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Biomedical subjects

J Clayton-Smith

Publications and source records attributed to J Clayton-Smith.

At least 19 recordsLinked to original sources
PubMed2006

Tall stature and duplication of the insulin-like growth factor I receptor gene.

Trisomy of 15q26-qter is frequently associated with tall stature and mental retardation. Here we describe a patient with such trisomy, without a partial monosomy of another chromosome. The tall stature in this patient is most probably caused by duplication of the IGF1R gene. A duplication of the IGF1R gene is not a frequent finding in patients with tall stature. In 38 patients with features of Sotos syndrome without NSD1 alterations, a duplication was found only once. This patient was already known to have an unbalanced 2;15 translocation. Looking for a duplication of the 15qter region is still worth consideration in patients with tall stature and features of Sotos syndrome without an NSD1 alteration, especially when there is craniosynostosis or marked speech delay.

Body Height↗
PubMed2006

A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus.

The expression of imprinted genes is mediated by allele-specific epigenetic modification of genomic DNA and chromatin, including parent of origin-specific DNA methylation. Dysregulation of these genes causes a range of disorders affecting pre- and post-natal growth and neurological function. We investigated a cohort of 12 patients with transient neonatal diabetes whose disease was caused by loss of maternal methylation at the TNDM locus. We found that six of these patients showed a spectrum of methylation loss, mosaic with respect to the extent of the methylation loss, the tissues affected and the genetic loci involved. Five maternally methylated loci were affected, while one maternally methylated and two paternally methylated loci were spared. These patients had higher birth weight and were more phenotypically diverse than other TNDM patients with different aetiologies, presumably reflecting the influence of dysregulation of multiple imprinted genes. We propose the existence of a maternal hypomethylation syndrome, and therefore suggest that any patient with methylation loss at one maternally-methylated locus may also manifest methylation loss at other loci, potentially complicating or even confounding the clinical presentation.

Birth Weight↗
PubMed2006

Detection of a deletion of exons 8-16 of the UBE3A gene in familial Angelman syndrome using a semi-quantitative dosage PCR based assay.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by failure of expression of the maternal copy of the imprinted UBE3A gene through a variety of mechanisms detected by methylation studies, mutation analysis of UBE3A and FISH. In 10-15% of suspected cases of AS these investigations do not reveal a genetic abnormality. We report here the development of a semi-quantitative dosage PCR technique used to identify sub-microscopic deletions involving UBE3A. Using this method we analysed a panel of 26 patients from 24 families, all fulfilling the clinical criteria for AS. We identified a deletion of UBE3A exons 8-16 in a sibling pair. Analysis of parental samples revealed the same deletion in their phenotypically normal mother. This is an inexpensive and valuable method for detecting UBE3A deletions in a small but important proportion of AS cases of unidentifiable cause.

Adolescent↗
PubMed2006

Epimutation of the TNDM locus and the Beckwith-Wiedemann syndrome centromeric locus in individuals with transient neonatal diabetes mellitus.

Transient neonatal diabetes mellitus (TNDM) is characterised by intra-uterine growth retardation, while Beckwith-Wiedemann syndrome (BWS) is a clinically heterogeneous overgrowth syndrome. Both TNDM and BWS may be caused by aberrant loss of methylation (LOM) at imprinted loci on chromosomes 6q24 and 11p15.5 respectively. Here we describe two patients with a clinical diagnosis of TNDM caused by LOM at the maternally methylated imprinted domain on 6q24; in addition, these patients had LOM at the centromeric differentially methylated region of 11p15.5. This shows that imprinting anomalies can affect more than one imprinted locus and may alter the clinical presentation of imprinted disease.

Beckwith-Wiedemann Syndrome↗
PubMed2005

Assisted reproductive therapies and imprinting disorders--a preliminary British survey.

BACKGROUND: Recent reports have suggested a higher risk of Beckwith-Wiedemann syndrome (BWS) and Angelman syndrome (AS) after assisted reproductive technologies (ARTs), but it is unclear whether this might also apply to other disorders of genomic imprinting. METHODS: We contacted families of children with BWS, AS, Prader-Willi syndrome (PWS) and transient neonatal diabetes mellitus (TNDM) to determine use of ART. RESULTS: A statistically significant increased frequency of ART in children with BWS was confirmed [2.9%, 95% confidence interval (CI) 1.4-6.3% vs 0.8% expected] but there was no significant association with PWS or TNDM. Consideration of the molecular subgroup of BWS and AS suggested the feasibility of association with ART. CONCLUSIONS: These differences may relate to variations in (i) the molecular mechanisms for disordered imprinting in the different disorders and (ii) the susceptibility of specific imprinting control regions to ART-associated methylation alterations (epimutations).

Angelman Syndrome↗
PubMed2005

Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes.

BACKGROUND: In utero exposure to antiepileptic drugs (AEDs) can result in several different teratogenic effects including major malformations, dysmorphic facial features, and learning and behavioural problems. It is estimated that there is a 2-3-fold increase in the risk of malformations compared with the general population. The risk of cognitive impairment and behavioural problems is less clear. OBJECTIVE: To report the frequency and specificity of individual dysmorphic features and to relate the dysmorphic facial phenotype to developmental outcome. METHODS: A retrospective study of 375 children born to 219 mothers with epilepsy. The age of the study group ranged from 6 months to 16 years. Each child underwent a physical examination and a battery of neuropsychological tests. Dysmorphic features were scored from photographs on a blind basis by a panel of dysmorphologists. RESULTS: A total of 274 children were exposed to AEDs (63 to valproate, 94 to carbamazepine, 26 to phenytoin, 15 to other monotherapies, and 76 to polytherapy). Major malformations were identified in 14% of children exposed to valproate in utero, 5% exposed to carbamazepine, and 4% in the non-exposed group. Overall, 47% of exposed children were correctly identified as having been exposed to AEDs in utero. There was a significant correlation between verbal intelligence quotient and dysmorphic facial features in the valproate exposed children only. CONCLUSION: Children exposed to valproate have more distinctive facial features, but a subtle and distinctive facial phenotype is also seen in children exposed to carbamazepine. Nearly half (45%) of unexposed children had some of the facial features associated with AED exposure, showing that many of these features may be seen as part of normal variation and that the diagnosis of the fetal anticonvulsant syndrome is difficult to make on the basis of facial gestalt alone. Developmental surveillance should be offered to children with prenatal exposure to AEDs, particularly those with exposure to high doses of valproate.

Abnormalities, Drug-Induced↗
PubMed2005

Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome.

The expression of a gene requires not only a normal coding sequence but also intact regulatory regions, which can be located at large distances from the target genes, as demonstrated for an increasing number of developmental genes. In previous mutation studies of the role of FOXL2 in blepharophimosis syndrome (BPES), we identified intragenic mutations in 70% of our patients. Three translocation breakpoints upstream of FOXL2 in patients with BPES suggested a position effect. Here, we identified novel microdeletions outside of FOXL2 in cases of sporadic and familial BPES. Specifically, four rearrangements, with an overlap of 126 kb, are located 230 kb upstream of FOXL2, telomeric to the reported translocation breakpoints. Moreover, the shortest region of deletion overlap (SRO) contains several conserved nongenic sequences (CNGs) harboring putative transcription-factor binding sites and representing potential long-range cis-regulatory elements. Interestingly, the human region orthologous to the 12-kb sequence deleted in the polled intersex syndrome in goat, which is an animal model for BPES, is contained in this SRO, providing evidence of human-goat conservation of FOXL2 expression and of the mutational mechanism. Surprisingly, in a fifth family with BPES, one rearrangement was found downstream of FOXL2. In addition, we report nine novel rearrangements encompassing FOXL2 that range from partial gene deletions to submicroscopic deletions. Overall, genomic rearrangements encompassing or outside of FOXL2 account for 16% of all molecular defects found in our families with BPES. In summary, this is the first report of extragenic deletions in BPES, providing further evidence of potential long-range cis-regulatory elements regulating FOXL2 expression. It contributes to the enlarging group of developmental diseases caused by defective distant regulation of gene expression. Finally, we demonstrate that CNGs are candidate regions for genomic rearrangements in developmental genes.

Animals↗
PubMed2005

MRI and neurological findings in macrocephaly-cutis marmorata telangiectatica congenita syndrome: report of ten cases and review of the literature.

MRI and neurological findings in macrocephaly-cutis marmorata telangiectatica congenita syndrome: report of ten cases and review of the literature: We describe the clinical history and magnetic resonance imaging (MRI) findings in 10 children with the Macrocephaly-Cutis Marmorata Telangiectatica Congenita syndrome (M-CMTC--MIM 602501). This syndrome has recently been delineated within the general group of patients with Cutis Marmorata Telangiectatica (CMTC) as a distinct and easily recognisable entity. In contrast to most children with CMTC, patients with M-CMTC syndrome have a high risk of neurological abnormalities, such as hydrocephalus, megalencephaly, developmental delay and mental retardation. An MRI scan showed structural cerebral abnormalities in all of our patients, including megalencephaly, asymmetry of the cerebral hemispheres and abnormally increased signal of white matter. Seven patients also had Chiari type I malformation. Reviewing all reported cases, we propose appropriate surveillance for known complications.

Abnormalities, Multiple↗
PubMed2004

Autosomal dominant brachydactyly, coloboma and anterior segment dysgenesis.

A three-generation family presenting with ocular developmental abnormalities, including anterior segment dysgenesis and coloboma, associated with brachydactyly and clinodactyly is presented. Several conditions incorporating ocular and bony limb abnormalities have been described. However, we believe that this family manifests a previously undescribed syndrome due to autosomal dominant or possibly x-linked inheritance with variable expression.

Adult↗
PubMed2004

The longer term outcome of children born to mothers with epilepsy.

OBJECTIVES: To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero. DESIGN: Retrospective study of children born to mothers with epilepsy. SETTING: Regional epilepsy clinics in Liverpool and Manchester, UK. PARTICIPANTS: Children aged between 6 months and 16 years born to mothers with epilepsy. MAIN OUTCOME MEASURES: Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features. RESULTS: A total of 249 children aged 6 and over were studied: 41 were exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the valproate group compared to unexposed and other monotherapy groups. Multiple regression analysis showed that both valproate exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ despite adjusting for other confounding factors. There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate. CONCLUSIONS: This study identifies valproate as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results need to be interpreted with caution given their retrospective nature. Women with epilepsy need careful counselling about individual risk benefit of AED treatment before pregnancy.

Abnormalities, Drug-Induced↗
PubMed2003

Neuropsychological assessment of a group of UK patients with Cohen syndrome.

Cohen syndrome is a rare autosomal recessive syndrome with a distinctive clinical phenotype that includes mental retardation and a characteristic sociable disposition. Variability in the level of learning disability and the behavioural phenotype is seen in the published literature. In a cohort of Finnish Cohen syndrome patients, severe mental retardation and non-maladaptive behaviour were described. Outside of Finland, autistic-spectrum behaviour has been reported in a few isolated Cohen syndrome patients but in a recent UK study was found to be highly prevalent. We report the results of neuropsychological studies in a group of 16 genetically heterogeneous patients, all with the characteristic clinical features of Cohen syndrome. Of the 9 patients who underwent formal neuropsychological testing, all but one was functioning in the severely mentally impaired range. Of the remaining patients, 3 were below the age of formal testing and 4 had such profound learning and behavioural problems that they were deemed unable to participate in testing. Mild maladaptive behaviour was observed in 13 patients and 3 were documented as having significant maladaptive behaviour. In contrast to the Finnish group of Cohen syndrome patients, this UK study identifies significant neuropsychological impairment combined with maladaptive behaviour as a characteristic of Cohen syndrome. Although autistic-type behaviour was observed, an increased prevalence of autism in Cohen syndrome was not confirmed.

Adolescent↗
PubMed2003

Angelman syndrome: a review of the clinical and genetic aspects.

Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe learning difficulties, ataxia, a seizure disorder with a characteristic EEG, subtle dysmorphic facial features, and a happy, sociable disposition. Most children present with delay in developmental milestones and slowing of head growth during the first year of life. In the majority of cases speech does not develop. Patients with AS have a characteristic behavioural phenotype with jerky movements, frequent and sometimes inappropriate laughter, a love of water, and sleep disorder. The facial features are subtle and include a wide, smiling mouth, prominent chin, and deep set eyes. It is caused by a variety of genetic abnormalities involving the chromosome 15q11-13 region, which is subject to genomic imprinting. These include maternal deletion, paternal uniparental disomy, imprinting defects, and point mutations or small deletions within the UBE3A gene, which lies within this region. UBE3A shows tissue specific imprinting, being expressed exclusively from the maternal allele in brain. The genetic mechanisms identified so far in AS are found in 85-90% of those with the clinical phenotype and all interfere with UBE3A expression.

Angelman Syndrome↗
PubMed2003

Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome.

Cohen syndrome is a rare, recessively inherited condition associated with facial dysmorphism, developmental delay, and visual disability. A delay in making the diagnosis commonly occurs, contributed to by the lack of a definitive molecular test and the clinical variability of published case reports. A specific clinical phenotype has been delineated in a homogeneous cohort of Finnish Cohen syndrome patients, but the applicability of their diagnostic criteria to non-Finnish patients has been debated. Detailed delineation of Cohen syndrome in patients from outside Finland is therefore warranted. We report on the clinical features of 33 non-Finnish Cohen syndrome patients. Variability within the clinical spectrum is identified and the natural history of Cohen syndrome described. Diagnostic guidelines for facilitating accurate and early diagnosis are discussed. Results from molecular genetic analysis using markers located within the previously mapped COH1 critical region support allelic but not genetic heterogeneity in this UK cohort.

Abnormalities, Multiple↗
PubMed2002

The ophthalmic findings in Cohen syndrome.

AIM: Cohen syndrome is an uncommon autosomal recessive condition comprising a characteristic facial appearance, mental retardation, benign neutropenia, and retinal dystrophy. This study aimed to identify patients with Cohen syndrome from across the United Kingdom in order to define the variability of ophthalmic manifestations. METHODS: Ophthalmic assessment was undertaken and past ophthalmic records reviewed in 22 patients with classic features of Cohen syndrome. RESULTS: All patients had visual problems which commonly started in the preschool years. 82% developed strabismus or refractive error during the first 5 years of life. 70% developed high myopia by the second decade. By contrast with the findings of others, early onset retinal dystrophy was common, occurring in 80% of study patients under age 5 years. 35% of patients were registered partially sighted or blind. CONCLUSION: The ophthalmic abnormalities associated with Cohen syndrome, including high myopia and a generalised, severe retinal dystrophy, are of early onset and frequently result in severe visual handicap. Cohen syndrome should be considered in the young, developmentally delayed child who presents with severe myopia and nyctalopia.

Adolescent↗
PubMed2001

De novo deletion of chromosome 18q in a baby with harlequin ichthyosis.

Harlequin ichthyosis, (MIM 242500), is a rare, autosomal recessive skin disorder due to an inborn error of epidermal keratinization. The gene for this condition has not been localized. We present a case of HI in which there was a de novo deletion of chromosome 18q: the karyotype was 46, XY, del(18)(q21.3). We postulate that the gene for HI may lie at, or distal to 18q21.3 and that the deletion observed in this case may have unmasked this autosomal recessive disorder.

Chromosome Banding↗
PubMed2001

A survey of TWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals.

The human TWIST gene encodes a 202 amino acid transcription factor characterized by a highly conserved basic-helix-loop-helix motif in the C-terminal half, and a less conserved N-terminal half that has binding activity toward the histone acetyltransferase p300. Between these domains is a repeat region of unknown function that encodes the glycine-rich sequence (Gly)5Ala(Gly)5. Heterozygous mutations of TWIST were previously described in Saethre-Chotzen craniosynostosis syndrome [El Ghouzzi et al., 1997; Howard et al., 1997]. During a search for TWIST mutations in patients with craniosynostosis, we identified, in addition to 11 novel and one previously described bona fide mutations, several individuals with rearrangements of the glycine-rich region, involving either deletion of 18 nucleotides or insertion of three, 15, or 21 nucleotides. None of these rearrangements was consistently associated with clinical disease and we conclude that they are at most weakly pathogenic. The glycine stretch may serve as a flexible linker between the functional domains of the TWIST protein, and as such may be subject to reduced evolutionary constraint.

Amino Acid Sequence↗
PubMed2001

Exploring the complex relationship between adolescent sexual offending and sex chromosome abnormality.

The nature and importance of the relationship between sex chromosome abnormalities (SCAs) and sexual maladaptive behaviour is uncertain. When considering the aetiology of sexual offending behaviour, the importance of sex chromosome disorder lies in its biopsychological manifestations and in its complex interactions with external influences. At the Adolescent Forensic Service, in keeping with previous research in institutional settings, we found a higher pick-up rate of SCAs among sexual offenders (5/121) than would be expected in an unbiased community sample (1.2/1000 male livebirths; Jacobs et al. (1992)). We present descriptive data on five patients with SCAs out of a total of 121 sexual offenders who presented to the Adolescent Forensic Service over a 6-year period. We discuss the biopsychosocial features of these five patients and compare them with the remainder of the sexual offenders in the series. We discuss the advantages of early diagnosis and the need for professional vigilance by adolescent forensic psychiatrists, child and adolescent psychiatrists, paediatricians and clinical geneticists.

Adolescent↗