RESUMO
Granular dystrophy Groenouw type I (CDGG1), Reis-Bücklers (CDRB), lattice type I (CDL1) and Avellino (ACD) are four 5q31-linked human autosomal dominant corneal dystrophies. Clinically, they show progressive opacification of the cornea leading to severe visual handicap. The nature of the deposits remains unknown in spite of amyloid aetiology ascribed to the last two. We generated a YAC contig of the linked region and, following cDNA selection, recovered the beta ig-h3 gene. In six affected families we identified missense mutations. All detected mutations occurred at the CpG dinucleotide of two arginine codons: R555W in one CDGG1, R555Q in one CDRB, R124C in two CDL1 and R124H in two ACD families. This suggests, as the last two diseases are characterized by amyloid deposits, that R124 mutated kerato-epithelin (the product of beta ig-h3) forms amyloidogenic intermediates that precipitate in the cornea. Our data establish a common molecular origin for the 5q31-linked corneal dystrophies.
Assuntos
Cromossomos Humanos Par 5 , Distrofias Hereditárias da Córnea/genética , Proteínas da Matriz Extracelular , Proteínas de Neoplasias/genética , Mutação Puntual , Fator de Crescimento Transformador beta , Processamento Alternativo , Sequência de Bases , Células Cultivadas , Mapeamento Cromossômico , Cromossomos Artificiais de Levedura , Córnea/metabolismo , Primers do DNA , Fosfatos de Dinucleosídeos , Éxons , Genes Dominantes , Ligação Genética , Humanos , Íntrons , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Pele/metabolismoRESUMO
Two important expanded studies about the early detection of prostate cancer were made and give contradictory results. The American study didn't demonstrate any benefit on rate of survival, whereas the European one demonstrated 20% lower mortality, however with a non-negligible morbidity, and indubitable necessity of additional treatment. The PCA3 genetic test, praticed on urine after rectal touch, will allow in the future improving selection of patients with a pathological PSA for whom the first series of biopsies are negative, and where the question of further biopsies is still opened. The active observation of some prostate cancers (latent cancer) is a valuable therapeutic option, which, when done in an adequate manner, does not question the long term vital prognostic. The vitamines E and C as well the Selenium have no effect in preventing prostate cancer.
Assuntos
Neoplasias da Próstata/diagnóstico , Antígenos de Neoplasias/genética , Biomarcadores/sangue , Humanos , Masculino , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/terapiaAssuntos
Aneuploidia , DNA/sangue , Testes Genéticos/métodos , Diagnóstico Pré-Natal/métodos , Análise de Sequência de DNA/métodos , Feminino , Humanos , Cariotipagem , Masculino , Gravidez , Sensibilidade e Especificidade , Aberrações dos Cromossomos Sexuais , Trissomia/diagnóstico , Trissomia/genéticaRESUMO
Granular Groenouw type I (CDGG1) and lattice type 1 (CDL1) corneal dystrophies are two distinct potentially blinding conditions. These two entities were recently mapped to a region on chromosome 5q. We have investigated 2 families of Swiss origin with CDGG1 and CDL1 by linkage analysis. Our data show a maximum lod score of 5.38 at theta = 0.00 for marker D5S393 in CDL1 and 4.17 at theta = 0.00 for D5S658 in CDGG1. When combined, these families show a maximum low score of 9.22 for D5S393 at theta = 0.00. This confirms previous reports. Furthermore, we describe a recombination centromeric to D5S399 in a member of the CDL1 family. Haplotype analysis in the 4 branches of the CDGG1 family demonstrated a common chromosomal region including D5S393 and D5S399 in all the affected members. By combining our data with previously reported mapping information and assuming that CDGG1 and CDL1 are allelic manifestations of the same gene, we can refine the location of the CDGG1/CDL1 gene to a 1-cM region on chromosome 5q. Using candidate genes in the 5q22-q32 interval, we investigated the possibility that mutations in the SPARC or LOX genes cause these corneal diseases. Several recombinations occurred between these two genes and CDGG1/CDL1 in our 2 families, thus excluding this hypothesis.
Assuntos
Cromossomos Humanos Par 5/genética , Distrofias Hereditárias da Córnea/genética , Alelos , Distrofias Hereditárias da Córnea/classificação , Feminino , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Masculino , Modelos Genéticos , Osteonectina/genética , Linhagem , Proteína-Lisina 6-Oxidase/genética , Recombinação Genética , SuíçaRESUMO
OBJECTIVE: The disparate occurrence of few cases of retinoblastoma in the same extended pedigree confronts us with the unsolved problem of a low-penetrant autosomal-dominant trait vs fortuitous familial aggregation of sporadic cases. Determination as to whether the disease arises from a common inherited mutation or sporadic mutations has important implications for genetic counseling. This is illustrated in this report of two presumed low-penetrant retinoblastoma pedigrees characterized by two distantly affected relatives connected through apparently healthy carriers. DESIGN: We mathematically modeled the inheritance patterns and calculated the a priori relative probabilities of heredity with low penetrance vs chance occurrence of independent mutations for each pedigree. The derived odds clearly show that the disease, which occurred twice in each family, most likely resulted from unrelated mutations. To prove this, extensive DNA testing was conducted, including determination of intragenic RB1 DNA sequence polymorphisms and screening for mutation using the polymerase chain reaction coupled with single-strand conformation polymorphism analysis. PATIENTS: All living key members from both pedigrees were included. RESULTS: Consistent with our initial expectation, there was no common intragenic haplotype or common germ-line mutation that segregated with the disease phenotype in either of these two families. CONCLUSIONS: We therefore conclude that collateral incidence of retinoblastoma in these two pedigrees occurred by chance and not according to autosomal-dominant inheritance with low penetrance. Furthermore, our data provide the first evidence, to our knowledge, that related individuals may have independent mutations involving an identical gene locus, giving rise to an artefactual inheritance pattern.
Assuntos
Neoplasias Oculares/genética , Mutação , Retinoblastoma/genética , Pré-Escolar , DNA de Neoplasias/genética , Feminino , Genes do Retinoblastoma , Ligação Genética/genética , Humanos , Lactente , Masculino , Modelos Biológicos , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , ProbabilidadeRESUMO
OBJECTIVE: To identify the chromosomal location of the gene involved in the pathogenesis of autosomal dominant radial drusen (malattia leventinese). PATIENTS: Eighty-six members of four families affected with radial drusen; one family of American origin and three families of Swiss origin. METHODS: Family members were clinically examined for the presence of radial drusen. Affected patients and potentially informative spouses were genotyped with short tandem repeat polymorphisms distributed across the autosomal genome. The clinical and genotypic data were subjected to linkage analysis. RESULTS: Fifty-six patients were found to be clinically affected. Significant linkage was observed between the disease phenotype and markers known to lie on the short arm of chromosome 2. The maximum two-point lod score (Zmax) observed for all four families combined was 10.5 and was obtained with marker D2S378. Multipoint analysis yielded a Zmax of 12, centered on marker D2S378. The lod-1 confidence interval was 8 cM, while the disease interval defined by observed recombinants was 14 cM. CONCLUSIONS: The gene responsible for autosomal dominant radial drusen has been mapped to the short arm of chromosome 2. This is an important step toward actually isolating the disease-causing gene. In addition, this information can be used to evaluate other familial drusen phenotypes such as Doyne's macular dystrophy for a possible allelic relationship.
Assuntos
Aberrações Cromossômicas/genética , Cromossomos Humanos Par 2 , Ligação Genética/genética , Drusas Retinianas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Cromossômicos , Mapeamento Cromossômico , DNA/análise , Feminino , Fundo de Olho , Genótipo , Humanos , Escore Lod , Degeneração Macular/genética , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
Thirteen years ago, Motegi and colleagues (J Med Genet 1987;24:696-697) summarized the specific facial phenotype of six Japanese retinoblastoma patients with interstitial 13q14 deletions. Among a series of 228 propositi with retinoblastoma referred to the Lausanne Retinoblastoma Clinic for treatment and genetic counseling between 1986 and 1997, 13 (5.7%) were diagnosed with a cytogenetic de-novo 13q14 deletion. We confirm the presence of the reported facial phenotype in our population of Caucasian patients and describe additional clinical traits, thus extending the facial phenotype associated with the 13q14 deletion. Del(13q14) comprises, among others, cranial anomalies, frontal bossing, deeply grooved and long philtrum, depressed and broad nasal bridge, bulbous tip of the nose, thick lower lip, thin upper lip, broad cheeks, and large ears and lobules. Recognition of this particular facial appearance was instrumental in the genetic diagnosis of 13q deletions and in the presymptomatic diagnosis of retinoblastoma in a significant number of our cases. Identification of this phenotype in a retinoblastoma patient allows for efficient diagnosis of recurrence in his progeny and/or sibship, while its ignorance will compromise genetic counseling due to the possible difficulties in detecting large deletions by standard molecular mutation analysis. Recognition of this syndrome in newborns without known familial risk for retinoblastoma is even more important as it is a clear warning sign that indicates immediate ophthalmic examination.
Assuntos
Cromossomos Humanos Par 13/genética , Fácies , Deleção de Genes , Neoplasias da Retina/genética , Retinoblastoma/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fenótipo , Neoplasias da Retina/etnologia , Neoplasias da Retina/patologia , Retinoblastoma/etnologia , Retinoblastoma/patologia , SíndromeRESUMO
The nature of the tumorigenic mutation was analyzed in 30 retinoblastoma (Rb) tumors (16 non-hereditary and 14 hereditary) and categorized into loss of heterozygosity (LOH) or retention of heterozygosity (non-LOH) at the RB1 locus. These genotypic characteristics were compared with the clinicopathological phenotype for possible correlation. The overall frequency of LOH was roughly 55%, in both hereditary and non-hereditary Rb. The presence of LOH was preferentially associated with differentiated tumors and absence of choroidal invasion. LOH was found in 82% of females versus 33% of males. Finally, LOH-initiated tumors were associated with a significantly younger age at diagnosis in hereditary Rb. In conclusion, the preferential association of LOH with absence of choroidal invasion, tumoral differentiation, and younger age at diagnosis may establish LOH as a prognostic marker in Rb patients.
Assuntos
DNA de Neoplasias/análise , Neoplasias Oculares/genética , Genes do Retinoblastoma/genética , Heterozigoto , Retinoblastoma/genética , Biomarcadores Tumorais , Southern Blotting , Pré-Escolar , Cromossomos Humanos Par 13/genética , Neoplasias Oculares/patologia , Feminino , Humanos , Lactente , Masculino , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Prognóstico , Retinoblastoma/patologiaRESUMO
It has recently been established that maternal serum pregnancy-associated plasma protein A (PAPP-A) was reduced in pregnancies with fetal Down syndrome in the first but not in the second trimester of gestation. In comparison with two other placental proteins, human chorionic gonadotrophin and pregnancy-specific beta 1-glycoprotein, an explanation for this can be formulated based on the large molecular weight of PAPP-A. With the increasing clinical demand for fetal abnormalities to be diagnosed in the first rather than in the second trimester of pregnancy, maternal serum PAPP-A is a strong potential candidate for being used in routine trisomy screening. We have developed a sensitive enzyme immunoassay (ELISA) intended at smaller laboratories due to its long shelf life. Here we show that repeated freezing and thawing, or the addition of iodoacetate (5 mM) did not affect the results, at both high or low concentration of PAPP-A. It is also possible to introduce the serum into the test as a dry sample on blotting paper, easily posted in an envelope. A decrease of 21% was observed after such dry storage for three weeks at room temperature, which can be compensated for by the inclusion of a dried control serum, mailed with the sample(s).
Assuntos
Síndrome de Down/diagnóstico , Ensaio de Imunoadsorção Enzimática/métodos , Proteína Plasmática A Associada à Gravidez/análise , Diagnóstico Pré-Natal , Gonadotropina Coriônica/sangue , Síndrome de Down/sangue , Estabilidade de Medicamentos , Ensaio de Imunoadsorção Enzimática/estatística & dados numéricos , Feminino , Congelamento , Temperatura Alta , Humanos , Iodoacetatos/farmacologia , Ácido Iodoacético , Gravidez , Primeiro Trimestre da Gravidez , Glicoproteínas beta 1 Específicas da Gravidez/análise , Sensibilidade e EspecificidadeRESUMO
Transplantation of allogenic split thickness skin grafts (STSG) and immunosuppression with cyclosporin A enable early and definitive skin replacement of extensive, deep partial and full thickness burns. Covering burn defects with definitely engrafted, allogenic dermis and cultivated epithelial autografts (CEA) permits the subsequent withdrawal of cyclosporin A medication. Light-microscopy examination of biopsies, taken 12 and 24 months postgrafting, and electron microscopy of biopsies taken 12 months postgrafting, demonstrates a re-established, but somewhat reduced anchoring of the CEA as compared with a normal epidermal-dermal junction. Clinical inspection, 20 months postgrafting, confirms the histological observations that epifascial transplantation is qualitatively inferior to placing the allogenic STSG on the subcutaneous tissue. In the first situation, the dermis is inelastic and collagen deposition is excessive, whereas in the second case collagen deposition is comparatively reduced and the dermis shows clinically some elasticity.
Assuntos
Queimaduras/cirurgia , Ciclosporina/administração & dosagem , Transplante de Pele , Adulto , Queimaduras/patologia , Técnicas de Cultura , Feminino , Adesivo Tecidual de Fibrina , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Pele/patologia , Transplante Autólogo , Transplante Homólogo , CicatrizaçãoRESUMO
We report on a sporadic case of Pfeiffer syndrome in a male newborn with complex craniosynostosis, broad thumbs and great toes and early demise. SSCP and direct sequencing revealed a missense mutation at position 1037 of the exon B (or IIIc) of the FGFR2 gene (codon 342) resulting in a cysteine to serine modification (TGC-TCC). Genotype-phenotype correlations between the FGFRs mutations and the different craniosynostotic syndromes are discussed.
Assuntos
Acrocefalossindactilia/genética , Fator 2 de Crescimento de Fibroblastos/genética , Mutação Puntual , Acrocefalossindactilia/diagnóstico por imagem , Craniossinostoses/classificação , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/genética , Evolução Fatal , Humanos , Recém-Nascido , Masculino , RadiografiaRESUMO
The major form of familial hyperekplexia, a rare autosomal dominant disorder, is characterized by an abnormal startle reaction elicited by auditory and somatosensory stimuli, with transitory stiffness during the neontam period, followed later by falling attacks accompanied by momentary generalized muscular stiffness. Affected neonates occasionally have fatal hypertonia. The minor form is characterized only by an inconstant excessive startle response. We encountered a family in which three females presented with a partial or complete major form of the disease. All our patients were hyperreflexic, insecure gait was present in two subjects, without concomitant spontaneous nocturnal myoclonus. The pathophysiological basis of the hyperekplexia remains unclear. The abnormal startle reflex, probably related to the lack of inhibition by higher centers, is relayed in the caudal brainstem (ponto-medullary reticular formation), where bulbospinal motor efferents originate. Moreover, nonspecific changes such as large somatosensory evoked potentials and long-loop reflexes ("C-responses") may indicate increased cortical neuronal excitability. Polygraphic studies in these patients were normal. The locus of the major form of the disorder is located on chromosome 5q33-q35. Sequence analysis of the alpha 1 subunit of the inhibitory glycine receptor (GLRA1) revealed a mutation at the same codon 271 in several families (G1192A and G1192T). We analyzed this gene and found a G1192A mutation changing an ARG to a LEU codon in all three presented patients. Sporadic cases may represent new mutations or lack of penetrance in some family members. Only one of our three patients needed clonazepam. The diagnosis of this disorder rules out epilepsy, or psychogenic pathological startle reaction. Electrophysiological criteria are useful, however perinatal hypertonia or a tonic generalized spasm accompanied with falls following an abnormal startle reaction and genetic studies remain the diagnostic milestones of familial hyperekplexia.
Assuntos
Hipertonia Muscular/genética , Reflexo de Sobressalto , Adolescente , Adulto , Mapeamento Cromossômico , Eletrofisiologia , Feminino , Humanos , Hipertonia Muscular/fisiopatologia , MutaçãoRESUMO
The authors report the results of a cystogenic study of 80 couples (160 individuals) who had early repeated abortions. A significant karyotype abnormality was found in 5 per cent of the partners. Where a translocation of 2 heterological chromosomes is found in a partner, the recommendations is to attempt an antenatal diagnostic. Once a couple have had 2 abortions karyotype investigation is absolutely indicated.
Assuntos
Aborto Habitual/genética , Aberrações Cromossômicas , Feminino , Aconselhamento Genético , Humanos , Cariotipagem , Masculino , Gravidez , Diagnóstico Pré-Natal , Translocação GenéticaRESUMO
Concerned by 2 cases of a recurring multiple fetal malformation syndrome in a consanguineous couple, the authors present the ultrasonic, clinical and paraclinical data that, when introduced into a computerised prenatal diagnostic programme, suggest a Meckel-Gruber or Carpenter-Hunter syndrome. The discovery of single or multiple fetal malformations requires not only complete echographic assessment, but also detailed post-abortum examination to allow optimal use of diagnostic aid programmes.
Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Encefalocele/diagnóstico por imagem , Deformidades Congênitas do Pé/diagnóstico por imagem , Meningocele/diagnóstico por imagem , Doenças Renais Policísticas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adulto , Consanguinidade , Diagnóstico por Computador , Encefalocele/genética , Encefalocele/patologia , Feminino , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/patologia , Humanos , Cariotipagem , Meningocele/genética , Meningocele/patologia , Linhagem , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/patologia , Gravidez , Software , Síndrome , Ultrassonografia Pré-Natal/métodosRESUMO
This paper reports the ultrasound diagnosis at 16 weeks' gestation of thoracopagus conjoined twins. Ultrasound examination showed the two fetuses conjoined at the sternum, with a single heart and a single liver. After informing the couple of the extremely poor prognosis, medical termination of pregnancy was requested. Pathologic examination of the conjoined female fetuses revealed a single, non-duplicated heart, two livers connected at the right lobe, completely separate bile ducts and digestive tract, and a single placenta and umbilical cord containing two arteries and six veins. The karyotype was normal. Diagnostic ultrasound criteria for thoracopagus conjoined twins include: the relative position of the two fetuses facing each other, hyperextension of the cervical spine, continuity of the skin and mirror image body parts with limbs close together. The presence of a single heart, liver and umbilical cord, all of increased size, confirms the diagnosis. Various degrees of fetal fusion result from incomplete division of the inner cell mass 13 to 15 days after fertilization. Although the precise causes are unknown, many workers believe that the factors responsible for monozygosity may also play a role in conjoined twins. In Switzerland, 1% of all live births are twins with approximately 1/4 of these monozygotic. If incomplete division of the inner cell mass occurs in 1% of these cases, the estimated incidence of conjoined twins is 1/40000 births. Although thoracopagus twins are more frequent, omphalopagus twins are more commonly encountered at birth, due to lower fetal mortality. The overall prognosis depends on the degree of organ sharing between fetuses. Very few surgically separated thoracopagus conjoined twins have lived and those who did survive had separate hearts. Also, conjoined twins can cause dystocia with the risk of rupture of the uterus, and often require cesarean section which may have negative consequences for the obstetrical future of the mother. However, an early ultrasound diagnostic can modify prognosis and allow medical termination of pregnancy in the case of seriously malformed thoracopagus conjoined twins. The risk that the condition recurs in a subsequent pregnancy may be considered negligible.