Biomedical subjects
V Murday
Publications and source records attributed to V Murday.
Genetic counselling in the cancer family clinic.
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Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy?
Cowden syndrome is an autosomal dominant condition of multiple hamartomas. Patients with this phakomatosis have an increased risk of breast cancer and thyroid tumours. Lhermitte-Duclos disease is usually a sporadic condition of cerebellar ganglion cell hypertrophy, ataxia, mental retardation, and self-limited seizure disorder. We describe a three generation family with Cowden syndrome and Lhermitte-Duclos disease. Karyotyping performed on the peripheral lymphocytes of the proband and her affected mother showed a 46,XX complement. Single strand conformational polymorphism analysis failed to show any germline p53 mutations as a cause of the syndrome in this family.
Isolation and sequencing of CA/GT repeat microsatellites from chromosomal libraries without subcloning.
A method for the isolation of (CA)n microsatellites from chromosome-specific genomic libraries is described. Clones were first screened using a polynucleotide CA/GT probe. Those shown to contain CA repeats were plaque purified and either subcloned or the insert amplified directly using vector primers. Polymerase chain reaction products were then used to directly sequence the regions flanking CA repeats by using biotinylated primers that amplify cloned inserts outward from CA repeat containing regions of DNA to vector primers. This method provides rapid access to microsatellites from chromosomes or chromosome regions of interest.
Microcephaly, focal segmental glomerulonephritis and marfanoid habitus in two sibs.
Two female sibs aged 15 and 18 years with microcephaly, mental retardation and marfanoid habitus who developed focal segmental glomerulonephritis leading to renal failure are described. This combination of features appears to represent a unique syndrome distinct from previous reports of microcephaly in association with the nephrotic syndrome. The mode of inheritance is likely to be autosomal recessive.
Helicobacter gastritis and intestinal metaplasia in a gastric cancer family.
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Risk estimates for screening adenomatous polyposis coli.
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Familial colorectal cancer and familial adenomatous polyposis.
Familial adenomatous polyposis (FAP) affects around 1 in 10,000 individuals; the gene for this condition was recently shown to be located on chromosome 5, and it is only a matter of time before its precise location and function are determined, making prephenotypic, and even prenatal, diagnosis more generally available and reliable. In the mean time, care of FAP families will continue to depend on careful registration of family information, prophylactic bowel surgery and surveillance for other potentially serious manifestations of the disease. Upper gastrointestinal malignancies and desmoid tumours have overtaken colorectal cancer as the leading causes of death in some centres. Other dominantly-inherited colorectal cancer syndromes produce less striking phenotypes, but affect far more individuals than FAP. It appears that there are two patterns of hereditary non-polyposis colorectal cancer (HNPCC) syndromes, one involving cases of bowel cancer alone, the other associated with breast and gynaecological cancers; these may prove to be variable expressions of a common gene abnormality. More effort is required by clinicians managing cases of colorectal cancer to identify affected families in order to offer surveillance and appropriate treatment in the hope that such measures may prevent cancer in family members.
CpG island clones from a deletion encompassing the gene for adenomatous polyposis coli.
Adenomatous polyposis coli (APC), a dominantly inherited disorder, has been mapped to chromosome 5q15-q21 by family linkage studies. Cells from patients with deletions in this region, in one case associated with polyposis in a family, have been used to construct human hamster hybrid cell lines that retain either the normal or deleted chromosome 5. These lines have been used to identify markers from the region of the polyposis gene obtained by cloning the ends of 0.5- to 2-megabase BssHII fragments purified by pulsed-field gel electrophoresis. Three markers are described that map within the deletions and must therefore be close to the APC gene.
Cancer and the Peutz-Jeghers syndrome.
Among 72 patients with the Peutz-Jeghers syndrome malignant tumours have developed in 16 (22%) of whom all but one have died. There were nine gastrointestinal and seven nongastrointestinal tumours. The relative risks of death from gastrointestinal cancer and all cancers were 13 (95% CI 2.7-38.1) and 9 (95% CI 4.2-17.3) respectively. The chance of dying of cancer by the age of 57 was 48%. There is evidence for a hamartoma/carcinoma sequence in the Peutz-Jeghers syndrome, suggesting that the gene locus involved is relevant to the development of malignancy in general.
Inherited disorders associated with colorectal cancer.
There is an increased risk of colorectal cancer among first degree relatives of affected men and women which is greater among relatives of young index patients. The high risk in some families can be explained by Mendelian patterns of inheritance and some syndromes associated with colorectal cancer have been recognized. Syndrome recognition with an accurate knowledge of the natural history of diseases caused by a single gene effect can offer opportunities for exploration of some of the mechanisms of carcinogenesis as well as enable more accurate predictions of diagnosis in susceptible individuals and in pregnancy. Recent progress with familial adenomatous polyposis illustrates some of the opportunities for prevention of colorectal cancer which may arise with syndrome recognition in the future.
An economic appraisal of screening for Down's syndrome in pregnancy using maternal age and serum alpha fetoprotein concentration.
The direct and indirect costs and benefits of expanding the existing screening programme for Down's syndrome by using maternal age and serum alpha fetoprotein concentrations have been calculated using an ascertainment of Down's syndrome pregnancies from the North East Thames Regions in 1982. In addition, a possible approach to evaluating the total costs and benefits to the families concerned is presented. If the uptake of the proposed screening programme is maximal, the replacement rate is zero and a discount rate of 5% is used, the benefit cost ratio is 23.6. If the uptake of the programme is 50%, the replacement rate is 100% and a discount rate of 7% is used, the benefit cost ratio is 12.2. The proposed screening programme, based upon a risk of Down's syndrome of at least 1 in 220 using maternal age and serum alpha fetoprotein is both equitable for families at risk and of economic benefit to both families and society.
Gene markers for inherited disease.
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Screening for Down's syndrome in the North East Thames region.
The suggested strategies for a screening programme for Down's syndrome by maternal serum alpha fetoprotein concentration were examined and tested on the experience of the North East Thames Regional. Screening by maternal serum alpha fetoprotein concentration may be used to identify pregnancies at increased risk, but this is useful only in women aged over 32 whose collective risk is greater than one in 200. The absolute probability of carrying babies with Down's syndrome for individuals in this high risk group can then be calculated and used to decide whether further diagnosis by amniocentesis is desired.
Screening and genetic counselling for relatives of patients with colorectal cancer in a family cancer clinic.
OBJECTIVE: To introduce and monitor a screening programme for first degree relatives of patients with colorectal cancer based on their calculated lifetime risk. DESIGN: Lifetime risks were calculated for first degree relatives of patients with colorectal cancer and used to offer screening based on estimated risk. SETTING: A family cancer clinic was set up as part of the North East Thames Regional Genetic Service for relatives of patients who had developed colorectal cancer before the age of 45 and members of families in which multiple cancer had occurred. PATIENTS: Self referrals as well as patients referred by general and hospital practitioners. INTERVENTION: Relatives with a lifetime risk of 1 in 10 or greater (high risk group) were offered screening five yearly by colonoscopy, and those whose risk was between 1 in 10 and 1 in 17 were offered yearly screening for faecal occult blood. Women with family histories compatible with Lynch type II cancer family syndrome were offered screening for breast and pelvic tumours. RESULTS: In four years 715 patients were seen. Acceptance of screening was 90% (644 patients). Of 151 patients screened for faecal occult blood, two were found to have polyps. This screening test was unsatisfactory for the high risk group, having a negative predictive value of 78% in 59 patients tested. Regular screening by colonoscopy was offered to 382 high risk patients; 62 patients with polyps and five with colonic cancer were found. One hundred and ten pedigrees were identified with the Lynch type II cancer family syndrome, and four of 35 women screened were found to have breast cancer. Of 14 relatives aged over 65 with a 1 in 2 risk of site specific colonic cancer or Lynch type II cancer family syndrome, seven were found to have polyps, one of whom had carcinoma in situ. CONCLUSIONS: Family history can be used to identify those at risk of colonic cancer and to target appropriate screening. Colonoscopy detected a high number of premalignant colonic polyps, but faecal occult blood testing was unsatisfactory for those at high risk of colorectal cancer.