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Biomedical subjects

L J Sheffield

Publications and source records attributed to L J Sheffield.

At least 37 records · Page 2Linked to original sources
PubMed1994

Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1.

Although ultrasound is commonly used for screening subjects at risk of polycystic kidney disease 1 (PKD1), there has been no evaluation of ultrasonographic diagnostic criteria. We used DNA linkage among subjects from 128 sibships within 18 PKD1 families as the basis for an assessment of ultrasound sensitivity. Positive and negative predictive values were calculated to allow assessment of different diagnostic cut-off points in previously undiagnosed cases. Currently used criteria (bilateral cysts with at least two in one kidney) provided good sensitivity (88.5% at age 15-29 years and 100% at 30 years and above) but performance could be improved by less stringent criteria in subjects aged 15-29 years and more stringent criteria in older family members, in whom simple renal cysts are frequent. The presence of at least two renal cysts (unilateral or bilateral) in individuals at risk and younger than 30 years may be regarded as sufficient to establish a diagnosis; among those aged 30-59 years, the presence of at least two cysts in each kidney may be required, and among those aged 60 years and above, at least four cysts in each kidney should be required.

Adolescent↗
PubMed1994

Asymmetry and skin pigmentary anomalies in chromosome mosaicism.

We report six persons mosaic for a chromosome anomaly. All were mentally retarded and dysmorphic. Unilateral or asymmetrical features were found in all cases, in one an unusual transverse terminal limb anomaly, and in the others various degrees of hemiatrophy of the left side of the body. Five of the subjects had skin pigmentary anomalies which were distributed in the lines of Blaschko. The abnormal cell lines found were ring chromosome 22, trisomy 22, a large acrocentric marker, a deletion of 18q, a deletion of 8q, and triploidy. In four cases the clinical diagnosis was only confirmed by skin biopsy. In one case low level mosaicism in blood was fortuitously detected because of cytogenetic fragile X screening and confirmed in a skin biopsy. The sixth case was of dynamic mosaicism of a non-mosaic deletion 18q with a chromosome 18 derived marker present in a proportion of cells. Chromosome mosaicisn may cause subtle and asymmetrical clinical features and can require repeated cytogenetic investigations. The diagnosis should be actively sought as it enables accurate genetic counselling to be given.

Abnormalities, Multiple↗
PubMed1993

Limb deficiencies, chorion villus sampling, and advanced maternal age.

Record linkage between a prenatal diagnosis register and a congenital malformation register in the state of Victoria, Australia, has enabled further evaluation of the suggested association between limb deficiencies and early chorion villus sampling (CVS). We found 3 anomalies in this category after later CVS (i.e., 9 weeks and beyond), but our data suggest that advanced maternal age may be a risk factor for both terminal and all limb deficiencies. The data from Victoria are tabulated with data obtained from other registers. Different birth prevalence figures are obtained by different registers, therefore limiting comparisons between registers.

Adult↗
PubMed1993

Between-generation differences in ascertainment and penetrance: relevance to genetic hypotheses in fragile X.

Between-generation differences in ascertainment were examined in 54 extended fragile X pedigrees, where all available members were clinically, psychometrically, and cytogenetically investigated. In 24 families a diagnosis was verified by molecular characterization using the pfxa3 fragile X-specific probe. We found considerable differences between generations in relative proportions of affected fragile X subjects versus 'non-penetrant' carriers. We also found deviation in the segregation ratio in unbiased samples of relatives in pedigrees. We claim that these irregularities are influenced by different rates of ascertainment, depending on the clinical expression of the condition (penetrance) and the fertility of fragile X individuals in a pedigree, as well as by the thoroughness of clinical investigation in individual families. Penetrance and fertility were estimated in fragile X females assessed by psychometric tests, and they were compared with earlier estimates based on a subjective judgement of their intellectual status. We suggest that the standard correction for ascertainment bias, such as has been applied in segregation analysis of this condition, is not sufficient to adjust for all types of bias.

Family Health↗
PubMed1993

An ultrasound renal cyst prevalence survey: specificity data for inherited renal cystic diseases.

This study documents the prevalence of simple renal cysts at various ages to produce a table of age-specific specificity values. The specificity of diagnosis for inherited renal cystic conditions depends primarily on the prevalence of simple renal cysts in disease-free subjects. To provide specificity data useful for the ultrasound assessment of individuals at genetic risk of having a renal cyst-forming condition, a prospective ultrasound study was performed. The urinary tract was examined in detail in 729 individuals referred for investigation of symptoms unrelated to the urinary tract and who had normal renal function. The prevalence of individuals with at least one renal cyst was 0% in those aged 15 to 29 years, 1.7% in those aged 30 to 49 years, 11.5% in those aged 50 to 70 years, and 22.1% in those aged 70 years and above. The prevalence of bilateral renal cysts (at least one cyst in each kidney) was 1% in those aged 30 to 49 years, 4% in those aged 50 to 70 years, and 9% in those aged 70 years and above. A table is provided that allows specificity estimates for differing diagnostic criteria together with 95% confidence limits for each estimate. In the younger age groups, bilateral renal cysts, particularly bilateral cysts with one or both kidneys having more than one cyst, are relatively uncommon. A reduced threshold for suspecting inherited renal cystic disease in younger individuals at high genetic risk will continue to have high specificity while improving the sensitivity of ultrasound diagnosis.

Adolescent↗
PubMed1992

Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease.

It is now clear that mutations of at least two genetic loci can lead to autosomal dominant polycystic kidney disease (ADPKD). We have compared the clinical features of ADPKD caused by mutations at the PKD1 locus (linked to the alpha-globin complex on chromosome 16) with those of disease not linked to the locus (non-PKD1). We identified 18 families (285 affected members) with mutations at PKD1 and 5 families (49 affected individuals) in which involvement of this locus could be dismissed. Non-PKD1 patients lived longer than PKD1 patients (median survival 71.5 vs 56.0 years), had a lower risk of progressing to renal failure (odds ratio 0.35, 95% CI 0.13-0.92), were less likely to have hypertension (odds ratio adjusted for age and family of origin 0.29, 0.11-0.80), were diagnosed at an older age (median 69.1 vs 44.8 years), and had fewer renal cysts at the time of diagnosis. Although most of the PKD1 families were ascertained through clinics treating patients with renal impairment, no non-PKD1 family was identified through this source. Non-PKD1 ADPKD has a much milder phenotype than that linked to PKD1. Partly as a result of this difference in severity, the reported prevalence of this genotype is probably an underestimate.

Adolescent↗
PubMed1992

Fragile X family with unusual digital and facial abnormalities, cleft lip and palate, and epilepsy.

We present a fragile X family with unusual clinical manifestations. These findings, which often occur in the X-linked FG syndrome, include minor limb anomalies, cleft lip and palate, characteristic facial appearance, gastrointestinal problems and epilepsy, and intellectual disability. In a total sample of 54 fra(X) families, the frequency of minor limb anomalies was estimated to be 32% in the affected males and 19% in the female heterozygotes. These anomalies tend to occur in several members of the same family, where some craniofacial abnormalities reported as characteristic of the FG syndrome have also been encountered. Possible mechanisms for the occurrence of these unusual manifestations in the fra(X) families are discussed.

Abnormalities, Multiple↗
PubMed1992

Importance of complete follow-up of spontaneous fetal loss after amniocentesis and chorion villus sampling.

Women who are the most difficult to trace after amniocentesis or chorion villus sampling are often those who have had an adverse pregnancy outcome. To calculate total fetal loss figures for use in prenatal counselling we have followed in a multicentre study 100% of women who had undergone these procedures. Early spontaneous loss (within three weeks of the procedure) and total spontaneous loss were much lower after amniocentesis (0.2% and 1.3%, respectively) than after chorion villus sampling (1.2% and 2.9%). Four spontaneous fetal losses among the 20 pregnancies that were the most difficult to follow-up increased the loss rate by 0.5% for chorion villus sampling. Risk of early fetal loss after chorion villus sampling was related to experience of the operator (relative risk [RR] 4.3, p = 0.003), and total fetal loss was lower in pregnancies tested at 10 weeks' or more gestational age compared with those tested before 10 weeks' (RR 0.4, p = 0.01). A table showing the frequency of each of the seven possible outcomes after amniocentesis and chorion villus sampling is useful in counselling those considering one or other test.

Abortion, Spontaneous↗
PubMed1992

Ultrastructure and immunocytochemistry of hepatic peroxisomes in rhizomelic chondrodysplasia punctata.

Peroxisomes were studied in the liver of two rhizomelic chondrodysplasia punctata patients using electron microscopy and catalase cytochemistry. Immunoelectron microscopy was carried out on the liver of one of these patients using antibodies to catalase, acyl-CoA oxidase, bifunctional protein, 3-ketoacyl-CoA thiolase and a 68 kDa peroxisomal membrane protein, in conjunction with protein-A colloidal gold. Moderately to markedly enlarged, flocculent peroxisomes were found in both patients. In one patient they were very heterogeneous with regard to the number per hepatocyte. The peroxisomes had very low levels of catalase as indicated by cytochemistry and immunocytochemistry. The three beta-oxidation enzymes were localised normally within the peroxisomes. The 68 kDa membrane protein was localised to the peroxisomal membranes. Some extra membrane loops were also identified using this antibody.

3,3'-Diaminobenzidine↗
PubMed1992

Binder's syndrome due to prenatal vitamin K deficiency: a theory of pathogenesis.

There is evidence that vitamin K-deficiency during human pregnancy can be caused by the therapeutic use of warfarin or phenytoin. The pregnancy histories of three cases of Binder's syndrome are reported. One was associated with warfarin exposure, one with phenytoin exposure and one with alcohol abuse. It is proposed that Binder's syndrome can be caused by prenatal exposure to agents that cause vitamin K-deficiency. Sprague-Dawley rats were treated from postnatal day 1 to 12 weeks with daily doses of warfarin (100 mg/kg) and concurrent vitamin K1 (10 mg/kg). This regimen creates a net extra-hepatic vitamin K-deficiency. The treated rats developed with a distinct facial appearance characterized by a markedly reduced snout. Histological examination showed that the normally non-calcified septal cartilage was extensively calcified. It is proposed that normal growth of the septal cartilage is necessary for the development of the profile of the nose and midface and that normal growth will only take place while the septal cartilage is uncalcified.

Adolescent↗
PubMed1991

Two forms of ring 13 in a child with rhabdomyosarcoma.

Mosaicism for two forms of ring 13 was found in a child with embryonal rhabdomyosarcoma of the bladder, minor anomalies, and developmental delay. Her chromosome constitution was 46,XX,r(13)(p11q34)/46,XX,r del(13)(p11q14). Both cell lines were present in lymphocytes and fibroblasts. The cell line with the smaller ring chromosome predominated in both tissues. The child's manifestations reflect the presence of both cell lines.

Abnormalities, Multiple↗
PubMed1991

Perceptions of genetic risk in individuals with a one in two chance of developing autosomal dominant polycystic kidney disease.

OBJECTIVE: To determine the level of understanding of personal genetic risk in people born with a one in two risk of having autosomal dominant polycystic kidney disease (ADPKD). DESIGN: Consenting individuals, contacted through affected family members, were asked standard questions about their knowledge of their own genetic risk. These questions were incorporated into a study investigating the use of DNA diagnostic techniques in ADPKD which was an opportunity to interview a substantial number of Australians at risk of inheriting this condition. SETTING: Interviews were conducted in the individuals' homes, or at the Royal Melbourne Hospital Renal Clinic or the Royal Children's Hospital Genetics Clinic. PATIENTS: Three hundred and eighty-seven individuals aged 15 years or more, born with a one in two risk but who had remained undiagnosed up until the time of study were identified within 46 families. Sixty-six were excluded from the study either because they resided too far away or they declined involvement. The remaining 321 were assessed clinically, 304 of whom were also interviewed about their understanding of their risk of having inherited this condition. RESULTS: Thirty per cent knew their risk at birth was one in two. Nine per cent were unaware that ADPKD was an inherited condition. Forty-one per cent were aware that ADPKD was inherited but had no opinion about their personal risk. Three per cent thought that they had no chance of having the condition, 3% thought that they were definitely affected, 8% considered their risk lay from 1%-49% and 6% thought their risk lay from 51%-99%. CONCLUSION: Within this group of people with a high risk of having an inherited condition with preventable and treatable components, the majority has a poor understanding of their genetic risk.

Adolescent↗
PubMed1991

Treatable complications in undiagnosed cases of autosomal dominant polycystic kidney disease.

In a study to determine the proportion of unrecognised cases and the prevalence of treatable complications of autosomal dominant polycystic kidney disease (ADPKD), 46 probands were identified through genetics and renal clinics in Melbourne, Australia. 321 offspring of the probands who were older than 15 years and had not been previously diagnosed as having ADPKD were identified. 68 (21%) had ultrasound evidence of polycystic kidney disease. Of this previously undiagnosed group, 25 (37%) had one or more treatable complications at the time of diagnosis. The complications included 20 cases of hypertension (diastolic blood pressure 95 mm Hg or above), 7 cases of impaired renal function (serum creatinine 0.12 mmol/l or above), and 4 cases of bacterial urinary tract infection. 8 people had several complications. ADPKD has an important treatable component which is not being treated in a substantial proportion of affected individuals, because the disease is not being diagnosed despite the presence of a positive family history.

Adolescent↗
PubMed1990

Pathology of hepatic peroxisomes and mitochondria in patients with peroxisomal disorders.

The morphology of hepatic peroxisomes in five patients with metabolic disorders believed to be due to inherited defects of peroxisomal function or biogenesis is described. Electron microscopy and cytochemical staining for catalase were used to identify peroxisomes in two boys with infantile Refsum's disease (IRD), a girl with autopsy confirmed neonatal adrenoleukodystrophy (NALD), and two boys with pseudo-Zellweger syndrome (PZS). In the patients with IRD and NALD hepatic peroxisomes were significantly reduced in size and number and contained electron dense centres. In the liver of the patients with PZS the peroxisomes were enlarged. Morphologically abnormal peroxisomes were also detected in autopsy tissue from one boy with PZS using electron microscopy. Lamellar-lipid inclusions and mitochondria with crystalline inclusions and/or abnormal cristae are also described in two patients, one with IRD, the other with NALD.

Adrenoleukodystrophy↗
PubMed1989

Analysis of DNA probes for the prenatal diagnosis of cystic fibrosis.

Cystic fibrosis is a common autosomal recessive disease in white persons. Prenatal diagnosis by DNA analysis became possible in families with a child who is affected by cystic fibrosis when the probes pJ3.11, metH and metD, which are linked closely to the cystic fibrosis gene (CF) were described. The recent description of the XV-2c and KM.19 probes has improved the prenatal diagnosis of cystic fibrosis greatly. The KM.19 probe alone was informative in eight of 12 families that were studied while XV-2c was informative in eight of 12 families that were studied while XV-2c was informative in only two of the 12 families. In contrast, the use of the pJ3.11, metH and metD probes in combination allowed full diagnosis in six of the 12 families. The combined use of the CF-linked probes produced informative data for all 12 families. Therefore, in most families with at least one affected living child, the first-trimester diagnosis of cystic fibrosis is possible with fetal DNA that has been prepared from chorionic villous samples. Strong linkage disequilibrium was found with both the KM.19-PstI polymorphism and the XV-2c-TaqI polymorphism and the CF gene.

Alleles↗