Peutz-Jeghers syndrome: a systematic review and recommendations for management.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

Treatment of fractures of the fifth metatarsal with the XS-nail retrospective study and comparison with tension-band wiring.

INTRODUCTION: Many different surgical methods and implants for the treatment of fifth metatarsal fractures have been established yet. A high rate of complications, such as nonunion, fragment dislocation, refracture, implant deformation and irritation are widely occurring due to the insufficient ability of the implants to compensate the tension applied to the proximal fragment through the peroneal tendon combined with an impaired blood supply at the fracture zone. Therefore, the search for improved surgical solutions is thoroughly understandable. Thus, we have introduced the XS-nail as an intramedullary nail system that bears the ability to provide a compression to the fracture zone through a grub screw. In this work, we have analyzed the position of the XS-nail in relationship to other methods with special regard to the tension-band wiring. METHOD: In a retrospective analysis, we examined 77 cases, where a proximal fifth metatarsal fracture has been treated with the XS-nail. As a comparison group, we collected data from 47 patients who had been treated with tension-band wiring for the same indication in our hospital. Altogether, we included 124 patients, representing the largest study population of surgically treated cases of proximal fifth metatarsal fractures as compared to the actual literature. RESULTS: When compared with the tension-band wiring group, we found in mean a shorter duration of the surgery, a lower necessity of an open reduction (18 vs. 100%), fewer postsurgical weight-bearing restrictions (54 vs. 100%) and a shorter duration of rehabilitation (48 vs. 71 days). Especially, the fracture compression was distinctively higher in the XS-nail group (postsurgical lateral dislocation was 0-59%). The advantages of the tension-band wiring were found in the fixation of small fragments and an easier implant removal. Generally, nonunion and refracture were not seen in both methods. When compared with the results from literature, we found positive results regarding the hospitalization duration, the weight-bearing ability, the rehabilitation course and the patients' satisfaction. CONCLUSION: Thus, the XS-nail proved to be an effective and technical optimized implant for the treatment of proximal fifth metatarsal fractures that provides a rapid full-weight-bearing mobilization and shows good long-term results.

Guidelines for the clinical management of familial adenomatous polyposis (FAP).

BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.

Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome.

Somatic epimutations in the MLH1 promoter mimic the phenotype of Lynch syndrome. To date, no somatic hypermethylation of the MLH1 promoter in the carrier of a pathogenic MLH1 germline mutation has been identified, prompting the recommendation that a germline mutation in MLH1 should only be sought in the absence of tumour tissue methylation. We aimed to determine whether methylation of the MLH1 promoter may coexist in carriers of a pathogenic germline mutation in MLH1. We examined the methylation status of the MLH1 promoter in 123 tumour tissue samples, demonstrating high microsatellite instability and loss of expression of a mismatch repair protein (60 cases with MLH1 germline mutation, 25 cases without mutation, 38 cases with MSH2 mutations), using combined bisulphite restriction analysis (COBRA) and SNaPshot analysis. Methylation of the MLH1 promoter was found in two patients with pathogenic germline mutations, one a carrier of a MLH1 mutation and the other a carrier of a MSH2 mutation. Our results demonstrate that methylation of the MLH1 promoter region does not exclude the presence of a germline mutation in a mismatch repair (MMR) gene. Hypermethylation of the MLH1 promoter may be present in most cases of sporadic colorectal cancers, but this does not exclude a diagnosis of Lynch syndrome.

High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome.

BACKGROUND: In patients with juvenile polyposis syndrome (JPS) the frequency of large genomic deletions in the SMAD4 and BMPR1A genes was unknown. METHODS: Mutation and phenotype analysis was used in 80 unrelated patients of whom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to have JPS. RESULTS: By direct sequencing of the two genes, point mutations were identified in 30 patients (46% of typical JPS). Using MLPA, large genomic deletions were found in 14% of all patients with typical JPS (six deletions in SMAD4 and three deletions in BMPR1A). Mutation analysis of the PTEN gene in the remaining 41 mutation negative cases uncovered a point mutation in two patients (5%). SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis (73%) than did patients with BMPR1A mutations (8%) (p<0.001); all seven cases of gastric cancer occurred in families with SMAD4 mutations. SMAD4 mutation carriers with gastric polyps were significantly older at gastroscopy than those without (p<0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, hereditary hemorrhagic telangiectasia (HHT) was also diagnosed clinically. The documented histologic findings encompassed a wide distribution of different polyp types, comparable with that described in hereditary mixed polyposis syndromes (HMPS). CONCLUSIONS: Screening for large deletions raised the mutation detection rate to 60% in the 65 patients with typical JPS. A strong genotype-phenotype correlation for gastric polyposis, gastric cancer, and HHT was identified, which should have implications for counselling and surveillance. Histopathological results in hamartomatous polyposis syndromes must be critically interpreted.

Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer).

Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.

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.

[Fracture of the neck of the talus in a child]. / Talushalsfraktur beim Kind.

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.

[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.

[Soft tissue protective, stable osteosynthesis of fractures after elbow ankylosis. Two case reports]. / Weichteilschonende stabile Versorgung nach Fraktur bei Ellbogenankylose. Zwei Fallberichte.

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.

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.

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.

[Pathological fracture in fibrous histiocytoma of the proximal radial metaphysisJoint-preserving stabilization with the IP-XXS nail]. / Pathologische Fraktur bei fibrösem Histiozytom der proximalen RadiusmetaphyseGelenkerhaltende Stabilisierung mit dem IP-XXS-Nagel.

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.

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.

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.

[New concept in therapy of distal tibial metaphyseal fractures and pilon fractures with minor dislocations and severe soft tissue damage]. / Neues Konzept in der Therapie der distalen Tibiametaphysenfrakturen und wenig dislozierten Pilonfrakturen mit schweren Weichteilschäden.

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.