Browsing by Author "Ramesar, R"

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    Open Access
    The clinical and pathological features of hereditary mixed polyposis syndrome: report on a South African family
    (Health and Medical Publishing Group, 2008) Algar, U; Duffield, M; Goldberg, P A; Ramesar, R; Vorster, A; Ibirogba, S B
    Background: Hereditary mixed polyposis syndrome is characterised by multiple large-bowel polyps of differing histological types including a mixture of atypical juvenile polyps, hyperplastic polyps and adenomas. Affected individuals are thought to have an increased risk of malignancy, possibly via the juvenile polyposis pathway. Methods: A 51-year-old woman (with a history of a colectomy for polyps during childhood) presented with rectal bleeding. Endoscopy demonstrated small rectal polyps which were hyperplastic on histology. A family tree was drawn up and the three children of the proband underwent flexible sigmoidoscopy. Results: Endoscopic surveillance of the three children revealed one who had a similar phenotype to the mother. This child underwent colectomy and ileorectal anastomosis. The pathological specimen revealed more than 70 polyps, with a combination of juvenile retention, hyperplastic, adenomatous and inflammatory polyps. A second child had multiple small hyperplastic polyps, and the third had a normal colon. Although the gene locus for the disorder has been mapped, neither the gene nor the disease-causing mutation has been defined. Conclusion: A rare inherited polyposis syndrome has been identified in a South African family. Where clinical suspicion of a possible inherited condition exists, investigating at-risk first-degree relatives confirms the inherited nature of the disease. It is possible to use genetic haplotyping (i.e. with a range of markers in the area of the gene) to provide statistical risk to immediate relatives and therefore those at highest risk.
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    Elucidation of the occurrence of extracolonic cancers in Lynch syndrome
    (2008) Kalideen, Kusha; Ramesar, R
    Lynch Syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) (OMIM #120435), is a familial disorder resulting from mutations within DNA MMR genes. Effective surveillance, diagnosis and treatment of the disorder is complicated due to the phenotypic and genetic heterogeneity of lynch syndrome, which exhibits an autosomal dominant mode of inheritance. Determine the molecular pathology of extracolonic cancers in Lynch syndrome and to elucidate whether or not the occurrence of these extracolonic cancers are a direct result of the mismatch repair deficiency. First, a modifier study was performed assessing the effect of a variant within the DNA MMR gene hMLH1 in a cohort of individuals predisposed to Lynch syndrome in order to examine a potential epistatic effect in the gene. In order to obtain a genetic signature of Lynch associated tumours, germline DNA and corresponding tumour DNA was isolated from Lynch syndrome patients. The genetic material was assessed via a panel of microsatellite rich genes and MS-MLPA. Finally, in silico analyses were undertaken assessing microarray data from microsatellite unstable colorectal and endometrial cancers to characterise novel candidate genes. The modifier study did not prove fruitful as no association was found between the hMLH1 promoter variant and site of cancer in individuals predisposed to Lynch syndrome. An association was observed heterozygous and homozygous variant genotypes and an increased risk of colorectal cancer, regardless of predisposing mutation (p = 0.000181). Two tumour suppressor genes; HIC1 and TIMP3, were found to be methylated in the tumour samples in the germline/tumour tissue study. This study also showed instability of the Erβ gene in the majority of tumour samples. Bioinformatic analysis utilising existing microarray data resulted in common under-expression of four genes and common overexpression in three genes in microsatellite unstable colorectal and endometrial cancers. Further investigation into the modifier study and elucidation of a genetic signature in MMR deficient, MSI cancers. The results obtained in this study contribute to the increasing body of knowledge in the field and the various stages of malignancies should be assessed for a more informative result. Genetic and functional studies should be performed on the information garnered from the bioinformatics analysis. Overall evaluation and molecular classification of Lynch syndrome tumours may guide better diagnosis, surveillance and treatment of those at risk.
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    Identifying Children with Constitutional Mismatch Repair Deficiency (CMMR-D) Syndrome in the Expanding Lynch Syndrome population in Cape Town
    (2021) Tu, Sindy Jen-Yi; Pillay, Komala; Ramesar, R; Wessels, A
    INTRODUCTION: Constitutional Mismatch Repair Deficiency (CMMR-D) syndrome is a rare tumour predisposition and polyposis syndrome that presents in childhood. It is caused by mutations in mismatch repair (MMR) genes that result in a tumour spectrum including colorectal cancers, high-grade gliomas, non-Hodgkin T-cell lymphomas and leukaemias. It is characterized by biallelic germline mutation of one of four possible MMR genes resulting in loss of protein expression that can be identified by applying immunohistochemistry to formalin fixed paraffin embedded tissue sections. Use of MMR immunohistochemistry is established in the setting of Lynch syndrome (LS); however, the pattern of loss of staining in the background, non-tumour tissue is unique to CMMR-D syndrome. CMMR-D syndrome is seen in LS families and occurs as a result of consanguinity or founder effect. The South African population has LS families concentrated in the Western Cape and Northern Cape Provinces and the mixed ancestry population shows a unique MLH1 c1528C>T mutation which may have implications on the incidence, penetrance and severity of CMMR-D syndrome seen in our population. The diagnosis of CMMR-D syndrome includes clinical findings outlined in the European Consortium's Care of CMMRD document and confirmation of the biallelic mutation in one of the MMR genes. MMR immunohistochemistry can be used in the diagnosis of CMMR-D syndrome by identifying cases for targeted molecular genetic tests. However, MMR immunohistochemical staining patterns are not usually described in detail, particularly the loss of staining of the affected gene in the background, non-tumour tissue, the key feature of CMMR-D syndrome. METHODS: We performed a retrospective analysis of archival formalin fixed paraffin embedded tissue of children attending Red Cross Children's Hospital with tumours that form part of the CMMR-D spectrum, outlined by the Care for CMMRD criteria. We used the criteria of high-grade gliomas (WHO Grade III or IV) occurring before 25 years of age, cutaneous lesions suggestive of CMMR-D syndrome and patients with a first or second degree relative diagnosed with LS. MMR immunohistochemistry was applied, and the staining pattern was documented in terms of proportion of tumour staining and intensity of staining using a modified Allred Scoring system. Specific attention was given to the characterization of the staining pattern of the background normal tissue. RESULTS: 21 samples taken from 18 patients were evaluated. 16 samples represented brain tumours, predominantly high-grade gliomas. Three samples were excluded due to suboptimal staining despite positive external controls. 12 samples showed intact staining of all four MMR stains. Two samples showed staining of unknown significance. Four samples from 3 different patients showed staining patterns compatible with MMR deficiency. This included two patients, each with a biopsy showing high-grade glioma and two samples of the same patient taken at a 1-year interval of a Burkitt lymphoma. Of these four samples, three samples showed loss of staining in background non-tumour tissue with positive external control, the unique staining pattern for CMMR-D syndrome. These cases will be referred for confirmatory testing by molecular genetic techniques. CONCLUSION: MMR immunohistochemistry can be used in the evaluation of CMMR-D syndrome, but care is needed in evaluating adequacy of staining, the pattern and scoring of staining of both the tumour and the background non-tumour tissue. Endothelial cells are easy to identify and evaluate as background tissue which is useful in extra-intestinal tumours. Neurons and choroid plexus can also be evaluated as background tissue in brain tumour samples. Selection bias in this study resulted in the underrepresentation of lymphomas and colorectal carcinomas. Improved characterization and search for Non-Hodgkin T-cell lymphomas and inclusion of samples of colorectal carcinomas of adolescents and adults would be needed to include these tumours. Use of MMR immunohistochemistry in postmortem tissue samples is not recommended because of suboptimal staining, even with a short post-mortem interval of 1 day. The diagnosis of CMMR-D syndrome depends on clinical application of Care for CMMRD criteria, MMR immunohistochemistry in conjunction with molecular genetic testing. It is important to identify cases of CMMR-D syndrome and offer cancer screening to prevent development of other cancers in the index patient. It also provides an opportunity for genetic counselling and testing of the parents and at-risk siblings.
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    Metabolic syndrome, the leptin gene and kidney disease in non-diabetic black South Africans
    (2008) Okpechi, Ikechi Gareth; Meissner, P; Rayner, B L; Ramesar, R; Pascoe, M D
    Obesity is a worldwide problem and is a factor in the pathogenesis of the metabolic syndrome and kidney disease through the development of obesity-related hypertension and neurohormonal mechanisms that include the action of leptin. As there appear to be no focussed studies that have looked at the association of the LEP gene with kidney disease phenotypes or cardiovascular disease markers like hypertension, the metabolic syndrome and obesity, and especially so in native black Africans, this study sought to establish an association between the obesity gene (LEP) and kidney disease phenotypes (independent of diabetes and hypertension) in a homogenous black African population.
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    Sudden unexpected death in infants: a forensic genetic investigation in a South African cohort
    (2019) Heathfield, Laura Jane; Ramesar, R; Martin, L J
    Sudden unexpected death in infants (SUDI) is a devastating event, and unfortunately occurs frequently in South Africa. The emerging molecular autopsy has added value to SUDI investigations by revealing genetic variants which contributed to their demise. Motivated by the value of this concept to family members as well as the limited research of SUDI locally, the aim of this study was to explore molecular autopsies in the medico-legal investigation of SUDI cases in South Africa. A 5-year retrospective study of 1.199 SUDI admissions to Salt River Mortuary, Cape Town showed that 110 (9.%) cases were still under investigation, while most had infectious causes of death. An ethical framework was established and used to prospectively recruit 201 SUDI cases from Salt River Mortuary. A pilot quality assessment of DNA from blood, buccal cells and formalin fixed paraffin embedded tissue motivated the prospective collection of blood samples. Three variants previously associated with the risk of infections (IL-6 rs1800795.G>C; TNF-α rs1800629.G>A; TLR4 rs4986790.A>G) were genotyped in the sampled cohort. The allele frequency data generated suggested a possible association between each of these variants and an infection-related cause of death in SUDI. Targeted genotyping of candidate variants revealed several pathogenic mutations, including a twin who was homozygous T/T for a founder mutation, GALT rs111033690.C>G/T, causative of galactosaemia (previously undiagnosed). Follow up with the family revealed that the other twin had subsequently demised. Additionally, 43 genes previously associated with cardiac arrhythmias, were sequenced in a subset of cases (n.=.19) and parental samples. Putative pathogenic variants were identified in four infants, and four additional novel variants were found. Lastly, using a hypothesis-free approach, clinical exome sequencing was performed on two cases, which suggested one infant was immune-compromised and the second may have had bronchopulmonary dysplasia. The findings in this study highlight possible new candidate variants to assess in SUDI cases, and has directly contributed to the development of a molecular autopsy which is locally relevant. It is evident that until newborn screening becomes routine and accessible in South Africa, molecular autopsies should include testing for inherited metabolic disorders, as it holds potential to save lives.