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Biomedical subjects

C McKeown

Publications and source records attributed to C McKeown.

At least 19 recordsLinked to original sources
PubMed2003

Retrospective screening for hepatitis C in a tertiary paediatric referral centre.

The true prevalence of hepatitis C virus in children in the UK is not known and targeted screening is not standard practice despite an anticipated rise in new cases due to vertical transmission. An extension of the Department of Health's 'look-back' exercise was undertaken in order to determine the prevalence of hepatitis C virus in high-risk patient groups who were transfused with blood and/or blood products before 1991. Five hundred and ninety-five patients transfused between 1971-91 were traced and offered counselling and testing. Blood samples from 405 were analysed for the presence of HCV antibodies and/or HCV RNA by RT-PCR and eight patients were found to be positive. The HCV seroprevalence rate in this cohort was 1.97% and the HCV genome detection rate was 1.72%. In view of the long-term complications from this infection and the availability of potentially effective anti-viral agents, we feel that targeted screening is of value in this setting.

Adolescent↗
PubMed2001

Joint and skin laxity with Dandy-Walker malformation and contractures: a distinct recessive syndrome?

We report the case of a girl who has joint and skin laxity with atrophic scarring, and was diagnosed at birth with a Dandy-Walker malformation. She subsequently developed joint contractures, hydrocephalus and syringomyelia. This case shows some similarities to Ehlers-Danlos syndrome type VI, but with no evidence of lysyl hydroxylase deficiency or ocular fragility. It is likely that she represents a distinct and recognizable syndrome. There was parental consanguinity and a subsequent pregnancy resulted in a similarly affected fetus, suggesting autosomal recessive inheritance.

Abnormalities, Multiple↗
PubMed2001

Clinical studies on submicroscopic subtelomeric rearrangements: a checklist.

BACKGROUND: Submicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions. METHODS: We studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history. Controls were 110 children with mental retardation of unknown aetiology with normal G banded karyotype and no detectable submicroscopic subtelomeric abnormalities. RESULTS: Prenatal onset of growth retardation was found in 37% compared to 9% of the controls (p<0.0005). A higher percentage of positive family history for mental retardation was reported in the study group than the controls (50% v 21%, p=0.002). Miscarriage(s) were observed in only 8% of the mothers of subtelomeric cases compared to 30% of controls (p=0.028) which was, however, not significant after a Bonferroni correction. Common features (>30%) among subtelomeric deletion cases were microcephaly, short stature, hypertelorism, nasal and ear anomalies, hand anomalies, and cryptorchidism. Two or more facial dysmorphic features were observed in 83% of the subtelomere patients. None of these features was significantly different from the controls. Using the results, a five item checklist was developed which allowed exclusion from further testing in 20% of the mentally retarded children (95% CI 13-28%) in our study without missing any subtelomere cases. As our control group was selected for the "chromosomal phenotype", the specificity of the checklist is likely to be higher in an unselected group of mentally retarded subjects. CONCLUSIONS: Our results suggest that good indicators for subtelomeric defects are prenatal onset of growth retardation and a positive family history for mental retardation. These clinical criteria, in addition to features suggestive of a chromosomal phenotype, resulted in the development of a five item checklist which will improve the diagnostic pick up rate of subtelomeric defects among mentally retarded subjects.

Abnormalities, Multiple↗
PubMed2000

Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.

Spondylocostal dysostosis (SD, MIM 277300) is a group of vertebral malsegmentation syndromes with reduced stature resulting from axial skeletal defects. SD is characterized by multiple hemivertebrae, rib fusions and deletions with a non-progressive kyphoscoliosis. Cases may be sporadic or familial, with both autosomal dominant and autosomal recessive modes of inheritance reported. Autosomal recessive SD maps to a 7.8-cM interval on chromosome 19q13.1-q13.3 that is homologous with a mouse region containing a gene encoding the Notch ligand delta-like 3 (Dll3). Dll3 is mutated in the X-ray-induced mouse mutant pudgy (pu), causing a variety of vertebrocostal defects similar to SD phenotypes. Here we have cloned and sequenced human DLL3 to evaluate it as a candidate gene for SD and identified mutations in three autosomal recessive SD families. Two of the mutations predict truncations within conserved extracellular domains. The third is a missense mutation in a highly conserved glycine residue of the fifth epidermal growth factor (EGF) repeat, which has revealed an important functional role for this domain. These represent the first mutations in a human Delta homologue, thus highlighting the critical role of the Notch signalling pathway and its components in patterning the mammalian axial

Adult↗
PubMed2000

Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations.

PURPOSE: Rieger syndrome is an autosomal dominant condition characterized by a variable combination of anterior segment dysgenesis, dental anomalies, and umbilical hernia. To date, reports have shown mutations within the PITX2 gene associated with Rieger syndrome, iridogoniodysgenesis, and iris hypoplasia. The purposes of this study were to determine the range of expression and intrafamilial variability of PITX2 mutations in patients with anterior segment dysgenesis. METHODS: Seventy-six patients with different forms of anterior segment dysgenesis were classified clinically. DNA was obtained and screened by means of polymerase chain reaction (PCR)-single-stranded conformation polymorphism (SSCP) and heteroduplex analysis followed by direct sequencing. RESULTS: Eight of 76 patients had mutations within the PITX2 gene. Anterior segment phenotypes show wide variability and include a phenocopy of aniridia and Peters', Rieger, and Axenfeld anomalies. Mutations include premature terminations and splice-site and homeobox mutations, confirming that haploinsufficiency the likely pathogenic mechanism in the majority of cases. CONCLUSIONS: There is significant phenotypic variability in patients with PITX2 mutations, both within and between families. Developmental glaucoma is common. The umbilical and dental abnormalities are highly penetrant, define those at risk of carrying mutations in this gene, and guide mutation analysis. In addition, there is a range of other extraocular manifestations.

Anterior Eye Segment↗
PubMed1999

Further evidence from two families that craniofrontonasal dysplasia maps to Xp22.

Craniofrontonasal dysplasia (CFND) is a rare X-linked disorder that maps to a 13-cM region on Xp22. Phenotypic features include craniosynostosis, hypertelorism and a broad nasal root with or without a bifid nasal tip. Multiple examples have been reported of males having a less severe phenotype than females. We report haplotype analyses in two CFND families over the critical region to which the gene has been mapped. In pedigree 1, a clinically unaffected male inherited the affected marker haplotype spanning the critical region. We suggest that this individual does have the CFND mutation, but has an extremely mild phenotype that is not detectable with clinical examination. Under the assumption that he is an unknown phenotype, a combined two-point LOD score of 1.68 at zero recombination was obtained, increasing the previously reported total to 5.61 (DXS8022). The data do not narrow down the critical region. This result stresses the importance of subjecting fathers of apparently sporadic cases to a highly critical medical examination and may also explain the unequal ratio of reported female-to-male cases.

Craniofacial Abnormalities↗
PubMed1999

Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer.

Inherited mutations in the E-cadherin gene ( CDH1 ) were described recently in three Maori kindreds with familial gastric cancer. Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations. Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of all 16 exons and flanking sequences. Each family contained: (i) two cases of gastric cancer in first degree relatives with one affected before age 50 years; or (ii) three or more cases of gastric cancer. Novel germline CDH1 mutations (a nonsense and a splice site) were detected in two families (25%). Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain. In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years. We have confirmed that germline mutations in the CDH1 gene cause familial gastric cancer in non-Maori populations. However, only a minority of familial gastric cancers can be accounted for by CDH1 mutations. Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer. Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers.

Adult↗
PubMed1999

Germline mutations of the LKB1 (STK11) gene in Peutz-Jeghers patients.

Germline mutations of the LKB1 (STK11) serine/threonine kinase gene (chromosome 19p13.3) cause Peutz-Jeghers syndrome, which is characterised by hamartomas of the gastrointestinal tract and typical pigmentation. Peutz-Jeghers syndrome carries an overall risk of cancer that may be up to 20 times that of the general population. Here, we report the results of a screen for germline LKB1 mutations by DNA sequencing in 12 Peutz-Jeghers patients (three sporadic and nine familial cases). Mutations were found in seven (58%) cases, in exons 1, 2, 4, 6, and 9. Five of these mutations, two of which are identical, are predicted to lead to a truncated protein (three frameshifts, two nonsense changes). A further mutation is an in frame deletion of 6 bp, resulting in a deletion of lysine and asparagine; the second of these amino acids is conserved between species. The seventh mutation is a missense change in exon 2, converting lysine to arginine, affecting non-conserved amino acids and of uncertain functional significance. Despite the fact that Peutz-Jeghers syndrome is usually an early onset disease with characteristic clinical features, predictive and diagnostic testing for LKB1 mutations will be useful for selected patients in both familial and non-familial contexts.

AMP-Activated Protein Kinase Kinases↗
PubMed1998

Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3.

A locus for Peutz-Jeghers syndrome (PJS) was recently mapped to chromosome 19p13.3. Each of 12 families studied was compatible with linkage to the marker D19S886. We have analysed 20 further families and found that the majority of these are consistent with a PJS gene on 19p13.3. Three families were, however, unlinked to 19p13.3 and none of the available PJS polyps from these families showed allele loss at D19S886. There were no obvious clinicopathological or ethnic differences between the 19p13.3 linked and unlinked families. There appears, therefore, to be a major PJS locus on chromosome 19p13.3 and the possibility exists of a minor locus (or loci) elsewhere.

Chromosomes, Human, Pair 19↗
PubMed1998

sma-1 encodes a betaH-spectrin homolog required for Caenorhabditis elegans morphogenesis.

Morphogenesis transforms the C. elegans embryo from a ball of cells into a vermiform larva. During this transformation, the embryo increases fourfold in length; present data indicates this elongation results from contraction of the epidermal actin cytoskeleton. In sma-1 mutants, the extent of embryonic elongation is decreased and the resulting sma-1 larvae, although viable, are shorter than normal. We find that sma-1 mutants elongate for the same length of time as wild-type embryos, but at a decreased rate. The sma-1 mutants we have isolated vary in phenotypic severity, with the most severe alleles showing the greatest decrease in elongation rate. The sma-1 gene encodes a homolog of betaH-spectrin, a novel beta-spectrin isoform first identified in Drosophila. sma-1 RNA is expressed in epithelial tissues in the C. elegans embryo: in the embryonic epidermis at the start of morphogenesis and subsequently in the developing pharynx, intestine and excretory cell. In Drosophila, betaH-spectrin associates with the apical plasma membrane of epithelial cells; beta-spectrin is found at the lateral membrane. We propose that SMA-1 is a component of an apical membrane skeleton in the C. elegans embryonic epidermis that determines the rate of elongation during morphogenesis.

Amino Acid Sequence↗
PubMed1997

Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract.

Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation. Typical cases have 3/4 finger and 4/5 toe syndactyly, with a duplicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13. We have studied 16 new and 4 previously published SPD families, with between 7 and 14 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of change in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of phenotype with increasing expansion size, affecting both hands (P = 0.012) and feet (P < 0. 00005). Affected individuals from a family with a 14-alanine expansion, the largest so far reported, all have a strikingly similar and unusually severe limb phenotype, involving the first digits and distal carpals. Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle. The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.

Base Sequence↗
PubMed1997

Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study.

We present clinical data on 558 patients with deletions within the DiGeorge syndrome critical region of chromosome 22q11. Twenty-eight percent of the cases where parents had been tested had inherited deletions, with a marked excess of maternally inherited deletions (maternal 61, paternal 18). Eight percent of the patients had died, over half of these within a month of birth and the majority within 6 months. All but one of the deaths were the result of congenital heart disease. Clinically significant immunological problems were very uncommon. Nine percent of patients had cleft palate and 32% had velopharyngeal insufficiency, 60% of patients were hypocalcaemic, 75% of patients had cardiac problems, and 36% of patients who had abdominal ultrasound had a renal abnormality. Sixty-two percent of surviving patients were developmentally normal or had only mild learning problems. The majority of patients were constitutionally small, with 36% of patients below the 3rd centile for either height or weight parameters.

Adolescent↗
PubMed1996

Parents' responses to predictive genetic testing in their children: report of a single case study.

There is a widely held view among health professionals that predictive genetic testing of children for late onset diseases is not desirable clinical practice. Yet, little is known about the views of parents, or their responses, to predictive genetic testing in their children. Since such testing is being carried out in some genetic centres, the opportunity was taken to conduct a single case study of the parents of 2 and 4 year old sisters who were tested for the gene for familial adenomatous polyposis. Interviews before testing, after, and 15 months later showed a stable attitude, that parental responsibility included making decisions about such testing, and that the role of health professionals should be one of information giving rather than decision making. These parents had no regrets about having their children tested and reported no changes in their behaviour towards either the child who tested positively or the child who tested negatively. Using standardised scales, mood was found to be within the normal range both before and after testing in the mother and father. This case study is a first step towards systematic empirical studies determining the consequences of acquiescing to parents' requests for genetic testing in their children.

Adenomatous Polyposis Coli↗
PubMed1995

Prenatal exclusion of the HHH syndrome.

Prenatal diagnosis of the hyperornithinaemia, hyperammonaemia, and homocitrullinuria syndrome is described by the analysis of ornithine incorporation in second-trimester cultured amniotic fluid cells. An unaffected fetus was predicted and confirmed in the newborn child. This is the third reported prenatal diagnosis for this disorder and the second predicting an unaffected fetus.

Amino Acid Metabolism, Inborn Errors↗