RESUMEN
WHAT IS KNOWN AND OBJECTIVE: Metamizole (dipyrone) is an analgesic that has been the focus of considerable controversy regarding its safety. Because of potentially life-threatening blood disorders such as agranulocytosis, it has been withdrawn in many countries but not in Germany, where prescribing even increased over recent years. We aimed to evaluate prescribing of metamizole in Germany with respect to age, sex and regional variations. METHODS: Using data of a statutory health insurance, we analysed a cohort of 1·7 million persons who were insured at least 1 day in each quarter of 2009. Outcome of interest was the outpatient prescription prevalence, for example the proportion of persons receiving at least one prescription of metamizole. RESULTS AND DISCUSSION: A total of 6·8% received metamizole with a higher prescribing prevalence in females (7·8% vs. 6·0%). The prevalence increased with age up to 26·7% in persons ≥85 years (men: 21·1%; and women: 30·4%). We found large regional variations with higher prevalences in the northern part of Germany. Most of the prescriptions were issued by general practitioners (78·9%). 58·3% were liquid oral formulations with considerable regional variations ranging between 32·3% in Mecklenburg-West Pomerania and 67·3% in North Rhine-Westphalia. Overall, liquid oral forms are much more often prescribed in the western than in the eastern part of Germany. WHAT IS NEW AND CONCLUSION: Metamizole - a drug with a relatively narrow indication - is often prescribed in Germany with relevant differences by age, sex and region. Qualitative studies should clarify reasons for this. Further quantitative research should investigate small-area variations, indications and treatment durations.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Dipirona/administración & dosificación , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/efectos adversos , Niño , Preescolar , Dipirona/efectos adversos , Femenino , Alemania , Humanos , Lactante , Masculino , Persona de Mediana Edad , Pacientes Ambulatorios , Factores Sexuales , Adulto JovenRESUMEN
Microcephalic osteodysplastic primordial dwarfism type I (MOPD I) is a rare autosomal recessive developmental disorder characterized by extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations, and early death. Recently, mutations in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome, were found to cause MOPD I. MOPD I is the first disease known to be associated with a defect in small nuclear RNAs. We describe here the clinical and molecular data for 17 cases of MOPD I, including 15 previously unreported cases, all carrying biallelic mutations in the RNU4ATAC gene.
Asunto(s)
Alelos , Enanismo/genética , Retardo del Crecimiento Fetal/genética , Microcefalia/genética , Mutación , Osteocondrodisplasias/genética , ARN Nuclear Pequeño/genética , Encéfalo/patología , Enanismo/diagnóstico , Facies , Femenino , Retardo del Crecimiento Fetal/diagnóstico , Humanos , Lactante , Esperanza de Vida , Imagen por Resonancia Magnética , Masculino , Microcefalia/diagnóstico , Osteocondrodisplasias/diagnóstico , FenotipoRESUMEN
Autosomal recessive cutis laxa is a genetically heterogeneous condition. Its molecular basis is largely unknown. Recently, a combined disorder of N- and O-linked glycosylation was described in children with congenital cutis laxa in association with severe central nervous system involvement, brain migration defects, seizures and hearing loss. We report on seven additional patients with similar clinical features in combination with congenital disorder of glycosylation type IIx. On the basis of phenotype in 10 patients, we define an autosomal recessive cutis laxa syndrome. The patients have a complex phenotype of neonatal cutis laxa, transient feeding intolerance, late closure of the fontanel, characteristic facial features including down-slanting palpebral fissures, short nose and small mouth, and developmental delay. There is a variable degree of the central nervous system involvement and variable systemic presentation. The biochemical analysis using transferrin isoelectric focusing gives false negative results in some of the youngest patients. Analysis of the apolipoprotein C-III isoelectric focusing, however, is diagnostic in all cases.
Asunto(s)
Anomalías Múltiples/genética , Cutis Laxo/diagnóstico , Cutis Laxo/genética , Glicosilación , Errores Innatos del Metabolismo/diagnóstico , Anomalías Múltiples/metabolismo , Anomalías Múltiples/patología , Niño , Preescolar , Cutis Laxo/congénito , Femenino , Genes Recesivos , Humanos , Lactante , Masculino , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Linaje , Fenotipo , SíndromeRESUMEN
Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC-affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty-four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC-affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty-eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1- and MAP2K2-mutation positive individuals, suggesting possible genotype-phenotype correlations.
Asunto(s)
Anomalías Múltiples/genética , Facies , Cardiopatías Congénitas/genética , Mutación , Anomalías Cutáneas/genética , Adulto , Niño , Análisis Mutacional de ADN , Discapacidades del Desarrollo , Humanos , Discapacidad Intelectual , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 2/genética , Fenotipo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras) , Síndrome , Proteínas ras/genéticaRESUMEN
BACKGROUND: Lissencephaly is a neuronal migration disorder leading to absent or reduced gyration and a broadened but poorly organized cortex. The most common form of lissencephaly is isolated, referred as classic or type 1 lissencephaly. Type 1 lissencephaly is mostly associated with a heterozygous deletion of the entire LIS1 gene, whereas intragenic heterozygous LIS1 mutations or hemizygous DCX mutations in males are less common. METHODS: Eighteen unrelated patients with type 1 lissencephaly were clinically and genetically assessed. In addition, patients with subcortical band heterotopia (n = 1) or lissencephaly with cerebellar hypoplasia (n = 2) were included. RESULTS: Fourteen new and seven previously described LIS1 mutations were identified. We observed nine truncating mutations (nonsense, n = 2; frameshift, n = 7), six splice site mutations, five missense mutations, and one in-frame deletion. Somatic mosaicism was assumed in three patients with partial subcortical band heterotopia in the occipital-parietal lobes or mild pachygyria. We report three mutations in exon 11, including a frameshift which extends the LIS1 protein, leading to type 1 lissencephaly and illustrating the functional importance of the WD domains at the C terminus. Furthermore, we present two patients with novel LIS1 mutations in exon 10 associated with lissencephaly with cerebellar hypoplasia type a. CONCLUSION: In contrast to previous reports, our data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity. Furthermore, patients presenting with mild cerebral malformations such as subcortical band heterotopia or cerebellar hypoplasia should be considered for genetic analysis of the LIS1 gene.
Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , Corteza Cerebral/anomalías , Predisposición Genética a la Enfermedad/genética , Proteínas Asociadas a Microtúbulos/genética , Mutación/genética , Malformaciones del Sistema Nervioso/genética , Adolescente , Adulto , Movimiento Celular/genética , Cerebelo/anomalías , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Niño , Preescolar , Coristoma/genética , Coristoma/metabolismo , Análisis Mutacional de ADN , Femenino , Marcadores Genéticos/genética , Pruebas Genéticas , Genotipo , Humanos , Lactante , Masculino , Malformaciones del Sistema Nervioso/metabolismo , Malformaciones del Sistema Nervioso/fisiopatología , Penetrancia , FenotipoRESUMEN
Cohen syndrome (CS) is an autosomal recessive disorder with variability in the clinical manifestations, characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in the gene COH1 have been found in an ethnically diverse series of patients. Brief clinical descriptions of 24 patients with CS are provided. The patients were from 16 families of different ethnic backgrounds and between 2.5 and 60 years of age at assessment. DNA samples from all patients were analysed for mutations in COH1 by direct sequencing. Splice site mutations were characterised using reverse transcriptase PCR analysis from total RNA samples. In this series, we detected 25 different COH1 mutations; 19 of these were novel, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in frame deletions, and 1 missense mutation. We observed marked variability of developmental and growth parameters. The typical facial gestalt was seen in 23/24 patients. Early onset progressive myopia was present in all the patients older than 5 years. Widespread pigmentary retinopathy was found in 12/14 patients assessed over 5 years of age. We present evidence for extended allelic heterogeneity of CS, with the vast majority of mutations leading to premature termination codons in COH1. Our data confirm the broad clinical spectrum of CS with some patients lacking even the characteristic facial gestalt and pigmentary retinopathy at school age.
Asunto(s)
Anomalías Múltiples/diagnóstico , Discapacidad Intelectual/diagnóstico , Proteínas de la Membrana/genética , Miopía/diagnóstico , Retinitis Pigmentosa/diagnóstico , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Cara/anomalías , Femenino , Heterogeneidad Genética , Humanos , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , Mutación , Miopía/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Retinitis Pigmentosa/genética , Síndrome , Proteínas de Transporte VesicularAsunto(s)
Codón/genética , Variación Genética/genética , Mutación Missense/genética , Proteínas Nucleares/genética , Síndrome de Rubinstein-Taybi/genética , Proteínas de Saccharomyces cerevisiae , Transactivadores/genética , Acetiltransferasas/genética , Adolescente , Adulto , Proteína de Unión a CREB , Niño , Preescolar , ADN/genética , Análisis Mutacional de ADN , Femenino , Histona Acetiltransferasas , Humanos , Lactante , Recién Nacido , Masculino , Proteínas Nucleares/química , Estructura Secundaria de Proteína/genética , Síndrome de Rubinstein-Taybi/diagnóstico , Transactivadores/químicaRESUMEN
The microphthalmia with linear skin defects syndrome (MLS) is an X-linked dominant disorder with male lethality. In the majority of the patients reported, the MLS syndrome is caused by segmental monosomy of the Xp22.3 region. To date, five male patients with MLS and 46,XX karyotype ("XX males") have been described. Here we report on the first male case with MLS and an XY complement. The patient showed agenesis of the corpus callosum, histiocytoid cardiomyopathy, and lactic acidosis but no microphthalmia, and carried a mosaic subtle inversion of the short arm of the X chromosome in 15% of his peripheral blood lymphocytes, 46,Y,inv(X)(p22.13 approximately 22.2p22.32 approximately 22.33)[49]/46,XY[271]. By fluorescence IN SITU hybridization (FISH), we showed that YAC 225H10 spans the breakpoint in Xp22.3. End-sequencing and database analysis revealed a YAC insert of at least 416 kb containing the genes HCCS and AMELX, and exons 2-16 of ARHGAP6. Molecular cytogenetic data suggest that the Xp22.3 inversion breakpoint is located in intron 1 of ARHGAP6, the gene encoding the Rho GTPase activating protein 6. Future molecular studies in karyotypically normal female MLS patients to detect submicroscopic rearrangements including the ARHGAP6 gene as well as mutation screening of ARHGAP6 in patients with no obvious chromosomal rearrangements will clarify the role of this gene in MLS syndrome.
Asunto(s)
Inversión Cromosómica , Cromosomas Humanos X/genética , Microftalmía/genética , Anomalías Cutáneas , Resultado Fatal , Proteínas Activadoras de GTPasa/genética , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación , Masculino , Microftalmía/patología , Mosaicismo , Aberraciones Cromosómicas Sexuales , SíndromeRESUMEN
We report two female patients, 11 and eight years old, with clinical findings consistent with the Floating-Harbor syndrome (FHS). The first patient presented with characteristic facial features, brachydactyly, broad thumbs, and delay of speech development, but less pronounced short stature (-2 standard deviation (SD) below mean) than previously reported. The second patient presented with short stature, characteristic facial features, brachydactyly, and delay of speech as well as mental development; she was successfully treated with growth hormone. Metacarpophalangeal pattern profiles (MCPP) were performed in both patients and compared to those of previously published patients.
Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Craneofaciales/diagnóstico , Trastornos del Crecimiento/tratamiento farmacológico , Hormona del Crecimiento/uso terapéutico , Niño , Femenino , Crecimiento/efectos de los fármacos , Trastornos del Crecimiento/diagnóstico , Hormona del Crecimiento/deficiencia , Humanos , Trastornos del Habla/diagnóstico , Síndrome , Resultado del TratamientoAsunto(s)
Proteínas Portadoras/genética , Osteocondrodisplasias/genética , Proteínas de Transporte de Anión , Femenino , Fémur/anomalías , Humanos , Húmero/anomalías , Masculino , Proteínas de Transporte de Membrana , Mutación , Osteocondrodisplasias/diagnóstico , Embarazo , Transportadores de Sulfato , Ultrasonografía PrenatalAsunto(s)
Sistema Nervioso Central/anomalías , Cromosomas Humanos Par 11 , Exostosis Múltiple Hereditaria/genética , Sistema Nervioso Central/diagnóstico por imagen , Deleción Cromosómica , Disostosis Craneofacial/genética , Exostosis Múltiple Hereditaria/diagnóstico por imagen , Humanos , Discapacidad Intelectual , Hueso Parietal/anomalías , Radiografía , Síndrome , Terminología como AsuntoRESUMEN
Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.
Asunto(s)
Cromosomas Humanos Par 8/genética , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Mutación/genética , Osteocondrodisplasias/clasificación , Osteocondrodisplasias/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Antropometría , Secuencia de Bases , Estatura , Niño , Preescolar , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Factores de Unión al ADN Específico de las Células Eritroides , Exones/genética , Femenino , Genotipo , Humanos , Lactante , Deformidades Congénitas de las Extremidades/diagnóstico por imagen , Deformidades Congénitas de las Extremidades/fisiopatología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/patología , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Radiografía , Síndrome , Factores de Transcripción/metabolismo , Dedos de Zinc/genéticaRESUMEN
Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. Recently, heterozygous mutations of the orphan receptor tyrosine kinase (TK) ROR2, located within a distinct segment directly after the TK domain, have been shown to be responsible for BDB. We report four novel mutations in ROR2 (two frameshifts, one splice mutation, and one nonsense mutation) in five families with BDB. The mutations predict truncation of the protein within two distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients affected with the distal mutations have a more severe phenotype than do those with the proximal mutation. Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK domain. His phenotype resembles an extreme form of brachydactyly, with extensive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he has vertebral anomalies, brachymelia of the arms, and a ventricular septal defect-features that are reminiscent of Robinow syndrome, which has also been shown to be caused by mutations in ROR2. The BDB phenotype, as well as the location and the nature of the BDB mutations, suggests a specific mutational effect that cannot be explained by simple haploinsufficiency and that is distinct from that in Robinow syndrome.
Asunto(s)
Dedos/anomalías , Deformidades Congénitas de la Mano/genética , Mutación/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Superficie Celular/genética , Secuencia de Aminoácidos , Secuencia de Bases , Codón sin Sentido/genética , Consanguinidad , Análisis Mutacional de ADN , Exones/genética , Femenino , Dedos/fisiopatología , Mutación del Sistema de Lectura/genética , Genotipo , Deformidades Congénitas de la Mano/clasificación , Deformidades Congénitas de la Mano/fisiopatología , Humanos , Intrones/genética , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Estructura Terciaria de Proteína , Sitios de Empalme de ARN/genética , Receptores Huérfanos Similares al Receptor Tirosina Quinasa , Receptores de Superficie Celular/química , SíndromeRESUMEN
An SOX9 mutation in a previously published case of campomelic dysplasia is described. This case did not have overt campomelia of the femora or tibiae although campomelic dysplasia has subsequently been confirmed by gene analysis.
Asunto(s)
Proteínas del Grupo de Alta Movilidad/genética , Mutación , Osteocondrodisplasias/genética , Factores de Transcripción/genética , Humanos , Factor de Transcripción SOX9RESUMEN
Holoprosencephaly (HPE) is the most common structural defect of the developing forebrain in humans (1 in 250 conceptuses, 1 in 16,000 live-born infants). HPE is aetiologically heterogeneous, with both environmental and genetic causes. So far, three human HPE genes are known: SHH at chromosome region 7q36 (ref. 6); ZIC2 at 13q32 (ref. 7); and SIX3 at 2p21 (ref. 8). In animal models, genes in the Nodal signalling pathway, such as those mutated in the zebrafish mutants cyclops (refs 9,10), squint (ref. 11) and one-eyed pinhead (oep; ref. 12), cause HPE. Mice heterozygous for null alleles of both Nodal and Smad2 have cyclopia. Here we describe the involvement of the TG-interacting factor (TGIF), a homeodomain protein, in human HPE. We mapped TGIF to the HPE minimal critical region in 18p11.3. Heterozygous mutations in individuals with HPE affect the transcriptional repression domain of TGIF, the DNA-binding domain or the domain that interacts with SMAD2. (The latter is an effector in the signalling pathway of the neural axis developmental factor NODAL, a member of the transforming growth factor-beta (TGF-beta) family.) Several of these mutations cause a loss of TGIF function. Thus, TGIF links the NODAL signalling pathway to the bifurcation of the human forebrain and the establishment of ventral midline structures.
Asunto(s)
Tipificación del Cuerpo/genética , Holoprosencefalia/genética , Proteínas de Homeodominio/genética , Transducción de Señal , Factor de Crecimiento Transformador beta/fisiología , Animales , Secuencia de Bases , Células COS , Cromosomas Humanos Par 18/genética , ADN/genética , ADN/metabolismo , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Exones/genética , Regulación de la Expresión Génica/genética , Proteínas de Homeodominio/química , Proteínas de Homeodominio/metabolismo , Humanos , Ratones , Mutación , Proteína Nodal , Mapeo Físico de Cromosoma , Prosencéfalo/anomalías , Prosencéfalo/embriología , Prosencéfalo/metabolismo , Unión Proteica , ARN Mensajero/análisis , ARN Mensajero/genética , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/química , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteína Smad2 , Transactivadores/metabolismoAsunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 4/genética , Frecuencia de los Genes/genética , Discapacidad Intelectual/genética , Translocación Genética/genética , Alelos , Niño , Preescolar , Bandeo Cromosómico , Rotura Cromosómica/genética , Deleción Cromosómica , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 8/genética , Cósmidos , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación , Complejo de Antígeno L1 de Leucocito , Linfocitos , Masculino , Glicoproteínas de Membrana/genética , Repeticiones de Microsatélite/genética , Moléculas de Adhesión de Célula Nerviosa/genética , Polimorfismo Genético/genética , Polimorfismo Conformacional Retorcido-Simple , SíndromeRESUMEN
Tricho-rhino-phalangeal syndrome type I (TRPS I, MIM 190350) is a malformation syndrome characterized by craniofacial and skeletal abnormalities and is inherited in an autosomal dominant manner. TRPS I patients have sparse scalp hair, a bulbous tip of the nose, a long flat philtrum, a thin upper vermilion border and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations and short stature. We assigned TRPS1 to human chromosome 8q24. It maps proximal of EXT1, which is affected in a subgroup of patients with multiple cartilaginous exostoses and deleted in all patients with TRPS type II (TRPS II, or Langer-Giedion syndrome, MIM 150230; ref.2-5). We have positionally cloned a gene that spans the chromosomal breakpoint of two patients with TRPS I and is deleted in five patients with TRPS I and an interstitial deletion. Northern-blot analyses revealed transcripts of 7 and 10.5 kb. TRPS1has seven exons and an ORF of 3,843 bp. The predicted protein sequence has two potential nuclear localization signals and an unusual combination of different zinc-finger motifs, including IKAROS-like and GATA-binding sequences. We identified six different nonsense mutations in ten unrelated patients. Our findings suggest that haploinsufficiency for this putative transcription factor causes TRPS I.
Asunto(s)
Síndrome de Langer-Giedion/genética , Mutación , Dedos de Zinc/genética , Northern Blotting , Mapeo Cromosómico , Cromosomas Humanos Par 8 , ADN Complementario , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , LinajeRESUMEN
Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain and midface where the cerebral hemispheres fail to separate into distinct left and right halves. We have previously reported haploinsufficiency for Sonic Hedgehog ( SHH ) as a cause for HPE. We have now performed mutational analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 unrelated affected individuals. Herein, we describe 13 additional unrelated affected individuals with SHH mutations, including nonsense and missense mutations, deletions and an insertion. These mutations occur throughout the extent of the gene. No specific genotype-phenotype association is evident based on the correlation of the type or position of the mutations. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 unrelated cases of HPE. They account for 14 cases of familial HPE and nine cases of sporadic HPE. Mutations in SHH were detected in 10 of 27 (37%) families showing autosomal dominant transmission of the HPE spectrum, based on structural anomalies. Interestingly, three of the patients with an SHH mutation also had abnormalities in another gene that is expressed during forebrain development. We suggest that the interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual and that variations among these factors may cause the wide variability in the clinical features seen in HPE.