The Experts below are selected from a list of 150 Experts worldwide ranked by ideXlab platform
William D Foulkes - One of the best experts on this subject based on the ideXlab platform.
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muir torre Syndrome and msh2 mutations the importance of dermatological awareness
British Journal of Cancer, 2006Co-Authors: Marc Tischkowitz, Adrian Gologan, H Srolovitz, M Khanna, William D FoulkesAbstract:Sir, We would like to give an update on a family with Lynch Syndrome (hereditary non-polyposis colorectal cancer, HNPCC) that we have previously reported with germline truncating mutations in MSH2 (exon 8 deletion) and BRCA2 (542G>T) (Thiffault et al, 2004). This was a 26-member kindred with five cases of colorectal cancer and five cases of breast cancer, all but one of the cancers occurring below the age of 45 years. We reported that one of the individuals who had been diagnosed with rectal cancer (III.10 in original pedigree) also had a keratoacanthoma. This type of skin lesion is seen in some families with MSH2 or, less commonly, MLH1 mutations when it is termed Muir–Torre Syndrome (MTS) (Ponti and Ponz de Leon, 2005). Immunohistochemistry (IHC) at the time showed normal MSH2 expression, so we felt that this family did not belong to the MTS group. Subsequently, the individual was diagnosed with two separate sebaceous carcinomas on each arm. Immunohistochemistry analysis of these lesions shows loss of MSH2 expression in both cases, one of which is shown in Figure 1, confirming that this is in fact an MTS family. Figure 1 Sebaceous carcinoma: haematoxylin and eosin (× 100): multilobulated expansile intradermal tumour showing large polygonal cells with differentiation into sebaceous cells, altered nuclear/cytoplasmic ratio, evidence of apoptosis and high ... This new development illustrates two points. Firstly the Lynch Syndrome and MTS phenotypes are pleiotropic and Lynch Syndrome can evolve into MTS in the same family. Lynch Syndrome is usually suspected when the Amsterdam Criteria are fulfilled or the less-specific Bethesda guidelines are met. The individual described here had an anal canal squamous carcinoma, a cancer type not associated with Lynch Syndrome, which was microsatellite stable. His father, who was an obligate MSH2 mutation carrier, had a rectal cancer which is also unusual (Hoogerbrugge et al, 2003), and an astrocytoma, raising the possibility of overlap with another variant, Turcot Syndrome. Although Turcot Syndrome was classically thought of as a combination of brain tumours and polyposis and has been mainly associated with mutations in the APC gene (Galiatsatos and Foulkes, 2006), a minority are also due to mutation in the Lynch Syndrome genes, particularly biallelic PMS mutation carriers (De Vos et al, 2006). Secondly, the case emphasises the importance of continuing dermatological vigilance in MSH2 families. The same MSH2 mutations are found in both MTS and Lynch families (Ponti and Ponz de Leon, 2005), so it is not possible to predict which families are more likely to develop MTS. The sebaceous cancers in MTS are possibly less aggressive than sporadic types (Ponti and Ponz de Leon, 2005), but little is known about survival in MTS.
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familial adenomatous polyposis
The American Journal of Gastroenterology, 2006Co-Authors: Polymnia Galiatsatos, William D FoulkesAbstract:Familial adenomatous polyposis (FAP) is an autosomal-dominant colorectal cancer Syndrome, caused by a germline mutation in the adenomatous polyposis coli (APC) gene, on chromosome 5q21. It is characterized by hundreds of adenomatous colorectal polyps, with an almost inevitable progression to colorectal cancer at an average age of 35 to 40 yr. Associated features include upper gastrointestinal tract polyps, congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and other extracolonic malignancies. Gardner Syndrome is more of a historical subdivision of FAP, characterized by osteomas, dental anomalies, epidermal cysts, and soft tissue tumors. Other specified variants include Turcot Syndrome (associated with central nervous system malignancies) and hereditary desmoid disease. Several genotype-phenotype correlations have been observed. Attenuated FAP is a phenotypically distinct entity, presenting with fewer than 100 adenomas. Multiple colorectal adenomas can also be caused by mutations in the human MutY homologue (MYH) gene, in an autosomal recessive condition referred to as MYH associated polyposis (MAP). Endoscopic screening of FAP probands and relatives is advocated as early as the ages of 10-12 yr, with the objective of reducing the occurrence of colorectal cancer. Colectomy remains the optimal prophylactic treatment, while the choice of procedure (subtotal vs proctocolectomy) is still controversial. Along with identifying better chemopreventive agents, optimizing screening of extracolonic cancers and applying new radiological and endoscopic technology to the diagnosis and management of extracolonic features are the major challenges for the future.
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a tale of four Syndromes familial adenomatous polyposis gardner Syndrome attenuated apc and Turcot Syndrome
QJM: An International Journal of Medicine, 1995Co-Authors: William D FoulkesAbstract:Familial adenomatous polyposis (FAP), Gardner Syndrome (polyposis, osteomas and epitheliomas), flat adenoma Syndrome (attenuated APC) and Turcot Syndrome (colorectal polyposis with brain tumours) are distinctive clinical Syndromes. Each is caused by mutations in the adenomatous polyposis coli (APC) gene on chromosome 5q21, although Turcot Syndrome may have other causes. A variety of APC mutations are recognized, which can be associated with the character and severity of the clinical Syndromes.
D. G. Evans - One of the best experts on this subject based on the ideXlab platform.
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homozygous germ line mutation of the pms2 mismatch repair gene a unique case report of constitutional mismatch repair deficiency cmmrd
BMC Medical Genetics, 2017Co-Authors: N. C. Ramchander, N. A. J. Ryan, E. J. Crosbie, D. G. EvansAbstract:Constitutional mismatch repair deficiency Syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency Syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family. The proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two cafe-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband’s family pedigree displays multiple relatives with cancers including a likely case of ‘true’ Turcot Syndrome. Constitutional mismatch repair deficiency Syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency Syndrome.
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Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD)
BMC, 2017Co-Authors: N. C. Ramchander, N. A. J. Ryan, E. J. Crosbie, D. G. EvansAbstract:Abstract Background Constitutional mismatch repair deficiency Syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency Syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family. Case presentation The proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband’s family pedigree displays multiple relatives with cancers including a likely case of ‘true’ Turcot Syndrome. Conclusions Constitutional mismatch repair deficiency Syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency Syndrome
Sue C Richards - One of the best experts on this subject based on the ideXlab platform.
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a homozygous mutation in msh6 causes Turcot Syndrome
Clinical Cancer Research, 2005Co-Authors: Madhuri R Hegde, Belinda Chong, Maria Blazo, Lip Hon E Chin, Patricia A Ward, Murali Chintagumpala, Sharon E Plon, Sue C RichardsAbstract:Heterozygous mutations in one of the DNA mismatch repair genes cause hereditary nonpolyposis colorectal cancer (MIM114500). Turcot Syndrome (MIM276300) has been described as the association of central nervous system malignant tumors and familial colorectal cancer and has been reported to be both a dominant and recessive disorder. Homozygous and compound heterozygous mutations in APC, MLH1, MSH2, and PMS2 genes have been reported in five families. Here we describe a nonconsanguineous Pakistani family, including a son with lymphoma and colorectal cancer diagnosed at ages 5 and 8, respectively, and an 8-year-old daughter with glioblastoma multiforme. Both children had features of neurofibromatosis type 1 including atypical cafe au lait spots and axillary freckling without a family history consistent with neurofibromatosis type 1, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer. Mutational analysis was done for MLH1, MSH2, and MSH6 using denaturing high-performance liquid chromatography and sequencing of a blood sample from the daughter. A novel homozygous single base insertion mutation was identified (3634insT) resulting in a premature stop at codon 1,223 in exon 7 of the MSH6 gene. Both parents were found to be heterozygous for the 3634insT mutation. Microsatellite instability testing showed instability in the glioblastoma sample. We report here the first identification of a homozygous mutation in MSH6 in a family with childhood-onset brain tumor, lymphoma, colorectal cancer, and neurofibromatosis type 1 phenotype. Our findings support a role for MSH6 in Turcot Syndrome and are consistent with an autosomal recessive mode of inheritance.
E. J. Crosbie - One of the best experts on this subject based on the ideXlab platform.
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homozygous germ line mutation of the pms2 mismatch repair gene a unique case report of constitutional mismatch repair deficiency cmmrd
BMC Medical Genetics, 2017Co-Authors: N. C. Ramchander, N. A. J. Ryan, E. J. Crosbie, D. G. EvansAbstract:Constitutional mismatch repair deficiency Syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency Syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family. The proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two cafe-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband’s family pedigree displays multiple relatives with cancers including a likely case of ‘true’ Turcot Syndrome. Constitutional mismatch repair deficiency Syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency Syndrome.
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Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD)
BMC, 2017Co-Authors: N. C. Ramchander, N. A. J. Ryan, E. J. Crosbie, D. G. EvansAbstract:Abstract Background Constitutional mismatch repair deficiency Syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency Syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family. Case presentation The proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband’s family pedigree displays multiple relatives with cancers including a likely case of ‘true’ Turcot Syndrome. Conclusions Constitutional mismatch repair deficiency Syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency Syndrome
David T Bonthron - One of the best experts on this subject based on the ideXlab platform.
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novel pms2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer Syndrome
American Journal of Human Genetics, 2004Co-Authors: Michel De Vos, Bruce E Hayward, Susan Picton, Eamonn Sheridan, David T BonthronAbstract:We investigated a family with an autosomal recessive Syndrome of cafe-au-lait patches and childhood malignancy, notably supratentorial primitive neuroectodermal tumor. There was no cancer predisposition in heterozygotes; nor was there bowel cancer in any individual. However, autozygosity mapping indicated linkage to a region of 7p22 surrounding the PMS2 mismatch-repair gene. Sequencing of genomic PCR products initially failed to identify a PMS2 mutation. Genome searches then revealed a previously unrecognized PMS2 pseudogene, corresponding to exons 9–15, within a 100-kb inverted duplication situated 600 kb centromeric from PMS2 itself. This information allowed a redesigned sequence analysis, identifying a homozygous mutation (R802X) in PMS2 exon 14. Furthermore, in the family with Turcot Syndrome, in which the first inherited PMS2 mutation (R134X) was described, a further truncating mutation was identified on the other allele, in exon 13. Further whole-genome analysis shows that the complexity of PMS2 pseudogenes is greater than appreciated and may have hindered previous mutation studies. Several previously reported PMS2 polymorphisms are, in fact, pseudogene sequence variants. Although PMS2 mutations may be rare in colorectal cancer, they appear, for the most part, to behave as recessive traits. For technical reasons, their involvement in childhood cancer, particularly in primitive neuroectodermal tumor, may have been underestimated.
