RESUMEN
The role of genetic background in childhood-onset combined pituitary hormone deficiency (CPHD) has been extensively studied. The major contributors are the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes coding transcription factors implicated in pituitary organogenesis. The clinical consequences of mutations encompass impaired synthesis of a growth hormone (GH) and one or more concurrent pituitary hormones (i.e. LH, FSH, TSH, PRL). Manifestation of the disorder may vary due to various mutation impacts on the final gene products or an influence of environmental factors during pituitary organogenesis. We describe the clinical and molecular characteristics of two brothers aged 47 and 39 years presenting an uncommon manifestation of congenital hypopituitarism. Sequencing of the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes was performed to confirm the genetic origin of the disorder. A compound heterozygosity in the PROP1 gene has been identified for both probands. The first change represents a mutational hot spot (c.150delA, p.R53fsX164), whereas the second is a novel alteration (p.R112X) that leads to protein disruption. Based on precise genetic diagnosis, an in silico prediction of a p.R112X mutation on protein architecture was performed. The resulting clinical phenotype was surprisingly distinct compared to most patients with genetic alterations in PROP1 reported in the current literature. This may be caused by a residual activity of a newly identified p.R112X protein that preserves over 70 % of the homeodomain structure. This examination may confirm a key role of a DNA-binding homeodomain in maintaining PROP1 functionality and suggests a conceivable explanation of an unusual phenotype.
Asunto(s)
Mutación del Sistema de Lectura , Proteínas de Homeodominio/genética , Hipopituitarismo/genética , Adulto , Secuencia de Aminoácidos , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
Recently, a truncating mutation of the UBE2A gene has been observed in a family with X-linked mental retardation (XLMR) (1). The three affected males had similar phenotypes, including seizures, obesity, marked hirsutism and a characteristic facial appearance. Here, we report on two families with a total of seven patients and a clinically very similar syndromic form of XLMR. Linkage analysis was performed in the larger of these families, and screening several positional candidate genes revealed a G23R missense mutation in the UBE2A gene. Subsequent UBE2A screening of a phenotypically similar second family revealed another missense mutation, R11Q, again affecting an evolutionarily conserved amino acid close to the N-terminus of the protein. SIFT and PolyPhen analyses suggest that both mutations are pathogenic, which is supported by their absence in 168 healthy controls. Thus, both missense and truncating mutations can give rise to a specific, syndromic form of XLMR which is identifiable in a clinical setting.
Asunto(s)
Discapacidad Intelectual Ligada al Cromosoma X/genética , Mutación Missense , Enzimas Ubiquitina-Conjugadoras/genética , Femenino , Ligamiento Genético , Humanos , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/patología , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Ubiquitinación/genéticaRESUMEN
Cabezas syndrome (MIM 300354) is a recently identified syndromic form of X-linked mental retardation (XLMR) caused by mutations in the CUL4B gene. In total, nine XLMR families carrying mutations in the CUL4B gene have been described to date. Here, we present a detailed clinical phenotype of three affected brothers of Polish descent. Based on the symptoms, we made a clinical diagnosis of Cabezas syndrome, which was subsequently confirmed by identification of a novel nonsense mutation (c.2107A-->T, p.703K-->X) in exon 18 of the CUL4B gene. The mutation was inherited from an asymptomatic mother and was present in all three affected brothers. The patients presented with typical features of Cabezas syndrome, such as severe mental retardation, speech impairment, hyperactivity, seizures, intention tremor, inguinal hernia, small feet, and craniofacial dysmorphism. In addition to previously described symptoms, syndactyly of the second and third toes and skin manifestations (hyperhydrosis and keratosis pilaris) were present in our cases. Our report provides further support that Cabezas syndrome is a recognizable syndromic form of XLMR. We conclude that the CUL4B gene should be screened in males with severe speech impairment and primary intention tremor, especially if characteristic facial dysmorphism is also present.
Asunto(s)
Codón sin Sentido , Proteínas Cullin/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteínas Cullin/química , Femenino , Humanos , Masculino , LinajeRESUMEN
Oculodentodigital dysplasia (ODDD) (OMIM #164200) is a rare congenital, autosomal dominant disorder comprising craniofacial, ocular, dental, and digital anomalies. The syndrome is caused by GJA1 mutations. The clinical phenotype of ODDD involves a characteristic dysmorphic facies, ocular findings (microphthalmia, microcornea, glaucoma), syndactyly type III of the hands, phalangeal abnormalities, diffuse skeletal dysplasia, enamel dysplasia, and hypotrichosis. In a Polish child with the clinical symptoms typical of ODDD, we demonstrated a novel missense mutation c.C31A resulting in p.L11F substitution. Our report provides evidence on the importance of this highly conserved amino acid residue for the proper functioning of GJA1 protein.
Asunto(s)
Conexina 43/genética , Anomalías del Ojo/genética , Mutación Missense , Sindactilia/genética , Anomalías Dentarias/genética , Preescolar , Femenino , Humanos , SíndromeRESUMEN
The methods of molecular cytogenetics, in particular fluorescence in situ hybridization (FISH), are widely applied in cytogenetics for identification of numerical and structural chromosomal abnormalities, which are difficult to detect by routine cytogenetic techniques. Due to many advantages, FISH is used in research (gene mapping, gene expression studies, interspecies chromosome homology), and clinical diagnostics (chromosomal aberrations analysis in pre- and postnatal diagnostics, oncology). The techniques of in situ hybridization (ISH) are often employed in addition to classical banding techniques, in case where banding pattern is not reliable. This paper focuses on particular clinical examples, where FISH was successfully used to identify structural and numerical chromosomal aberrations.
Asunto(s)
Hibridación Fluorescente in Situ/métodos , Aborto Espontáneo/patología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/ultraestructura , Enfermedad de Charcot-Marie-Tooth/patología , Vellosidades Coriónicas/metabolismo , Pintura Cromosómica , Cromosomas/efectos de los fármacos , Cromosomas/ultraestructura , Cromosomas Humanos Par 16 , Marcadores Genéticos , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Linfocitos/ultraestructura , Cromosoma Filadelfia , Translocación Genética , Trisomía/patologíaRESUMEN
The results of lung cancer treatment have not significantly improved for many years. About 35% of patients with non-small cell lung cancer (NSCLC) are in clinical stage IIIA. Clinically asymptomatic distant metastases occur in the majority of these patients. In such cases only combined treatment offers a chance of cure. In the Chest Surgery Center in Lublin a clinical trial was carried out aimed to assess late results of combined treatment in patients with IIIA NSCLC. Over 700 patients were enrolled in the study. The results of the trial disclosed, that neoadjuvant chemotherapy prolonged life of the operated patients and improved their life quality. However, a question of qualification for this complex treatment and complexity of assessment criteria, still remain to be answered.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Neoadyuvante , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Metástasis de la Neoplasia , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Hereditary motor-sensory neuropathies (HMSN) are a heterogeneous group of disorders of peripheral nervous system. Four genes in HMSN have been characterized so far i.e.: PMP22, MPZ, Cx32 and EGR-2. The advent of molecular genetic techniques over the past few years has provided identification of molecular defects in a few forms of HMSN. The present study describes the application of modern molecular genetic methods, which are used in the studies of HMSN. Southern blot hybridisation, Fluorescence in situ hybridisation (FISH), Short Tandem Repeat analysis (STR), Semiquantitative PCR analysis (SQ-PCR), Single Strand Conformation Polymorphism method (SSCP), Heteroduplex analysis (HD) and finally DNA automated sequencing are described in the present paper. In the conclusions the advantages and limits of mentioned methods of DNA analysis in HMSN have been described.