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Biomedical subjects

A Fryer

Publications and source records attributed to A Fryer.

At least 19 recordsLinked to original sources
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

The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene.

BACKGROUND: The majority of COL2A1 missense mutations are substitutions of obligatory glycine residues in the triple helical domain. Only a few non-glycine missense mutations have been reported and among these, the arginine to cysteine substitutions predominate. OBJECTIVE: To investigate in more detail the phenotype resulting from arginine to cysteine mutations in the COL2A1 gene. METHODS: The clinical and radiographic phenotype of all patients in whom an arginine to cysteine mutation in the COL2A1 gene was identified in our laboratory, was studied and correlated with the abnormal genotype. The COL2A1 genotyping involved DHPLC analysis with subsequent sequencing of the abnormal fragments. RESULTS: Six different mutations (R75C, R365C, R519C, R704C, R789C, R1076C) were found in 11 unrelated probands. Each mutation resulted in a rather constant and site-specific phenotype, but a perinatally lethal disorder was never observed. Spondyloarthropathy with normal stature and no ocular involvement were features of patients with the R75C, R519C, or R1076C mutation. Short third and/or fourth toes was a distinguishing feature of the R75C mutation and brachydactyly with enlarged finger joints a key feature of the R1076C substitution. Stickler dysplasia with brachydactyly was observed in patients with the R704C mutation. The R365C and R789C mutations resulted in classic Stickler dysplasia and spondyloepiphyseal dysplasia congenita (SEDC), respectively. CONCLUSIONS: Arginine to cysteine mutations are rather infrequent COL2A1 mutations which cause a spectrum of phenotypes including classic SEDC and Stickler dysplasia, but also some unusual entities that have not yet been recognised and described as type II collagenopathies.

Adult↗
PubMed2005

Surgical implications of the Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a syndrome of rare multiple congenital anomalies/mental retardation associated with low plasma cholesterol levels. Prior to receiving the diagnosis of SLOS, affected children may present as a neonatal surgical emergency with ambiguous genitalia, Hirschsprung's disease, and pyloric stenosis. We present two fatal cases of SLOS with near-total Hirschsprung's disease; the surgical, anaesthetic, and medical aspects of the cases are discussed, and a literature review is presented.

Fatal Outcome↗
PubMed2005

A framework for genetic service provision for haemophilia and other inherited bleeding disorders.

This framework document offers guidance to patients, doctors, nurses, laboratory scientists, funders and hospitals on the provision of clinical and laboratory genetic services for haemophilia. With recent advances in molecular laboratory techniques it is now possible to give the vast majority of individual patients and family members very reliable genetic information. To enable these genetic data to be used for both the optimal treatment of patients with inherited bleeding disorders and for appropriate reproductive decisions in carriers, there needs to be a clear and robust framework for systematically acquiring the necessary clinical, personal, family and laboratory information upon which decisions can be made. This document provides guidance on the range and standards of clinical and laboratory genetic services which should be offered to patients and their families. Included are arrangements for genetic counselling and testing (including consent and confidentially issues), management of early pregnancy, standards for laboratory genetic services, as well as advice on data storage, security and retrieval.

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

Hereditary vocal cord palsy.

Hereditary vocal cord palsy is an uncommon cause of neonatal stridor that has significant implications for patients, their families, and their future progeny.

Genetic Counseling↗
PubMed2003

Nail patella syndrome: a review of the phenotype aided by developmental biology.

Nail patella syndrome (NPS) is an autosomal dominant condition affecting the nails, skeletal system, kidneys, and eyes. Skeletal features include absent or hypoplastic patellae, patella dislocations, elbow abnormalities, talipes, and iliac horns on x ray. Kidney involvement may lead to renal failure and there is also a risk of glaucoma. There is marked inter- and intrafamilial variability. The results of a British study involving 123 NPS patients are compared with previously published studies and it is suggested that neurological and vasomotor symptoms are also part of the NPS phenotype. In addition, the first data on the incidence of glaucoma and gastrointestinal (GI) symptoms in NPS are presented. NPS is caused by loss of function mutations in the transcription factor LMX1B at 9q34. The expansion of the clinical phenotype is supported by the role of LMX1B during development.

Adolescent↗
PubMed2002

Nasomaxillary hypoplasia and severe orofacial clefting in a child of a mother with phenylketonuria.

The offspring of mothers with untreated or poorly controlled phenylketonuria (PKU) (McKusick 261600) are at risk of having congenital anomalies including microcephaly, congenital heart defects and developmental delay (Rouse et al 1997). We report a child born to a mother with poorly controlled PKU and suggest that the facial abnormalities seen in this child could be part of the specturn of maternal PKU embryopathy.

Cleft Lip↗
PubMed2002

Comparison of genetic services with and without genetic registers: knowledge, adjustment, and attitudes about genetic counselling among probands referred to three genetic clinics.

Genetic register services incorporating long term follow up and a proactive approach to at risk subjects have been recommended as a way of improving access to genetic counselling for families with dominant or X linked genetic disorders and chromosome translocations. The aims of the present study were to evaluate the psychosocial benefits and drawbacks of long term family contact, and to evaluate the attitudes of probands and their general practitioners towards proactive genetic counselling. We interviewed 192 people referred to three regional genetic clinics because of a family history of Duchenne or Becker muscular dystrophy, myotonic dystrophy, or chromosome translocations, and 43 of the referring GPs. Probands attending the centre using a genetic register approach were compared with those from the two centres offering the standard clinical genetic service. A very high proportion of probands in both groups were well informed about the genetic risks to themselves and their children, were satisfied with the service they had received from their local genetic clinic, and felt adequately prepared to discuss the family illness with their children. The register probands expressed approval of the ongoing contact and open access provided by the register service. Asked whether previously unaware relatives should be informed of their at risk status, 98% (188/192) said it was acceptable for this information to be disclosed by a family member, while three quarters of the probands (149/192) and just over half the GPs (27/43) thought it acceptable for the genetic service to approach them; a similar proportion of both GPs and probands also found it acceptable for GPs to do so. More than half the probands (107/190) thought it was the family's responsibility to pass on genetic risk information, but 43% said that either the genetic service or the GP should be responsible for this. The findings show that the genetic register approach incorporating long term follow up and a proactive approach to genetic counselling is highly acceptable to the families concerned, and although the register and non-register probands did not differ significantly on any of the main outcome measures used in this relatively short term study, it may be that the continuing contact associated with the register approach offers long term benefits, especially for those genetic conditions where medical surveillance may have an impact on the prognosis.

Adult↗
PubMed2002

Comparison of genetic services with and without genetic registers: access and attitudes to genetic counselling services among relatives of genetic clinic patients.

The pedigrees of 192 subjects at risk of Duchenne or Becker muscular dystrophy, myotonic dystrophy, or balanced chromosome translocations attending three regional genetic clinics were inspected to identify relatives who were themselves at high risk of these disorders. Of the 342 relatives eligible for inclusion, 43% (63/147) of the register relatives and 26% (50/195) of the non-register relatives had had contact with the clinical genetic services, a significant difference (p<0.02). Relatives from families with muscular dystrophy were significantly more likely to have been in contact with genetic services than those from BT families. Fifty-two relatives were interviewed about their experience and attitudes regarding genetic counselling. Almost all regarded knowledge about the family genetic disorder as helpful, and only one thought it unacceptable for relatives to be informed that they are at risk; 94% thought it was acceptable for this information to come from family members, 92% from general practitioners, and 90% from the clinical genetic service. A majority of relatives (53%) thought it was the family's responsibility to pass on genetic risk information, but 22% said the genetic service should be responsible and 18% thought it should be the GP. These data, together with the findings from the study of probands attending genetic clinics for these disorders, indicate that the genetic register approach incorporating long term follow up and a proactive approach to genetic counselling is acceptable to the families concerned and improves access to genetic services for at risk relatives.

Adult↗
PubMed2001

Meier-Gorlin syndrome: report of eight additional cases and review.

The Meier-Gorlin syndrome or ear, patella, short stature syndrome (MIM 224690) is a rare autosomal recessive disorder, characterized by the association of bilateral microtia, aplasia/hypoplasia of the patellae, and severe pre- and postnatal growth retardation. Twenty-one cases have been reported in literature thus far. Here we report on eight patients from seven families and compare them with previously described cases. One of the present cases had previously undescribed genital anomalies. There is a difference in facial characteristics between patients reported in early infancy and those described at older age; follow-up of patients is needed to substantiate this changing facial phenotype. We recommend radiographic survey of the patellae in patients at older age to investigate the weight of absent or hypoplastic patellae in the diagnosis of the syndrome.

Abnormalities, Multiple↗
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

Metabolic gene polymorphism frequencies in control populations.

Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.

Black People↗
PubMed2000

Char syndrome: a new family and review of the literature emphasising the presence of symphalangism and the variable phenotype.

We report a family of three affected individuals with the facial features of Char syndrome. The family also demonstrates symphalangism of the distal interphalangeal joints of the fifth fingers, extending the digital phenotype seen in this condition. We review the features of previously reported patients and emphasise the variability in the phenotype of Char syndrome.

Adult↗
PubMed1999

Mutation analysis of iduronate-2-sulphatase gene in 24 patients with Hunter syndrome: characterisation of 6 novel mutations. Mutation in brief no. 249. Online.

Hunter syndrome is a rare, X-linked, recessively inherited disease affecting approximately 1 in 132,000 males. The disease is caused by the inability to degrade dermatan sulphate and heparan sulphate due to mutations in the iduronate-2-sulphatase gene (IDS). The mutations causing the disorder are heterogeneous, ranging from small micro-lesions to gross deletions and inversions. We have screened DNA samples from a panel of 24 unrelated Hunter syndrome patients and have identified mutations in 16 individuals. Six mutations represent novel changes in the gene and these include two single base deletions (1264DC and 1632/3DT); two single base insertions (776/8insC and 1082insT); and two missense mutations--Y264N (914T-->G) and Q465P (1518A-->C). An additional two missense mutations and one splice site alteration identified in this study have been described previously. Southern analysis revealed complete or partial gene deletions in a further 7 patients.

DNA Mutational Analysis↗
PubMed1999

Multiple basal cell carcinomas in a patient with acute myeloid leukaemia and chronic lymphocytic leukaemia.

Skin cancer is a well-recognized risk of prolonged immunosuppression, for example, following renal transplantation. These tumours contrast with idiopathic lesions in that squamous cell, rather than basal cell carcinomas usually predominate. We report a Caucasian female who developed multiple basal cell carcinomas following protracted cytotoxic therapy for acute myeloid leukaemia and subsequently chronic lymphocytic leukaemia. No other clinical risk factors nor relevant polymorphisms of genes encoding for detoxifying enzymes were identified. Immune suppression is a well-recognized cause of multiple skin tumours, the most striking increase usually being of squamous cell carcinomas. We believe this woman is representative of a subgroup of immunosuppressed patients who, for as yet poorly understood reasons, have a predisposition to basal cell, rather than squamous cell carcinoma accrual.

Acute Disease↗