Genotype-phenotype correlations in attenuated adenomatous polyposis coli

Germ-line mutations of the tumor suppressor APC are implicated in attenuated adenomatous polyposis coli (AAPC), a variant of familial adenomatous polyposis (FAP). AAPC is recognized by the occurrence of <100 colonic adenomas and a later onset of colorectal cancer (age >40 years). The aim of this study was to assess genotype-phenotype correlations in AAPC families. By protein-truncation test (PTT) assay, the entire coding region of the APC gene was screened in affected individuals from 11 AAPC kindreds, and their phenotypic differences were examined. Five novel germ-line APC mutations were identified in seven kindreds. Mutations were located in three different regions of the APC gene: (1) at the 5' end spanning exons 4 and 5, (2) within exon 9, and (3) at the 3' distal end of the gene. Variability in the number of colorectal adenomas was most apparent in individuals with mutations in region 1, and upper-gastrointestinal manifestations were more severe in them. In individuals with mutations in either region 2 or region 3, the average number of adenomas tended to be lower than those in individuals with mutations in region 1, although age at diagnosis was similar. In all AAPC kindreds, a predominance of right-sided colorectal adenomas and rectal polyp sparing was observed. No desmoid tumors were found in these kindreds. Our data suggest that, in AAPC families, the location of the APC mutation may partially predict specific phenotypic expression. This should help in the design of tailored clinical-management protocols in this subset of FAP patients.     

Congenital cholesteatoma in a child carrying a gene mutation for adenomatous polyposis coli

A 53-year-old woman with a history of cervical carcinoma 14 years ago, treated with hysterectomy and radiation therapy, was admitted to the intensive care unit with severe SIRS (systemic inflammatory response syndrome) progressing to shock, multiple organ failure and death within 5 d. Bilateral hydronephrosis diagnosed by sonography and an enlarged left kidney with suspected abscesses verified in a CT-scan suggested the diagnosis of urosepsis. However, multiple microbiological examinations remained sterile. Despite surgical treatment and aggressive intensive care, she died in unresponsive shock. Pathohistologically, an angiotropic large B-cell lymphoma, a rare diffuse intravascular neoplasm of lymphoid origin, was diagnosed. The patient's history of abdominal radiation therapy 14 years earlier as well as multiple negative microbiological specimens in a patient with suspected urosepsis should have initiated the search for a non-infectious cause of the disease.     

Retinal pigment epithelium cells cultured on synthetic biodegradable polymers

Glycation of proteins of the vessel wall is thought to play an important role in the pathogenesis of vascular complications in diabetes by affecting structure and function of these proteins. Adhesive proteins in the extracellular matrix (ECM) of endothelial cells (ECs) are essential for attachment of ECs to the subintima. In this study, we investigated the effect of glycation of ECM and purified adhesive proteins on EC adhesion and spreading. ECM was incubated with the reactive sugar glucose-6-phosphate (0-500 mmol/l) for different time periods (0-14 days) at 37 degrees C. Degree of glycation, measured in an enzyme-linked immunosorbent assay using a monoclonal antibody specific for advanced glycation end products, increased in a time- and concentration-dependent manner. Glycation of ECM with 50 mmol/l glucose-6-phosphate resulted in increased coverage by ECs as measured in a cell adhesion assay and was the result of an increase in number of adhered cells, while cell size was unaffected. Glycation of ECM with higher concentrations of glucose-6-phosphate resulted in decreased coverage by ECs caused by both a reduction in number of adhered ECs and impaired spreading. Experiments with purified glycated matrix proteins indicate that the decrease in EC adhesion and spreading on glycated ECM may result from glycation of vitronectin. Impaired EC adhesion and spreading caused by vitronectin glycation may result in impaired endothelial function and contribute to vascular disease.     

Infrequent somatic mutation of the adenomatous polyposis coli gene in aberrant crypt foci of human colon tissue

BACKGROUND: The authors examined somatic mutations of the adenomatous polyposis coli (APC) gene in 84 human aberrant crypt foci (ACF) to determine whether APC gene mutations were involved in the histologic progression of ACF. METHODS: Mutation cluster regions of the APC gene were subjected to polymerase chain reaction single-strand conformation polymorphism analysis and direct sequencing. RESULTS: Four kinds of deletion were detected in the mutation cluster regions of APC gene in five ACF. APC mutation was detected in 1 of 18 ACF with Stage I abnormalities (6%). Four of 10 adenomatous ACF (40%) harbored the mutation. There were no mutations in 56 hyperplastic ACF. CONCLUSIONS: These results suggest that APC mutations may be involved initially in only a limited number of adenomas in ACF.     

Retinal vascular changes in congenital hypertrophy of the retinal pigment epithelium

The overlying retinal blood vessels were abnormal in five cases of congenital hypertrophy of the retinal pigment epithelium. This illustrated the well-recognized association between outer retinal degeneration and obliteration of the overlying retinal vasculature. The proposed pathophysiological mechanisms, however, seem inadequate to explain completely the morphological changes of the retinal blood vessels in the presence of atrophy of the outer retina.     

Adrenal masses in patients with familial adenomatous polyposis

PURPOSE: The aims of this study were 1) to report the characteristics and the clinical outcome of familial adenomatous polyposis (FAP) patients with adrenal masses in the FAP registry at the Cleveland Clinic Foundation and 2) to estimate the prevalence of adrenal masses detected by computed tomography in FAP patients compared with that expected in a normal population. METHODS: A retrospective review was undertaken of the FAP registry database at our institution. Only 738 patients treated at the Cleveland Clinic Foundation were included in the study. A meta-analysis was conducted to determine the relative risk of adrenal incidentaloma in this series of FAP patients and in a general population as reported in the four largest pertinent studies published in the past 15 years. RESULTS: Fifteen patients (11 females) were identified. Two patients had symptoms related to cortisol hypersecretion (arterial hypertension) and underwent surgery. The final pathology was adrenocortical carcinoma and bilateral nodular hyperplasia. Adrenal masses were found incidentally (incidentalomas) in 13 patients: 12 were detected by computed tomography and one during laparotomy for total abdominal colectomy. Only one patient underwent left adrenalectomy for a 5-cm mass. Pathologic report revealed adrenocortical adenoma. Among the 738 patients considered in this study, only 162 underwent abdominal computed tomographic scan, mainly for assessing intra-abdominal desmoid. The prevalence of incidentaloma in our series compared with that reported in the literature is significantly different (7.4 vs. 0.6-3.4 percent; P < 0.001 (chi-squared test)). DISCUSSION: Although the presence of other extracolonic manifestations represents a selection bias for computed tomographic study in our series, the incidence of incidentalomas in FAP patients seems to be higher than in a general population. However, incidental detection of an adrenal mass in FAP patients has probably a limited clinical relevance, and the management should be the same as that for the normal population.     

Management of advanced duodenal polyposis in familial adenomatous polyposis

Farmers are exposed to high levels of organic dust with a high content of bacteria, fungi and endotoxins. The main exposure takes place during the many hours of work in closed animal confinement buildings, and working in swine confinement buildings gives the highest exposure. Corresponding to this, farmers have a high prevalence of respiratory symptoms and cross-sectional studies show evidence of airways obstruction. Swine farming seems to be an important risk factor for this in the farming community. Allergy plays a minor role in the development of symptoms, the most important allergy being towards storage mites. Longitudinal studies suggest that exposure to high concentrations of organic dust is associated with an accelerated decline in forced expiratory volume in one second.     

Effect of indomethacin suppositories on rectal polyposis in patients with familial adenomatous polyposis

BACKGROUND: Oral sulindac is known to reduce polyps in patients with familial adenomatous polyposis (FAP). The authors speculated that rectal administration of indomethacin would be effective therapy for adenomas in the rectal remnant of FAP. METHODS: Eight patients with FAP who had been treated by total colectomy with ileorectal anastomosis were administered an indomethacin suppository (50 mg) once or twice daily during a period of 4 or 8 weeks. The number of polyps at the same site within the rectum was counted under proctoscopy prior to, at the end of, and after the treatment. In four patients, proliferative activity of the rectal mucosa was assessed by immunohistochemical staining for MIB-1. RESULTS: In six of the eight patients who initially had ten or more polyps, the number of polyps decreased to fewer than five, whereas such a decrease could not be observed in the remaining two patients. In the six patients, the number of polyps increased after indomethacin was discontinued. The proliferative activity of the rectal mucosa was higher at the end of treatment than it was prior to indomethacin administration. CONCLUSIONS: Indomethacin suppositories may be effective in the management of rectal adenomatosis in patients with FAP.     

Ocular findings in familial adenomatous polyposis

This article describes a systematic approach to understanding the needs of the terminally ill who are also subject to serious mental health problems. A compilation of potential issues that could arise is provided along with specific techniques that could be useful to staff and volunteers who encounter them. Vignettes from clinical experience are used to provide a framework for understanding the unique aspects of cognitively impaired patients and for enhancing confidence in helpers. This article will give serious consideration to dispelling some misconceptions and to detailing resources for helpful interventions in difficult cases.     

Desmoid tumours in familial adenomatous polyposis

Desmoids are rare, benign fibromatous lesions, which can arise in patients with familial adenomatous polyposis (FAP), a disorder caused by germline adenomatous polyposis coli (APC) gene mutation. This study investigated the risk of desmoids in FAP, the relation between specific APC gene mutations and desmoid formation, and the clinical characteristics of FAP patients with desmoids. Eighty three of 825 FAP patients (10%) from 49 of 161 kindreds (30%) had desmoids. The absolute risk of desmoids in FAP patients was 2.56/1000 person years; comparative risk was 852 times the general population. APC gene mutations were similar in families with and without desmoids. The female/male ratio was 1.4 (p = NS). Previous abdominal surgery was noted in 68% of patients with abdominal desmoids (55% developed within five years postoperatively). Desmoid risk in FAP family members of a desmoid patient was 25% in first degree relatives v 8% in third degree relatives. Desmoids are a comparatively common complication of FAP associated with surgical trauma and familial aggregation. Desmoid development was not linked to specific APC gene mutations and was not found predominantly in women. Studies of chemopreventive therapy, given within five years after abdominal surgery, should be considered in FAP patients with a family history of desmoid disease.     

Upper gastrointestinal disease in patients with familial adenomatous polyposis

BACKGROUND: Upper gastrointestinal disease has become an important aspect in the management of patients with familial adenomatous polyposis (FAP). METHODS: A review of the literature was carried out using Medline. Epidemiology, pathology and treatment options are considered. RESULTS AND CONCLUSION: Despite the fact that over 90 per cent of patients with FAP develop duodenal adenomas, only 5 per cent go on to develop cancer. In the absence of methods to detect who is at risk of cancer, all patients undergo regular endoscopic surveillance at present. Chemoprevention in the form of drug therapy may be the answer to controlling the disease.     

Genetic counselling and gene mutation analysis in familial adenomatous polyposis in Western Australia

OBJECTIVE: To assess the provision of accurate pre-symptomatic genetic testing with DNA analysis and appropriate counselling for individuals and families known to be at high risk of developing familial adenomatous polyposis coli (FAP). PATIENTS AND METHODS: Thirty-one families with clinically and pathologically documented FAP were ascertained from the Western Australian Polyposis Registry. DNA was collected from over 200 individuals in these families to establish their genetic risk status for FAP, either by direct mutation analysis, or by linkage analysis. Individuals undergoing DNA testing were given intensive psychosocial support and counselling. RESULTS: In 19 families DNA-based counselling could not be offered because either the adenomatous polyposis coli (APC) gene mutation could not be detected or there were insufficient family members for linkage analysis. Gene testing yielded mutations of the APC gene in 87 individuals from 12 families; by gene tracking (or linkage analysis) in three families and by mutation analysis in the remaining nine (four of which had only one affected individual). DNA results conformed with a definite clinicopathological diagnosis in 27 FAP patients and, of the remaining 60 high-risk subjects tested, 14 had inherited the mutated APC gene. CONCLUSIONS: DNA analysis allowed accurate genetic counselling for 12 of 31 families affected by FAP, thus improving the medical and personal management in asymptomatic people who would otherwise be subjected to the uncertainty of long term surveillance and repeated colonic examinations. In future a superior biomolecular approach to gene mutation analysis, such as the protein truncation test, will facilitate management for most FAP individuals and families.     

Variable phenotype of familial adenomatous polyposis in pedigrees with 3'' mutation in the APC gene

Traumatic rupture of the corpus cavernosum is relatively frequent in the authors' experience. Based on the study of a series of 80 cases and a review of the literature, the authors analyse the diagnostic and therapeutic aspects and outcome of this disease. The patients in this series had a mean age of 30 years. Meticulous and intimate clinical interview demonstrated that the commonest mechanism is forced manipulation of the erect penis (68%). Clinical examination localized the site of the fracture (proximal: 57%, distal 43%). The fracture was unilateral (78 cases), rarely bilateral (2 cases) and associated with complete rupture of the urethra (1 case). Treatment was surgical in 79 patients. A distal semicircumferential incision was used in the case of bilateral rupture, distal rupture and associated urethral lesion (34 cases). A favourable course was observed in 86% of cases. However, 9 postoperative complications (12.5%) were observed (6 cases of fibrous plaques, 3 cases of chordee of the penis), due either to the extent of the haematoma or to the delay in treatment. Traumatic rupture of the corpus cavernosum is a disease of young adults, which requires early surgical treatment with an approach adapted to the type of lesions.     

APC intragenic haplotypes in familial adenomatous polyposis

Genetic epidemiological studies are useful for the knowledge of the association of markers and genes involved in diseases. In the present work, we studied the frequency of four adenomatous polyposis coli intragenic RFLP markers often used in risk evaluation in a population of 10 familial adenomatous polyposis patients from 10 unrelated Portuguese familial adenomatous polyposis families not sharing the same mutation, and in a population of 55 unrelated healthy Portuguese volunteers. We compared the frequency obtained to normal and affected populations and to results already reported in other populations. We observed allelic frequencies for the Portuguese population that agree with the published ones. The intragenic polymorphisms show strong gametic disequilibrium suggesting little recombination between them. We observed haplotype frequencies significantly different in patients and controls. The gametic disequilibrium may be due to a common founder for a proportion of apparently unrelated probands.     

Type I choledochal cyst in association with familial adenomatous polyposis

Choledochal cysts and familial adenomatous polyposis are infrequent disorders that are often manifest in childhood or in early adult life. The rarity and early presentation of these diseases suggests a genetic basis, which has been established for familial polyposis but not for choledochal cysts. We report a case of a 26-yr-old woman with both disorders and offer an alternative genetics-based etiology for the formation of choledochal cysts.