Phenotypic expression of disease in families that have mutations in the 5' region of the adenomatous polyposis coli gene.

BACKGROUND: Germline mutation in a gene on chromosome 5 (the adenomatous polyposis coli gene) causes familial adenomatous polyposis of the colorectum. Phenotypic manifestations of this condition vary, but the exact relation of the phenotype to the mutation site along the gene has not been fully described. OBJECTIVE: To determine how the location of mutations along a gene that is associated with multiple colorectal polyps (the adenomatous polyposis coli gene) is related to the phenotypic expression of the syndrome in families. DESIGN: Prospective cohort study. SETTING: Polyposis registry. PATIENTS: 20 patients from 7 families that had mutations in the adenomatous polyposis coli gene that were located toward the 5' end of codon 158 (proximal 5' families), were compared with 52 patients from 7 families that had mutations downstream from codon 158, in codons 179 to 625 (distal 5' families). MEASUREMENTS: Sex, age at diagnosis of familial adenomatous polyposis, number of polyps at first examination of the colon, distribution of polyps, age at diagnosis of colorectal cancer, and location of colorectal cancer. RESULTS: Mutations that were proximal to codon 158 were found in 7 of 112 families (6%). At the first examination of the colon, 8 of 17 (47%) patients in proximal 5' families and 9 of 48 (19%) patients of similar ages in distal 5' families were found to have fewer than 100 adenomas (P = 0.029). The distribution of polyps was frequently right-sided in patients in proximal 5' families (P = 0.001). The cumulative probability of survival without colorectal cancer was greater for patients in proximal 5' families (P = 0.041). CONCLUSIONS: Families with adenomatous polyposis that have proximal 5' mutations of the adenomatous polyposis coli gene are more likely to have a heterogeneous phenotype with delayed development of colonic polyposis and colorectal cancer than are families with distal 5' mutations of the gene. Management should include genotyping of patients who are at risk, colonoscopic surveillance of genotypically positive persons, and prophylactic colectomy if several adenomas are found.

APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome 5q. AIMS: This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP. METHODS: Mutations of the APC gene were compared with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adjusted for different ages of patients using person years of exposure. In pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed. RESULTS: FAP patients from the 42 families (82%) with identified mutations of the APC gene had more frequent expression of extraintestinal manifestations than affected individuals without identified mutations (risk ratio 1.2-4.0; significant difference for cutaneous cysts). The presence of a cutaneous cyst or extraintestinal cancer significantly increased the likelihood of detection of a mutation in the APC gene (94% and 92% respectively; p < 0.05). In patients without identified APC gene mutation, linkage to the APC gene was found in one large family (lod = 5.1, theta 0.01), and replication error phenotype was absent in all 24 neoplasms from 16 members of these nine pedigrees. Expression of pigmented ocular fundus lesions was strongly associated with mutations in codons 541-1309, but no other extraintestinal manifestations were related to mutation position. Multiplicity of extraintestinal manifestations was high with mutation in codons 1465, 1546, and 2621. CONCLUSIONS: Patients with the colorectal phenotype of FAP but no extraintestinal manifestations may have non-truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associated with pigmented ocular fundus lesions (codons 542-1309) and predisposition to multiplicity of extraintestinal manifestations (codons 1465, 1546, and 2621).

Pigmented ocular fundus lesions and APC mutations in familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) results from a germline mutation in the adenomatous polyposis coli (APC) gene on chromosome 5q21. The extracolonic manifestations of FAP include pigmented ocular fundus lesions (POFLS), cutaneous cysts, osteomas, occult radio-opaque jaw lesions, odontomas, desmoids, and extracolonic cancers. POFLS are present at birth in about 80% of patients with FAP and are excellent clinical congenital markers for the disease. We studied the distribution of POFLS by number and APC mutation in families of the Johns Hopkins Polyposis Registry. MATERIALS AND METHODS: Of the 51 families with FAP, 42 (82%) had an identifiable APC mutation. We correlated the presence/absence and distribution by number of POFLS with the type and location of the mutation in the APC gene in 21 families where an ocular examination had been performed in at least one affected member, and where a systematic search for mutations in the APC gene had been undertaken. Families were considered POFL-positive if the average number of lesions per patient was three or more, or if at least one family member had three or more lesions. RESULTS: Fifteen of the 21 families (71.4%) were POFL-positive. Mutations of the APC gene were detected in 15 of the 21 families. Of these, 12 (80%) were POFL-positive. Families with mutations at condons 215 (exon 5) and 302 (exon 8) were POFL-negative. Families with mutations at condons 541, 625, 1055, 1059, 1061, 1230, 1309, 1465, and 1546 (exons 12-15) were POFL-positive. One patient with a mutation at codon 2621 (exon 15) had no POFLS. CONCLUSIONS: Mutations in exons 1-8 and the distal portion of exon 15 of the APC gene are associated with a POFL-negative phenotype, while those in exons 10 to the proximal portion of exon I5 are generally associated with a POFL-positive

Sulindac induced regression of colorectal adenomas in familial adenomatous polyposis: evaluation of predictive factors.

BACKGROUND: Sulindac, a non-steroidal anti-inflammatory drug, causes regression of colorectal adenomas in patients with familial adenomatous polyposis (FAP) but the response is variable. Specific clinical factors predictive of sulindac induced regression have not been studied. METHODS: 22 patients with FAP were given sulindac 150 mg orally twice a day. Polyp number and size were determined before treatment and at three months. The relation of nine clinical factors to polyp regression (per cent of baseline polyp number after treatment) was evaluated by univariate and multivariate analysis. RESULTS: After three months of sulindac, polyp number had decreased to 45 per cent of baseline and polyp size to 50 per cent of baseline (p < 0.001 and p < 0.01, respectively). Univariate analysis showed greater polyp regression in older patients (p = 0.004), those with previous colectomy and ileorectal anastomosis (p = 0.001), and patients without identifiable mutation of the APC gene responsible for FAP (p = 0.05). With multivariate regression analysis, response to sulindac treatment was associated with previous subtotal colectomy. CONCLUSIONS: Sulindac treatment seems effective in producing regression of colorectal adenomas of FAP patients with previous subtotal colectomy regardless of baseline polyp number and size. Changed sulindac metabolism, reduced area of the target mucosa, or changed epithelial characteristics after ileorectal anastomosis may explain these findings.

The molecular basis of Turcot's syndrome.

BACKGROUND: Turcot's syndrome is characterized clinically by the concurrence of a primary brain tumor and multiple colorectal adenomas. We attempted to define the syndrome at the molecular level. METHODS: Fourteen families with Turcot's syndrome identified in two registries and the family originally described by Turcot and colleagues were studied. Germ-line mutations in the adenomatous polyposis coli (APC) gene characteristic of familial adenomatous polyposis were evaluated, as well as DNA replication errors and germline mutations in nucleotide mismatch-repair genes characteristic of hereditary nonpolyposis colorectal cancer. In addition, a formal risk analysis for brain tumors in familial adenomatous polyposis was performed with a registry data base. RESULTS: Genetic abnormalities were identified in 13 of the 14 registry families. Germ-line APC mutations were detected in 10. The predominant brain tumor in these 10 families was medulloblastoma (11 of 14 patients, or 79 percent), and the relative risk of cerebellar medulloblastoma in patients with familial adenomatous polyposis was 92 times that in the general population (95 percent confidence interval, 29 to 269; P < 0.001). In contrast, the type of brain tumor in the other four families was glioblastoma multiforme. The glioblastomas and colorectal tumors in three of these families and in the original family studied by Turcot had replication errors characteristic of hereditary nonpolyposis colorectal cancer. In addition, germ-line mutations in the mismatch-repair genes hMLH1 or hPMS2 were found in two families. CONCLUSIONS: The association between brain tumors and multiple colorectal adenomas can result from two distinct types of germ-line defects: mutation of the APC gene or mutation of a mismatch-repair gene. Molecular diagnosis may contribute to the appropriate care of affected patients.

Phenotypic variability of familial adenomatous polyposis in 11 unrelated families with identical APC gene mutation.

BACKGROUND/AIMS: Familial adenomatous polyposis is caused by germline mutation of the adenomatous polyposis coli (APC) gene. Affected individuals develop hundreds of colorectal adenomas at young age and can have extracolonic lesions. METHODS: This study evaluated the phenotype of 74 patients with familial adenomatous polyposis from 11 unrelated families with an identical 5-base pair deletion at codon 1309 of the APC gene. RESULTS: Polyp density in the sigmoid colon of 16 patients from 9 families varied from 3.8 to 13.1/cm2, and mean polyp diameter ranged from 1.4 +/- 0.1 to 2.7 +/- 0.1 mm. The distribution of colonic adenomas also varied, with diffuse polyposis in 6 patients but relative polyp sparing in the more proximal colon in 6 others. Age at diagnosis of colorectal cancer ranged from 19 to 62 years, but the mean age did not differ among the 4 families with multiple cases. Colorectal cancers occurred predominantly in the rectosigmoid (80%) but also in the more proximal colon. The percentage of patients affected by various extracolonic lesions differed widely among and within the 11 families (range, 0%-100%). CONCLUSIONS: APC gene mutation at codon 1309 results in intrafamily and interfamily phenotypic variation in familial adenomatous polyposis. Environmental and/or other genetic factors must play roles in the expression of germline APC gene mutations.

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.

Molecular diagnosis of familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis is an inherited disease characterized by multiple colorectal tumors. The diagnosis has classically been based on the detection of multiple colorectal adenomas. The recent identification of germline mutations of the APC gene in patients with familial adenomatous polyposis makes presymptomatic molecular diagnosis possible, but the widespread distribution of the many mutations within this very large gene have heretofore made the search for such mutations impractical. We describe a novel approach that allows molecular genetic diagnosis in the majority of patients with the disease. METHODS: We screened 62 unrelated patients from the Johns Hopkins Familial Adenomatous Polyposis Registry for germline APC mutations. Primary screening was accomplished by analysis of protein synthesized in vitro from surrogate APC genes. In addition, the relative amount of transcript from each APC allele was determined with an allele-specific--expression assay. RESULTS: The protein assay revealed truncated protein in 51 of the 62 patients (82 percent). In 3 of the 11 remaining patients, the allele-specific--expression assay revealed significantly reduced expression of one allele of the APC gene. The use of these two assays in combination successfully identified germline APC mutations in 87 percent of the 62 patients. CONCLUSIONS: The protein and allele-specific--expression assays provide a practical and sensitive method for molecular diagnosis of familial adenomatous polyposis. This approach will facilitate care, allowing routine testing of subjects at risk and genetic confirmation of spontaneous mutations.

Nasopharyngeal angiofibroma in patients with familial adenomatous polyposis.

Four patients with nasopharyngeal angiofibroma and familial adenomatous polyposis are reported here. Nasopharyngeal angiofibroma was 25 times more frequent in our patient population with familial adenomatous polyposis than in an age-matched hospital population. The association of these two rare conditions suggests that nasopharyngeal angiofibroma is an extracolonic manifestation of adenomatous polyposis. In addition, somatic mutation of the adenomatous polyposis coli gene, which causes adenomatous polyposis when mutated in the germline, could play a role in the pathogenesis of sporadic nasopharyngeal angiofibroma.

Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis.

Familial adenomatous polyposis has been associated with several extraintestinal cancers, but the relative and absolute risks of these malignancies have not been determined. Extraintestinal cancers reportedly associated with adenomatous polyposis (thyroid gland, adrenal gland, pancreas, and biliary tract) were identified in polyposis patients and their at risk relatives in The Johns Hopkins Registry. The incidence rates of identified tumours were then compared with the general population through person year analysis with adjustment for population. For comparison, the incidence rates of the two most common cancers not associated with polyposis (breast cancer in women and lung cancer) were also calculated. There was an increased relative risk of thyroid cancer (relative risk 7.6; 95% confidence limits (CL) 2.5-17.7) and pancreatic adenocarcinoma (relative risk 4.46; 95% CL 1.2-11.4) in polyposis patients and at risk relatives. The absolute risk was 26.8 and 21.4 cases/100,000 person years, respectively. No cases of adrenal or biliary cancer were found in this cohort. There was no increased relative risk of lung cancer (95% CL 0.04-1.4) or breast cancer (95% CL 0.04-1.4) over the general population. The relative risks of thyroid and pancreatic cancer are increased in familial adenomatous polyposis, but the absolute lifetime risk is low. Screening for pancreatic cancer may not be worthwhile with currently available methods, but careful physical examination of the thyroid gland is warranted along with consideration for ultrasonography.

Cytogenetic analysis of intestinal polyps in polyposis syndromes: comparison with sporadic colorectal adenomas.

Few cytogenetic studies of polyps from patients with polyposis syndromes have been reported. We studied 27 colonic adenomatous polyps from familial adenomatous polyposis (FAP), two polyps of the small bowel from Peutz-Jeghers syndrome (PJS), and four colorectal juvenile polyps from juvenile polyposis syndrome (JPS). The karyotypic results were compared with 32 sporadic colorectal adenomatous polyps. Nineteen colorectal adenomas had abnormal karyotypes; of these, five were from patients with FAP and 14 were sporadic adenomas. Numerical changes were the most frequent change (14 adenomas); additional copies of chromosome 7 (eight adenomas) and 13 (seven adenomas) occurred most often and were present in both FAP and sporadic adenomas. Only five adenomas, all sporadic, had structural chromosome abnormalities. Normal karyotypes were obtained from 32 adenomas, and chromosome counts but not karyotypes were obtained from eight polyps owing to poor chromosome morphology. The JPS and PJS polyps had normal karyotypes. These data indicate that adenomas from patients with FAP tend to have fewer structural abnormalities than sporadic adenomas and that numerical abnormalities are the most common chromosome abnormality in both FAP and sporadic polyps and suggest that the mechanism which causes loss of heterozygosity (LOH) in the adenoma to carcinoma sequence operates on a level below that of the whole chromosome.

Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported. METHODS: We conducted a randomized, double-blind, placebo-controlled study of 22 patients with familial adenomatous polyposis, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every three months for one year. RESULTS: A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac, as compared with those given placebo. When treatment was stopped at nine months, the number of polyps had decreased to 44 percent of base-line values and the diameter of the polyps to 35 percent of base-line values (P = 0.014 and P < 0.001, respectively, for the comparison with the changes in the group given placebo). No patient had complete resolution of polyps. Three months after treatment with sulindac was stopped, both the number and the size of the polyps increased in sulindac-treated patients but remained significantly lower than the values at base line. No side effects from sulindac were noted. CONCLUSIONS: Sulindac reduces the number and size of colorectal adenomas in patients with familial adenomatous polyposis, but its effect is incomplete, and it is unlikely to replace colectomy as primary therapy.

The risk of upper gastrointestinal cancer in familial adenomatous polyposis.

Adenomas with potential for malignancy occur frequently in the upper gastrointestinal tract of patients with familial adenomatous polyposis. However, an assessment of relative risk of upper gastrointestinal cancer in patients with adenomatous polyposis has never been performed. Therefore, the incidence rate of upper gastrointestinal cancer in patients with familial adenomatous polyposis in The Johns Hopkins Registry was compared with the rate of the general population through person-year analysis with adjustment for demographics. There was an increased relative risk of duodenal adenocarcinoma (relative risk, 330.82; 95% confidence limits, 132.66 and 681.49; P less than 0.001) and ampullary adenocarcinoma (relative risk, 123.72; 95% confidence limits, 33.65 and 316.72; P less than 0.001). No significant increased risk was found for gastric or nonduodenal small intestinal cancer. These results indicate that periodic surveillance of the upper gastrointestinal tract for duodenal and periampullary cancer is needed in patients with familial adenomatous polyposis. Prophylactic duodenectomy is a consideration when large adenoma(s) with high-grade dysplasia are identified but awaits risk benefit analysis.

Gardner syndrome: study and follow-up of a family.

A study is in progress of a family (Family P) with Gardner syndrome (familial adenomatous polyposis with extraintestinal manifestations-FAPG). Occult bone lesions of the jaws and ocular fundus lesions were found in a number of affected and at-risk relatives. In some, these "markers" were found early in life before the appearance of colonic polyps. Family P is remarkable for differences in expression of the gene manifested by differences in the age-at-onset of polyps of the colon, in number and size of polyps, and in occurrence of desmoids. These differences may explain why some at-risk relatives wisely followed medical surveillance plans while others, who lacked symptoms, failed to do so. Others without medical guidance undertook their own independent "treatment." As knowledge about extracolonic lesions has increased and surgical treatment for FAPG improved from the time the first affected member of Family P received her diagnosis in 1953, the outlook for survival has also improved. Family communication and that among professionals treating families with FAPG may be improved as worldwide Polyposis Registries increase in number. The risk of postsurgical extraintestinal complications is reason enough to urge life-long medical surveillance for all at-risk relatives.

Value of combined phenotypic markers in identifying inheritance of familial adenomatous polyposis.

Familial adenomatous polyposis is an autosomal dominant disease characterised by the development of hundreds of colorectal adenomas in young adults. Occult radio-opaque jaw lesions and pigmented ocular fundus lesions (formerly called congenital hypertrophy of the retinal pigment epithelium) are extraintestinal phenotypic markers for this disorder. We evaluated the usefulness of the combination of these markers for identifying patients who have inherited familial adenomatous polyposis. Forty three affected patients and 12 unaffected first degree relatives from 24 families with familial adenomatous polyposis, including four families without extraintestinal manifestations, were examined for both phenotypic markers. Thirty three of the 43 patients (77%) with familial adenomatous polyposis were positive for both markers, including patients from two families without extraintestinal manifestations. By contrast, only one of 12 (8%) unaffected first degree relatives over 35 years of age had both markers. The sensitivity of the combination of these markers in identifying patients who inherited familial adenomatous polyposis was 77%, the specificity 92%, the predictive value of a positive test 97%, the predictive value of a negative test 52%, and the efficacy 80%. The combined markers had improved efficacy over either marker alone (70% for occult radio-opaque jaw lesions and 67% for pigmented ocular fundus lesions). We conclude that the presence of both occult radio-opaque jaw lesions and pigmented ocular fundus lesions in a person at risk indicates a high probability of inheritance and expression of familial adenomatous polyposis.

Colorectal neoplasia in juvenile polyposis or juvenile polyps.

Juvenile (retention) polyps are usually solitary lesions in the colorectum but may be multiple in juvenile polyposis. The association between juvenile polyps and colorectal neoplasia is controversial. We present three patients with juvenile polyposis who had colorectal adenomas or adenomatous epithelium in juvenile polyps at ages 3, 4, and 7 years. In a retrospective study of 57 additional patients with one or more juvenile polyps, 10 patients (18%) had colorectal neoplasia including three with adenocarcinoma, two with tubular adenoma, and six with adenomatous epithelium in a juvenile polyp (one had both adenomatous epithelium and an adenocarcinoma). Nine of these 10 patients had juvenile polyposis defined by the presence of at least three juvenile polyps; and eight of the nine had a family history of juvenile polyps. Colorectal neoplasia occurred at young age (mean (SEM) 37 (5) years). Our findings suggest that patients with juvenile polyps who have three or more juvenile polyps or a family history of juvenile polyps should undergo surveillance for colorectal neoplasia.

Congenital hypertrophy of the retinal pigment epithelium predicts colorectal polyposis in Gardner's syndrome.

We studied prospectively the utility of congenital hypertrophy of the retinal pigment epithelium as a predictor of colonic polyposis in offspring of patients with familial adenomatous polyposis with extracolonic manifestations (Gardner's syndrome). After they underwent initial indirect ophthalmoscopy, we followed up 34 individuals at 50% genetic risk for familial adenomatous polyposis with extracolonic manifestations due to an affected parent. All 34 obtained their first colorectal endoscopic examination during a follow-up period of up to 4 years. The 16 individuals who did not have congenital hypertrophy of the retinal pigment epithelium (aged 13 to 40 years; mean, 25 years) remained polyp free, while 14 of 18 individuals with congenital hypertrophy of the retinal pigment epithelium (aged 9 to 30 years; mean, 18 years) were found to have colorectal adenomatous polyposis. Our findings indicate that the presence of multiple patches of congenital hypertrophy of the retinal pigment epithelium in children and young adults at risk for familial adenomatous polyposis with extracolonic manifestations is a clinically useful predictor of colorectal polyposis.

Hepatoblastoma and familial adenomatous polyposis.

Eleven children have been identified as having hepatoblastoma and a family history of adenomatous polyposis, and 14 additional instances of this association have been collected from the literature. Among the 11 survivors of hepatoblastoma in the combined series, adenomatous lesions have been sought in seven and detected in six patients at ages 7 to 25 years. Five of these patients also have congenital hypertrophy of the retinal pigment epithelium, a marker for carriers of the polyposis gene. These findings strengthen the association between hepatoblastoma and familial adenomatous polyposis and have led to the establishment of the Hepatoblastoma-Adenomatous Polyposis Registry.