diagnosis was confirmed in all the male individuals with mental retardation. In the postpubertal subjects the most frequent clinical signs were inner canthal distance < 3.5 cm, macro-orchidism, long and narrow face and high arched palate while in the prepubertal subjects the behavioral characteristics as hyperactivity and poor eye contact were the most frequent and were observed in all patients. Twenty six percent of the heterozygous women presented with mental retardation and showed clinical signs rather than behavioral ones. All male individuals with mental retardation were observed as having fragile X [fra(X)] in lymphocytes culture. Sixty three percent of women showed fra(X). There was a positive correlation between the frequency of fra(X) and the clinical characteristics. We emphasize the importance of the clinical evaluation in the study of familial mental retardation and in the screening of isolated cases with suspect of having the fragile X syndrome.
Assuntos
Síndrome do Cromossomo X Frágil/diagnóstico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Citogenética , Feminino , Síndrome do Cromossomo X Frágil/genética , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-IdadeRESUMO
Spondylocarpotarsal synostosis syndrome (SSS) or congenital synspondylism is a recently delineated clinical entity. At least 15 patients have been reported. We present 3 new patients, 2 of whom were sibs born to first-cousin parents. All of our patients had multiple synostoses involving cervical, thoracic and/or lumbar vertebral bodies and carpal/tarsal bones, scoliosis/lordosis, and short stature. Sensorineural deafness was found in 2 of the 3 patients. Analysis of clinical manifestations suggests clinical variability and genetic heterogeneity in SSS. Of a total of 18 SSS patients, 10 were five pairs of sibs from five families, with first-cousin consanguinity of parents in 3, indicating that at least one type of SS is an autosomal-recessive disorder.