RESUMEN
OBJECTIVE: The 2-2½ year universal health visiting review in England is a key time point for assessing child development and promoting school readiness. We aimed to ascertain which children were least likely to receive their 2-2½ year review and whether there were additional non-mandated contacts for children who missed this review. DESIGN, SETTING, PARTICIPANTS: Cross-sectional analysis of the 2-2½ year review and additional health visiting contacts for 181 130 children aged 2 in England 2018/2019, stratified by ethnicity, deprivation, safeguarding vulnerability indicator and Looked After Child status. ANALYSIS: We used data from 33 local authorities submitting highly complete data on health visiting contacts to the Community Services Dataset. We calculated the percentage of children with a recorded 2-2½ year review and/or any additional health visiting contacts and average number of contacts, by child characteristic. RESULTS: The most deprived children were slightly less likely to receive a 2-2½ year review than the least deprived children (72% vs 78%) and Looked After Children much less likely, compared with other children (44% vs 69%). When all additional contacts were included, the pattern was reversed (deprivation) or disappeared (Looked After children). A substantial proportion of all children (24%), children with a 'safeguarding vulnerability' (22%) and Looked After children (29%) did not have a record of either a 2-2½ year review or any other face-to-face contact in the year. CONCLUSIONS: A substantial minority of children aged 2 with known vulnerabilities did not see the health visiting team at all in the year. Some higher need children (eg, deprived and Looked After) appeared to be seeing the health visiting team but not receiving their mandated health review. Further work is needed to establish the reasons for this, and potential solutions. There is an urgent need to improve the quality of national health visiting data.
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Etnicidad , Grupos Minoritarios , Niño , Estudios Transversales , Inglaterra , Humanos , Bienestar SocialRESUMEN
BACKGROUND: Congenital insensitivity to pain (CIP) is a rare extreme phenotype characterised by an inability to perceive pain present from birth due to lack of, or malfunction of, nociceptors. PRDM12 has recently been identified as a new gene that can cause CIP. The full phenotype and natural history have not yet been reported. METHODS: We have ascertained five adult patients and report their clinical features. RESULTS: Based on our findings, and those of previous patients, we describe the natural history of the PRDM12-CIP disorder, and derive diagnostic and management features to guide the clinical management of patients. CONCLUSIONS: PRDM12-CIP is a distinct and diagnosable disorder, and requires specific clinical management to minimise predictable complications.
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Proteínas Portadoras/genética , Proteínas del Tejido Nervioso/genética , Insensibilidad Congénita al Dolor/diagnóstico , Insensibilidad Congénita al Dolor/genética , Dolor/diagnóstico por imagen , Dolor/genética , Adulto , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability. METHODS: 99 patients with severe intellectual disability and resemblance to Pitt-Hopkins syndrome and/or suspected recessive inheritance were screened for mutations in CNTNAP2 and NRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in either CNTNAP2 or NRXN1, the remaining allele was sequenced. RESULTS: By molecular karyotyping and mutational screening of CNTNAP2 and NRXN1 in a group of severely intellectually disabled patients we identified a heterozygous deletion in NRXN1 in one patient and heterozygous splice-site, frameshift and stop mutations in CNTNAP2 in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions within NRXN1 or CNTNAP2 we could identify a defect on the second allele. One deletion in NRXN1 and one deletion in CNTNAP2 occurred de novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation. CONCLUSIONS: We report on patients with heterozygous defects in CNTNAP2 or NRXN1 associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not necessarily located in the same gene.
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Moléculas de Adhesión Celular Neuronal/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Alelos , Proteínas de Unión al Calcio , Niño , Trastornos Generalizados del Desarrollo Infantil/genética , Preescolar , Codón de Terminación , Facies , Femenino , Mutación del Sistema de Lectura , Eliminación de Gen , Heterocigoto , Humanos , Hiperventilación/genética , Cariotipificación , Masculino , Moléculas de Adhesión de Célula Nerviosa , Sitios de Empalme de ARN , Adulto JovenRESUMEN
Mutations in PQBP1 were recently identified in families with syndromic and non-syndromic X-linked mental retardation (XLMR). Clinical features frequently associated with MR were microcephaly and/or short stature. The predominant mutations detected so far affect a stretch of six AG dinucleotides in the polar-amino-acid-rich domain (PRD), causing frameshifts in the fourth coding exon. We searched for PQBP1 exon 4 frameshifts in 57 mentally retarded males in whom initial referral description indicated at least one of the following criteria: microcephaly, short stature, spastic paraplegia or family history compatible with XLMR, and in 772 mentally retarded males not selected for specific clinical features or family history. We identified a novel frameshift mutation (23 bp deletion) in two half-brothers with specific clinical features, and performed prenatal diagnosis in this family. We also found two different 21 bp in-frame deletions (c.334-354del(21 bp) and c.393-413del(21 bp)) in four unrelated probands from various ethnic origins, each deleting one of five copies of an imperfect seven amino-acid repeat. Although such deletions have not been detected in 1180 X chromosomes from European controls, the c. 334-354del(21 bp) was subsequently found in two of 477 Xs from Indian controls. We conclude that pathogenic frameshift mutations in PQBP1 are rare in mentally retarded patients lacking specific associated signs and that the 21 bp in-frame deletions may be non-pathogenic, or alternatively could act subtly on PQBP1 function. This touches upon a common dilemma in XLMR, that is, how to distinguish between mutations and variants that may be non-pathogenic or represent risk factors for cognitive impairment.
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Proteínas Portadoras/genética , Exones , Mutación del Sistema de Lectura , Discapacidad Intelectual/genética , Proteínas Nucleares/genética , Eliminación de Secuencia , Adolescente , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Preescolar , Proteínas de Unión al ADN , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , LinajeRESUMEN
We and others previously identified a region of hemizygous or homozygous deletion at chromosome band 8p23 in oral and oropharyngeal squamous cell carcinomas (OSCCs) and many other cancer types, suggesting the presence of a tumor-suppressor gene (TSG) in this region. Recently, based on a single region of homozygous deletion in head and neck squamous cell carcinomas (HNSCC), a putative TSG, CUB and sushi multiple domains-1 (CSMD1), has been identified. In the present study, we mapped three OSCC cell lines with previously described homozygous deletions at a high resolution onto a detailed physical map. Critically, this map covered a wider region than that used in previous studies, and in contrast to these studies, our results revealed multiple regions of homozygous deletion within a small interval on 8p23. To investigate this deletion pattern further, we generated a panel of 34 sequence tagged site (STS) markers spanning the region and tested these three cell lines and an additional 34 OSCC cell lines, identifying homozygous deletions in a further four. Combining the results from all seven deleted cell lines identified three non-overlapping regions of homozygous deletion. This complex pattern could be consistent with the presence of multiple TSGs or one very large TSG in this region, and/or specific chromosomal instability. CSMD1 spans two of the three deleted regions and, therefore, would appear to be an excellent candidate for a TSG. However, deletion mapping with STSs corresponding to the exons of CSMD1 shows that some of the deletions do not interrupt its coding region, and in other cell lines the coding region is interrupted by two discontinuous homozygous deletions, suggesting the presence of redundant deletions. These results call into question whether the CSMD1 gene is the 8p23 TSG or whether this or any other genes at this locus are involved in the development of OSCC.