MSH6 mutation in Muir-Torre syndrome: could this be a rare finding?
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Adult↗
Biomedical subjects
W Friedl
Publications and source records attributed to W Friedl.
Frequency of hereditary non-polyposis colorectal cancer among unselected patients with colorectal cancer in Germany.
INTRODUCTION: Hereditary non-polyposis colorectal cancer (HNPCC) is a major form of familial colorectal cancer (CRC). It is diagnosed when either the Amsterdam criteria (AC) are fulfilled or mutations in one of the mismatch repair (MMR) genes have been identified. This project aims at estimating the proportion of HNPCC among unselected patients with CRC. PATIENTS AND METHODS: During a period of 2 years, a total of 351 non-selected patients with CRC were registered prospectively. 92 patients met the Bethesda criteria (9 of them fulfilled the AC) and 259 did not. 348 tumours were examined for microsatellite instability (MSI) and expression of MMR proteins. RESULTS: MSI-H and MSI-L were identified in 17 and 6%, respectively. Loss of MSH2 or MLH1 was found in 1.5 and 8.8%, respectively. Based on the results of tumour tissue analyses, 80 patients with MSI and/or loss of MSH2 or MLH1 expression were identified as candidates for germline mutation screening. DNA of 40/80 patients was available. These patients were screened for MSH2 and MLH1 mutations; 19/40 patients with MSI and normal MSH2 or MLH1 expression were screened for mutations in MSH6. Three patients had relevant MMR gene mutations and six variants of unknown functional relevance were detected. CONCLUSIONS: After adjusting for the cases not evaluable for germline mutations, 1.7% of the CRC patients had HNPCC proven by molecular genetics.
Adaptor Proteins, Signal Transducing↗
[Fracture of the neck of the talus in a child].
Fractures of the talus in children are rare. Repeated clinical examination and imaging techniques such as magnetic resonance imaging are often needed to establish a diagnosis. In case of the late recognition of talus fractures, catastrophic results may occur for the hind-foot. This case report presents a 5 year old boy with a non-displaced talus neck fracture with good outcome after minimally invasive osteosynthesis.
Ankle Injuries↗
[Soft tissue protective, stable osteosynthesis of fractures after elbow ankylosis. Two case reports].
The two cases presented are fractures of ankylosed elbow joints with severe soft tissue damage. Closed reduction and percutaneous osteosynthesis were performed using the IP-XS-nail system to prevent further soft tissue damage. By implanting two parallel XS-nails between the humerus and ulna and humerus and radius, we achieved a situation allowing early functional treatment of the weight bearing joints. There were no complications.
Aged↗
Bronchioloalveolar carcinoma: a new cancer in Peutz-Jeghers syndrome.
Besides gastrointestinal hamartomatous polyposis and melanin spots in the skin and mucosa, patients with the Peutz-Jeghers syndrome (PJS) have repeatedly been observed with a variety of tumours, including lung cancer. Available data indicate an increased cancer risk among PJS patients, which suggests that the gene involved in PJS, STK11 on chromosome 19p13.3, may be a tumour suppressor gene. Herein, bronchioloalveolar carcinoma (BAC) of mucinous type is reported in a 22-year old male PJS patient with a novel germline frameshift insertion in exon 2 at codon 118 of the STK11 gene. Molecular studies of his BAC indicated loss of heterozygosity (LOH) in the region of STK11 on chromosome 19p13.3. This observation supports the hypothesis that STK11 is a tumour suppressor gene which is involved in the development of lung adenocarcinoma.
AMP-Activated Protein Kinase Kinases↗
Large submicroscopic genomic APC deletions are a common cause of typical familial adenomatous polyposis.
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Adenomatous Polyposis Coli↗
Analysis of germline mutations in the APC gene in familial adenomatous polyposis patients.
OBJECTIVE: This study was aimed at establishing an efficient mutation analysis technique system to screen the germline mutations in the adenomatous polyposis coli (APC) gene that predisposes the disease susceptibility in familial adenomatous polyposis (FAP) and to investigate the relationship between genotype and phenotype of APC gene. METHODS: Genomic DNA was extracted from the peripheral blood lymphocytes of 22 patients with clinically diagnosed FAP and was forwarded to screening for germline mutations by using denaturing high-performance liquid chromatography(DHPLC), protein truncation test (PTT) and DNA sequencing in APC gene. Analysis of genotype-phenotype was also performed on the clinical data of the FAP patients. RESULTS: Thirteen APC germline mutations were identified in 22 FAP patients. All of the mutations were nonsense or framshift mutations. Analysis of genotype-phenotype demonstrated that the FAP patients with mutations in the 5'or 3'extreme parts of the APC gene showed mild clinical symptoms. However, the FAP patients with mutations in the middle of the APC gene displayed typical or severe clinical symptoms. CONCLUSION: The technique system established in this study can efficiently and sensitively detect the mutations in APC gene. It is useful in the molecular diagnosis of pre-symptomatic FAP cases in FAP family. The clinical features of FAP patients may be related to their genotypes of APC gene.
Adenomatous Polyposis Coli↗
[Detection of germline mutations in the APC gene with the protein truncation test].
The protein truncation test was established for analyzing mutations in the adenomatous polyposis coli (APC) gene which plays an important role in familial adenomatous polyposis (FAP). The sites of APC mutations and the clinic features of FAP patients were examined to find the relationship between them. Genomic DNA, which was extracted from peripheral blood lymphocytes of 22 FAP patients and the normal colon tissues of 43 sporadic colorectal cancers, were examined for mutations in exon15 of the APC gene by using PCR-TNT T7 Quick Coupled Tanscription/Translation System. The subsequent sequencing was used to confirm the mutation sites. Germline mutations were found in 5 of 22 FAP patients. All of the five mutations showed base pair deletions and led to produce truncated protein. No truncating germline mutation was found in normal tissues of 43 sporadic colorectal cancers. The protein truncation test is a sensitive and accurate technique to detect truncated mutations especially in the large exons of APC gene. It can be used as an routine method for assisting the early diagnosis of the FAP patients.
Adenomatous Polyposis Coli↗
E-cadherin expression is homogeneously reduced in adenoma from patients with familial adenomatous polyposis: an immunohistochemical study of E-cadherin, beta-catenin and cyclooxygenase-2 expression.
BACKGROUND AND AIMS: The adenomatous polyposis coli (APC) protein plays a crucial role in the regulation of beta-catenin, which is linked to the cell adhesion molecule E-cadherin. Furthermore, beta-catenin and cyclooxygenase-2 (COX-2) are both involved in the activation of nuclear transcription factors inducing cell proliferation. Germline mutations in the APC gene are the cause of familial adenomatous polyposis (FAP). To characterise the expression pattern of these proteins in FAP in comparison with sporadic adenomas, we studied 18 FAP-associated adenomas, 16 sporadic adenomas and seven normal colonic controls. METHODS: E-cadherin, beta-catenin, COX-2 expression and the proliferative index (Ki67) were assessed by immunohistochemistry (index of expressing cells / total number of cells) in adenomatous mucosa, adjacent non-neoplastic tissue and normal colonic controls. RESULTS: E-cadherin expression was significantly and homogeneously reduced in FAP adenomas (24%; 95%CI 16-32; sporadic adenomas 61%; 38-84; normal controls 98%; 96-100). Membraneous beta-catenin expression was significantly reduced in both FAP (30%; 11-49) and sporadic (42%; 19-65) adenomas (normal controls 96%; 88-104), whereas marked nuclear staining occurred in sporadic, but not in FAP adenomas. Stromal COX-2 expression and the proliferative index were increased only in sporadic adenomas (sporadic adenomas: COX-2 12%; 7-17, Ki67 24%; 15-33, FAP adenomas: COX-2 8%; 5-11, Ki67 5%; 2-9, normal controls: COX-2 4%; 2-7, Ki67 6%; 1-11). CONCLUSION: Proteins involved in cell adhesion and cell proliferation, especially E-cadherin, are expressed differently in FAP and sporadic adenoma, pointing to possible differences in the molecular pathways to adenoma.
Adenoma↗
[Pathological fracture in fibrous histiocytoma of the proximal radial metaphysisJoint-preserving stabilization with the IP-XXS nail].
In this paper the authors report on a rare site for a benign bone lesion. They describe the clinical, radiological diagnostic, and therapeutic procedures for a benign fibrous histiocytoma (BFH) of the proximal radial metaphysis. Good results of operative treatment after excochleation, transplantation of an autologous bone chip, and stabilization with the IP-XXS nail are presented.
Adult↗
A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome.
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Adaptor Proteins, Signal Transducing↗
New concepts in the treatment of ankle joint fractures. The IP-XS (XSL) and IP-XXS (XXSL) nail in the treatment of ankle joint fractures.
INTRODUCTION: The most important factor in the treatment of ankle joint fractures is stable anatomical reconstruction of the syndesmosis and joint surface. In the course of this, attention must be paid to soft-tissue damage with the risk of deep infections. Early functional therapy and exercise tolerance must be called for. The choice of surgical access route, in particular in the case of critical arterial circulation, and the possible irritation of the soft tissue by the osteosynthesis material prompted us to seek alternative osteosynthesis techniques. MATERIAL AND METHODS: Following a preclinical study and very good initial results with the XS nail in the treatment of patella and olecranon fractures, this was now also used for ankle joint fractures at the medial malleolus and lateral malleolus. In the period from 5/2000 to 1/2002, 194 ankle joint fractures were treated using the XS nail. These were predominantly Weber B, C and bimalleolar fractures. In the case of ankle joint fractures, osteosynthesis was carried out following precise open fracture repositioning. In the case of isolated fibula fractures, early loading was allowed within 1 week; in the case of bimalleolar fractures, there was immediate partial loading with 20 kg for 4 weeks, after which they were subjected to full loading. Where there was an additional Volkmann fracture, we allowed only immediate partial loading with 10 kg for 6 weeks. All 194 patients were observed prospectively, and 162 (83.5%) could be followed up after 15 months. The results were classified according to the scale described by Olerud. RESULTS: It has been possible to follow up 162 patients, with an average age of 49.7 years. There were 62 (38.3%) Weber B and 45 (27.8%) Weber C fractures. In 55 (34.0%) cases, bimalleolar fractures were present. According to the Olerud score, 95 (58.6%) of the patients had an excellent outcome, 54 (33.3%) a good one, 9 (5.5%) a fair one and 4 (2.5%) an unsatisfactory outcome. In 3 cases a threaded wire dislocation occurred, without complications. Two mesh graft transplants were necessary; otherwise, there were no soft-tissue problems requiring review. One pseudarthrosis was seen. CONCLUSION: The XS nail which is introduced here fulfils the requirements made of an implant as regards maximum protection of soft tissue, secure fracture fixation and early exercise tolerance, including ankle fractures. No implant dislocation, no deep infection and no re-osteosynthesis were observed. Its advantages over conventional techniques lie precisely in the treatment of complex fractures and for patients with poor bone, vascular and soft-tissue situations.
Adolescent↗
[New concept in therapy of distal tibial metaphyseal fractures and pilon fractures with minor dislocations and severe soft tissue damage].
The treatment of pilon fractures and distal metaphysial tibia fractures demands very high standards on the osteosynthesis material regarding the soft tissue and the essential joint reconstruction. The selection of the surgical entrance, particularly in case of a critical arterial or venous circulation and the possible irritation of the soft tissue caused by the osteosynthesis material led us to search for alternative osteosynthesis methods. After the elaboration of a pre-clinical study and good first results in the treatment of patella, olecranon and ankle joint fractures by means of the XS-nail the latter is now also employed for pilon fractures. Within a time period of 8 month 5 fibula fractures coming with pilon fractures had been treated with the XS-nail. This case report will demonstrate both the technique of treatment and the flexibility of the new implant.
Aged↗
[Secondary dislocations after Synex Cage implantation].
For ventral instrumentation of spine fractures it is necessary to have an special implant for replacement of spine-body. Therefore we use titanium-cages, bone-cement and cortico-spongious pelvis bone. These are afflicted with a not so small morbidity. So in these days we have with the synex-cage a new allograft as a possible solution for that problem. In experimental studies it shows good stability. In the following cases we describe four cases of dislocation of the synex-cage. In one patient an operative revision was indicated. In the other cases the mobilization was to be reduced.
Aged↗
Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors.
Primitive neuroectodermal tumors (PNETs) represent the most frequent malignant brain tumors in childhood. The majority of these neoplasms occur in the cerebellum and are classified as medulloblastomas (MB). Most PNETs develop sporadically; however, their incidence is highly elevated in patients carrying germline APC gene mutations. The APC gene encodes a central component of the WNT/wingless developmental signaling pathway. It regulates the levels of cytoplasmic beta-catenin protein that plays a central role in neural development and cell proliferation. We analyzed 87 sporadic PNETs and 10 PNET cell lines for mutations of the APC gene and beta-catenin (CTNNB1) gene using single strand conformational polymorphism (SSCP) and sequencing analysis. We examined the mutation cluster region of APC (codons 1255--1641) for germline variants and somatic mutations. The medulloblastoma cell line MHH-MED-2 carried a Glu1317Gln missense germline variant and a sporadic MB sample showed a somatic Pro1319Leu substitution. Mutational analysis of exon 3 of CTNNB1 uncovered 4 PNETs (4.8%) with somatic missense mutations. These mutations caused amino acid substitutions in 3 of 80 medulloblastomas (Ser33Phe, Ser33Cys and Ser37Cys) and 1 of 4 supratentorial PNETs (Gly34Val). All mutations affected GSK-3 beta phosphorylation sites of the degradation targeting box of beta-catenin and resulted in nuclear beta-catenin protein accumulation. Deletions of CTNNB1 were not detected by PCR amplification with primers spanning exons 1--5. Our data indicate that inappropriate activation of the WNT/wingless signaling pathway by mutations of its components may contribute to the pathogenesis of a subset of PNETs.
Adenomatous Polyposis Coli Protein↗
[Hereditary colorectal carcinoma: predictive diagnosis and genetic counseling].
5 to 10 percent of colorectal cancers occur due to a genetic predisposition. Familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) belong to the autosomal-dominant inherited colorectal cancer syndromes. First degree relatives of affected persons are at high risk for colorectal cancer and therefore should undergo regular surveillance programs. The genetic background of FAP and HNPCC is known today, but not in every affected family the germline mutation causing the inherited disorder can be found. In some cases identification of a germline mutation is helpful to confirm a suspected diagnosis in a patient. In almost all cases it is of major importance for their family members, as it makes genetic testing and prediction of cancer risk available for persons at risk. Predictive genetic testing opens up a new dimension in relationship between patients and physicians. Test results are of great importance for future plans of a person at risk, therefore predictive genetic testing should never be performed without genetic counselling. Accordingly the German Bundesärztekammer has worked out guidelines for predictive genetic testing in hereditary tumours.
Adenomatous Polyposis Coli↗
DHPLC mutation analysis of the hereditary nonpolyposis colon cancer (HNPCC) genes hMLH1 and hMSH2.
Denaturing high-performance liquid chromatography (DHPLC) is an efficient method for detection of mutations involving a single or few numbers of nucleotides, and it has been successfully used for mutation detection in disease-related genes. Colorectal cancer is one of the most common cancers, and mutations in the genes for hereditary nonpolyposis colon cancer (HNPCC), hMLH1 and hMSH2, also involve mainly point mutations. Sequence analysis is supposed to be a screening method with high sensitivity; however, it is time-consuming and expensive. We therefore decided to test sensitivity and reproducibility of DHPLC for 71 sequence variants in hMLH1 and hMSH2 initially found by sequence analysis in DNA samples of German HNPCC patients. DHPLC conditions of the PCR products were based on the melting pattern of the wild-type sequence of the corresponding PCR fragments. All but one of the 71 mutations was detected using DHPLC (sensitivity of 97%). Running time per sample averaged only 7 min, and the system is highly automated. Thus DHPLC is a rapid and sensitive method for the detection of hMLH1 and hMSH2 sequence variants.
Adaptor Proteins, Signal Transducing↗
[Problems in osteosynthesis of patella fractures with the AO tension belt and consequences for new implants. The XS nail].
The eccentric ventral AO tension belt system represents the standard therapy of fractures of the patella. This often leads to unsatisfying results. Relating to Klute and Meenen [10] and the results of our own retrospective study, expressed as a percentage, 5-34% (own results 12.4%) have extremely poor treatment outcome, 23-60% (39%) end in deficiencies of bending, and there are 51-79.5% (65.7%) with subjective complaints after patella osteosynthesis. The disadvantages due to the eccentric tension belt position and the impossibility of applying the tension belt directly to the bone surface are abolished with the development of the XS nail. Due to its central position, constant compression of the entire fracture surface is provided. This is valid for all tension-stressed fractures such as those of the patella and olecranon. In synthetic patellae [5] standardized stress testing with changing tension up to 500 Newton was carried out. The XS nail was compared with the AO tension belt osteosynthesis after osteotomy and osteosynthesis in synthetic patellae. The XS nail was superior to the tension belt for all tests and therefore can be applied to all types of fractures where tension stress exists. We repaired the first 15 patella fractures with the XS nail. In 13 of 15 cases, full load of the injured leg was possible (for stairs a plaster splint was used). The experimental patella tests and first clinical results with the XS nail osteosynthesis after patella fracture confirm the new type of osteosynthesis, and functional treatment with loading seems possible.
Adolescent↗