Attenuated familial adenomatous polyposis (AFAP): a review of the literature

Over the last decade, a subset of familial adenomatous polyposis(FAP) patients with a milder course of disease termed attenuated familial adenomatous polyposis (AFAP) has been described. AFAP is not well-defined as a disease entity – the reports on AFAP are largely casuistic or only deal with a few kindreds – and the diagnostic criteria and methods of investigation differ markedly. The true incidence and frequency of AFAP is not known. The mutations in APC associated with AFAP have mainly been detected in three parts of the gene: in the 5′ end (the first five exons), in exon 9 and in the distal 3′ end. The main features of AFAP are 100 or less colorectal adenomas with a tendency to rectal sparing, a delay in onset of adenomatosis and bowel symptoms of 20–25 years, a delay in onset of colorectal cancer (CRC) of 10–20 years and death from CRC of 15–20 years, and although the lifetime penetrance of CRC appears to be high, CRC does not seem to develop in nearly all affected patients. A more limited expression of the extracolonic features is seen, but gastric and duodenal adenomas are frequently encountered. Colonoscopy is preferred to sigmoidoscopy, should begin at the age of 20–25 years and no upper age limit of stopping surveillance is justified. Regular esophago-gastro-duodenoscopy (EGD) is recommended. Until further research has provided us with a more substantiated knowledge about AFAP changes in current surveillance and treatment are not recommended. Prophylactic colectomy with ileorectal anastomosis (IRA) is recommended in most patients.     

Surgical treatment of familial adenomatous polyposis: Experience from a single institution in China

Aim: Surgical options for familiar adenomatous polyposis (FAP) have been standardized in developed countries but are still controversial in China. The aim of this study was to retrospectively evaluate the results of patients with FAP treated in a university hospital. Methods: In all 42 consecutive patients with FAP were operated on between May 1988 and June 2008. Median follow up was 7.2 years (2.2–20 years). Of these 33 patients were treated by proctocolectomy and ileal pouch anal anastomosis. A total colectomy with ileorectal anastomosis was undertaken in six and a proctocolectomy with ileostomy in three patients who had invasive rectal cancer. Results: Postoperative morbidity was insignificant. There were five wound infections, one intestinal obstruction, one anastomotic leakage, one anastomotic stenosis and one refractory pouchitis. One patient died from stroke. Five died from FAP‐related disorders, namely, abdominal desmoids, liver metastases and advanced rectal cancer. Desmoid tumor occurred in five patients. Periampullary adenoma and carcinoma developed in four patients. In those with pouch procedure the 24‐h bowel movement was 7.14 ± 1.28 (range 5–11) and their 10‐year overall survival was 87.5%. Conclusion: A proctocolectomy with ileal pouch anal anastomosis maybe the best choice for FAP patients in China. Surgical expertise, good teamwork and careful long‐term follow up are mandatory.     

Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients

Background:

The optimal treatment of desmoid tumours is controversial. We evaluated desmoid management in Dutch familial adenomatous polyposis (FAP) patients.

Methods:

Seventy-eight FAP patients with desmoids were identified from the Dutch Polyposis Registry. Data on desmoid morphology, management, and outcome were analysed retrospectively. Progression-free survival (PFS) rates and final outcome were compared for surgical vs non-surgical treatment, for intra-abdominal and extra-abdominal desmoids separately. Also, pharmacological treatment was evaluated for all desmoids.

Results:

Median follow-up was 8 years. For intra-abdominal desmoids (n=62), PFS rates at 10 years of follow-up were comparable after surgical and non-surgical treatment (33% and 49%, respectively, P=0.163). None of these desmoids could be removed entirely. Eventually, one fifth died from desmoid disease. Most extra-abdominal and abdominal wall desmoids were treated surgically with a PFS rate of 63% and no deaths from desmoid disease. Comparison between NSAID and anti-estrogen treatment showed comparable outcomes. Four of the 10 patients who received chemotherapy had stabilisation of tumour growth, all after doxorubicin combination therapy.

Conclusion:

For intra-abdominal desmoids, a conservative approach and surgery showed comparable outcomes. For extra-abdominal and abdominal wall desmoids, surgery seemed appropriate. Different pharmacological therapies showed comparable outcomes. If chemotherapy was given for progressively growing intra-abdominal desmoids, most favourable outcomes occurred after combinations including doxorubicin.     

Abdominal desmoid in familial adenomatous polyposis presenting as a pancreatic cystic lesion

A 17-year-old male with familial adenomatous polyposis (FAP) presented with chest pain and significant weight loss. An abdominal CT scan detected a cystic pancreatic lesion of unknown etiology. The patient therefore underwent surgical resection of the distal pancreas, which included the lesion, because of the known association of pancreatic cancer with FAP. Histopathological examination of the resected specimen showed a benign pancreatic cyst and fibrous plaque with desmoid fibromatosis adherent to the surface of the pancreas, serosa of the stomach, and colon. The fibrous plaque was histologically identical to the fibrous mesenteric plaque known to occur in FAP and associated mesenteric fibromatosis. We present pathologic evidence that the pancreatic cyst formation was induced by FAP-associated desmoid invasion. Desmoid growth should be considered in the differential diagnosis of a pancreatic cystic mass lesion in patients with FAP or its Gardner syndrome variant. This case report provides the first pathologic evidence for benign epithelial cyst formation in the pancreas caused by fibromatosis invasion of that organ as a part of FAP.     

Dacarbazine-Doxorubicin therapy ameliorated an extremely aggressive mesenteric desmoid tumor associated with familial adenomatous polyposis: report of a case

A 30-year-old man with familial adenomatous polyposis (FAP)underwent prophylactic proctocolectomy by laparoscopy-assistedsurgery. After 10 months, we found an intra-abdominal tumor,which grew rapidly to 25 cm in diameter. We performed an emergencyoperation, which revealed that it was a desmoid tumor derivedmainly from colorectal mesenterium. The tumor was removed withthree short segments of intestine and the left ureter. A computedtomography (CT) scan done 3 months later showed a 10 cm mesentericdesmoid tumor at the beginning of jejunum, approaching the rootof the superior mesenteric artery (SMA). Fortunately, we wereable to remove the tumor without injuring the SMA. To our distress,however, another recurrent mesenteric desmoid tumor was discoveredin the pelvis one month later, which grew rapidly from 5 cmto 16 cm within 4 months. During this period, we gave the patientseveral regimens, including antiestrogen (tamoxifen), a nonsteroidalanti-inflammtory drug and imatinib mesylate (Gleevec), whichhad little or no effect. Finally, when the desmoid occupiedthe pelvic space, we gave the patient dacarbazine (DTIC) anddoxorubicin (DOX). After seven courses, the mesenteric tumorshowed an almost complete response (CR). The chemotherapy causedgrade 3 to 4 leukocytopenia, but without any hazardous events.No evidence of further recurrence of mesenteric desmoid hasbeen seen for 4 years. This combination chemotherapy is a promisingstrategy, even against an extremely aggressive, life-threateningmesenteric desmoid associated with FAP.     

Total gastrectomy with isoperistaltic jejunal interposition flap for symptomatic management of gastric polyposis from familial adenomatous polyposis

Patients with familial adenomatous polyposis (FAP) oftentimes have extracolonic polyps. The patient discussed in this case report had innumerable gastric polyps which were significantly affecting his ability to tolerate oral intake and his overall nutrition. Medical management was not sufficiently controlling his symptoms; therefore we proceeded with surgical intervention. We discuss the use of a total gastrectomy with an Isoperistaltic jejunal interposition flap for the symptomatic management of gastric polyposis. We describe the technique used and benefits to this specific procedure when it comes to long term outcome, complications, and monitoring.     

Desmoid tumours

Desmoid tumours exhibit fibroblastic proliferation and arise from fascial or musculoaponeurotic structures. Despite their benign microscopic appearance, and their negligible metastatic potential, the propensity of desmoid tumours for local infiltration is potentially significant in terms of deformity, morbidity and mortality due to pressure effects and obstruction of vital structures and organs. The rarity of desmoid tumours, coupled with the variability in their clinical course, renders these lesions a vexing entity, and makes demonstration of the efficacy of any specific intervention difficult. Failure to recognize the potential for malignant behaviour in this tumour renders desmoids susceptible to inadequate treatment. This distinct pathological entity is reviewed with a specific focus on aetiology and treatment.     

Balance between endoscopic and genetic information in the choice of ileorectal anastomosis for familial adenomatous polyposis

BACKGROUND AND OBJECTIVES: The number of rectal polyps and the site of mutations in the APC (Adenomatous polyposis coli) gene have been used to guide the surgical management in patients with familial adenomatous polyposis (FAP). The aim of this study is to assess the utility of the APC mutation screening compared to the degree of the rectal polyposis in surgical decision making. METHODS: The post-surgical courses of 25 patients submitted to subtotal colectomy with ileorectal anastomosis (IRA) were reviewed. Preservation of the rectum was prospectively decided on the basis of well-defined endoscopic criteria. The number of rectal polyps was assessed preoperatively and every 6-12 months. APC gene was screened for mutations by heteroduplex analysis, single strand conformation polymorphism, in vitro synthesized protein (IVSP), and DNA sequencing. Patients negative for APC mutations were tested for MYH mutations. RESULTS: On the basis of preoperative polyp rectal count we categorized patients as follows: Group I, 5 or fewer adenomas; Group II, 6-9 adenomas; Group III, 10 or more adenomas. After a follow-up ranging from 12 to 225 months we have observed a significant difference of recurrent rectal adenomas between Groups I-II versus III. No difference was detected among patients of Group I and II. The mean number of adenomas/year/patient was 0.67, 1.62, and 9.29 for Group I, II, and III, respectively. Carpeting polyposis of the rectal stump developed in three patients with APC mutation at codon 1309 and two of them needed later proctectomy. Diffuse rectal polyposis was observed in one patient with mutation at exon 9 who had 10 small polyps at time of surgery. Mutation at the 5'-end of APC (codons 144-232), mutation of MYH and unknown APC or MYH mutation were correlated with a low number of polyps both at presentation and follow-up. No IRA patients developed rectal cancer. CONCLUSIONS: In our experience fewer than 10 rectal polyps at presentation can predict a favorable outcome after IRA. Identification of specific germ-line APC or MYH mutation can address the choice of surgical treatment.     

Restorative proctocolectomy and ileal pouch-anal anastomosis for familial adenomatous polyposis revisited

Since restorative proctocolectomy (RPC) with ileal-pouch anal anastomosis (IPAA) removes the entire diseased mucosa, it has become firmly established as the standard operative procedure of choice for familial adenomatous polyposis (FAP). Many technical controversies still persist, such as mesenteric lengthening techniques, close rectal wall proctectomy, endoanal mucosectomy vs. double stapled anastomosis, loop ileostomy omission and a laparoscopic approach. Despite the complexity of the operation, IPAA is safe (mortality: 0.5–1%), it carries an acceptable risk of non-life-threatening complications (10–25%), and it achieves good long-term functional outcome with excellent patient satisfaction (over 95%). In contrast to the high incidence in patients operated for ulcerative colitis (UC) (15–20%), the occurrence of pouchitis after IPAA seems to be rare in FAP patients (0–11%). Even after IPAA, FAP patients are still at risk of developing adenomas (and occasional adenocarcinomas), either in the anal canal (10–31%) or in the ileal pouch itself (8–62%), thus requiring lifelong endoscopic monitoring. IPAA operation does not jeopardise pregnancy and childbirth, but it does impair female fecundity and has a low risk of impairment of erection and ejaculation in young males. The latter can almost completely be avoided by a careful “close rectal wall” proctectomy technique. Some argue that low risk patients (e.g. <5 rectal polyps) can be identified where ileorectal anastomosis (IRA) might be reasonable. We feel that the risk of rectal cancer after IRA means that IPAA should be recommended for the vast majority of FAP patients. We accept that in some very selected cases, based on clinical and genetics data (and perhaps influenced by patient choice regarding female fecundity), a stepwise surgical strategy with a primary IPA followed at a later age by a secondary proctectomy with IPAA could be proposed.     

Desmoids in familial adenomatous polyposis are monoclonal proliferations

Desmoids are poorly-understood, locally aggressive, non-metastasizing fibromatoses that occur with disproportionate frequency in patients with familial adenomatous polyposis (FAP). Their nature is controversial with arguments for and against a neoplastic origin. Neoplastic proliferations are by definition monoclonal, whereas reactive processes originate from a polyclonal background. We examined clonality of 25 samples of desmoid tissue from 11 female FAP patients by assessing patterns of X-chromosome inactivation to calculate a clonality ratio. Polymerase chain reaction (PCR) amplification of a polymorphic CAG short tandem repeat (STR) sequence adjacent to a methylation-sensitive restriction enzyme site within the human androgen receptor (HUMARA) gene using fluorescent-labelled primers enabled analysis of PCR products by Applied Biosystems Genescan II software. Twenty-one samples from nine patients were informative for the assay. Samples from all informative cases comprised a median of 66% (range 0-75%) clonal cells but from the six patients with a clonality ratio < or =0.5 comprised a median of 71% (65-75%) clonal cells. FAP-associated desmoid tumours are true neoplasms. This may have implications in the development of improved treatment protocols for patients with these aggressive tumours.     

三器械联合应用于IPAA治疗家族性腺瘤性息肉病的体会

目的 总结家族性腺瘤性息肉病(FAP)的诊断和二器械联合IPAA外科治疗经验。方法 回顾分析19例FAP的临床资料及IPAA手术治疗效果。结果 所有患者预后良好，无明显并发症的发生，术后大便控制能力良好，术后癌变率与传统手术无差异，手术时间缩短、手术难度降低。结论 三器械联合IPAA手术是治疗FAP的最佳方法，易于推广。     

Brain tumors in individuals with familial adenomatous polyposis: a cancer registry experience and pooled case report analysis

BACKGROUND: Most individuals with Familial Adenomatous Polyposis (FAP) harbor mutations in the APC gene on chromosome 5q21. They are at an increased risk of brain tumors, including cerebellar medulloblastoma, when compared with the general population (Brain Tumor Polyposis-BTP Type 2). Genotype-phenotype correlations between APC gene mutations and central nervous system (CNS) tumors have, thus far not been successful. Herein the authors have pooled their registry experience in BTP type 2 with the published reports. METHODS: The authors analyzed their established hereditary CRC Registry for brain tumors in FAP pedigrees (56 families, 213 individuals), pooled their patients with BTP and known APC mutations with those reported thus far elsewhere, and compared the resulting mutation distribution of FAP-BTP with the mutation distribution for APC mutations in the US. RESULTS: Twenty-eight patients from 24 families were accrued, the most common brain tumor in BTP was medulloblastoma (60%) predominantly in females (12:5) under the age of 20 (mean age 14.7 SD 9.2). Other histologic subtypes included astrocytoma and ependymoma. Analysis of the pooled APC mutation data by Chi-square test of association shows an odds ratio of 3.7 (P < .005) for all brain tumor subtypes and 13.1 (P < .001) for medulloblastoma in patients harboring segment 2 APC mutation (codons 679-1224) compared to nonsegment 2 mutation. CONCLUSIONS: In patients with FAP and identifiable APC gene mutation, CNS tumors, especially medulloblastoma which developed in most cases during childhood, are more common in females with FAP and APC gene mutation in codons 686-1217. Further studies are necessary to determine if this observation and the natural history of medulloblastoma in children justifies novel, aggressive, targeted screening of at-risk individuals.     

Recurrent idiopathic pancreatitis in familial adenomatous polyposis: Report of a case-series and review of the literature

Familial adenomatous polyposis (FAP) is characterized by the development of multiple adenomatous polyps predominantly in the colon but also in the duodenum. Scattered case reports indicate that there is a risk for pancreatitis in FAP. The most likely cause of pancreatitis in FAP is obstructing ampullary adenomas. We describe 7 FAP patients who experienced one or more episodes of pancreatitis. Two patients experienced pancreatitis after endoscopic treatment of ampullary adenoma. The cause of the pancreatitis in 5 of 7 patients could not be determined, as none of the patients had obstruction of the ampulla. Furthermore, other risk factors for pancreatitis such as pancreatic serine protease inhibitor Kazal type I (SPINK1) gene mutations were ruled out. A review of literature identified 20 FAP patients who developed the first episode of pancreatitis at a mean age of 45 years (range 23–72 years). Some 55% had recurrent episodes of pancreatitis. Eight patients had (peri) ampullary adenomas or carcinomas. In most cases, the course of pancreatitis was mild with an uneventful outcome, but one patient died after an episode of acute pancreatitis. Grant support: Joost P.H. Drenth is a recipient of a NWO-VIDI grant     

Using genotype to assist clinical surveillance: a retrospective study of Chinese familial adenomatous polyposis patients

Without treatment, familial adenomatous polyposis (FAP) patients will inevitably develop colorectal cancer (CRC) during lifetime. Yet, surgical trauma is a high risk of desmoid tumor (DT), one of the main causes of death in FAP patients. So far, the timing for colectomy is primarily based on the clinician’s experience and the patient’s preference; most patients undergo surgery at mid-20’s. In this study, we analyzed the germline mutation distribution in 35 FAP patients from different families, 16 of them diagnosed with DTs. We also investigated the association between the molecular alterations and the clinicopathological features. Capture-based targeted sequencing using a panel of 520 genes was performed on tumor tissue and paired normal mucosa or white blood cells from 18 FAP probands who were initially diagnosed with CRC. Of all 35 FAP patients, 30 (85.7%) of them harbored germline APC mutations scattered from codon 161 to 1578. The mutations in the 16 DT patients scattered from codon 457 to 1578. All three patients with the mutation at the 3’ of 1444 codon were diagnosed with DT. The percentage of high-risk DT (stage III or IV) harboring mutations at the 5’ of 1062 or 1062-1578 was 14.3% and 77.8%, respectively, and all three patients with 3’ of 1399 codon mutation had high risk. In addition, by using public database, we compared 140 FAP patients with DT to all 1880 FAP patients on the Leiden Open Variation Database and found that the odd ratio of DT in codon 159 to 495 was 0.34, while in codon 1310 to 2011 was 2.36. Compared to sporadic CRCs, the somatic spectrum of FAP CRCs was similar to the early onset CRCs, with higher TP53 (94.1%) and lower somatic APC mutations (65.7%), but the KRAS mutation rate was the highest (58.5%). One of the 18 FAP CRCs was identified as microsatellite instability-high (MSI-H), with tumor mutation burden (TMB) of 115.65 mut/Mb. Given that no TP53 mutations were detected in the low- and high-grade adenomas, ctDNA TP53 sequencing might be used for the close monitoring before FAP colectomy. In conclusion, except mutations at the 5’ end of APC (5’ to 495), all FAP patients need to consider the risk of DT after colectomy. The chance of life-threating DTs was higher in patients with 3’ 1062 codon mutation and peaked in patients with 3’ 1399 codon mutation. Scheduled monitoring of TP53 ctDNA is proposed to be a novel tool for optimizing the operation time.     

COX-2在直肠腺瘤性息肉与癌组织中的表达及意义

目的 :研究COX 2在直肠家族性腺瘤性息肉病 (familialadenomatouspolyposis,FAP)与癌组织中的表达及意义。方法 :用流式细胞仪 (FCM )分别检测 1 2例正常直肠粘膜组织、1 9例FAP、7例FAP癌变组织及 36例直肠癌组织的COX 2蛋白表达。结果 :1 2例正常直肠粘膜组织COX 2蛋白表达的平均FI值为 0 .67± 0 .2 8,均呈阴性表达 ;FAP 1 8(94.74% )例、FAP癌变组织 7(1 0 0 % )例及直肠癌组织 36 (1 0 0 % )例阳性表达 ,COX 2蛋白表达平均FI值分别为 1 .97± 0 .36、2 .0 2± 0 .2 4、2 .1 4± 0 .31 ,COX 2蛋白表达及阳性表达率与正常直肠粘膜组织差异均有显著性 (P <0 .0 1 ) ,而三者之间差异无显著性 (P >0 .0 5)。结论 :提示COX 2蛋白表达检测对预测腺瘤性息肉癌变可能性、进而用化学干预具有重要意义     

Possible involvement of hyperlipidemia in increasing risk of colorectal tumor development in human familial adenomatous polyposis

BACKGROUND: Familial adenomatous polyposis (FAP) results from germline adenomatous polyposis coli (APC) gene mutations and many affected patients die from colorectal cancers which arise from colorectal polyps. We previously reported that two strains of Apc gene-deficient mice developing multiple intestinal polyps exhibit a hyperlipidemic state. The triglyceride (TG) levels were approximately 10-fold higher than the levels observed in wild-type mice. METHODS: To examine whether a positive relationship might exist between hyperlipidemia and colorectal tumor development in FAP patients, as with Apc gene-deficient mice, a pilot experiment was performed using readily available clinical data such as ages, serum lipid levels, number of colorectal polyps and cancer development in 28 FAP patients from the National Cancer Center Hospital, Japan. RESULTS: The overall prevalence of hyperlipidemia in FAP cases was 58%. Average TG levels in the 40-60 year age groups of FAP patients were > or =150 mg/dl (the defined threshold level of hyperlipidemia). Moreover, there was a tendency for higher serum TG levels in patients who developed colorectal cancer, as compared with those without colorectal cancer. CONCLUSIONS: These results show that a hyperlipidemic state occurs in FAP patients. Although it is weaker than that in Apc gene-deficient mice, it may be linked to colon tumor development. These data warrant further studies for wider populations of FAP patients.     

A nation‐wide study comparing sporadic and familial adenomatous polyposis‐related desmoid‐type fibromatoses

Desmoid‐type fibromatoses are neoplasms of fibroblastic origin, occurring sporadically or associated with familial adenomatous polyposis (FAP) coli. By comparing sporadic and FAP‐associated desmoid‐type fibromatoses, we tried to identify clinical characteristics, which may indicate FAP. Histopathology data of all Dutch patients with desmoid‐type fibromatoses diagnosed between 1999 and 2009 were retrieved from PALGA, the nation‐wide network and registry of histopathology in the Netherlands. For calculation of incidence rates, person‐years from the general matched population were used. Based on polyp counts in pathological records, the cohort was divided into a FAP group and a non‐FAP group. Patient‐ and tumor characteristics were compared between the two groups. A total number of 519 patients older than 10 years with a confirmed diagnosis of desmoid‐type fibromatoses were included. Thirty‐nine (7.5%) desmoid patients were documented of having FAP. The incidences of sporadic and FAP‐related desmoid‐type fibromatoses were 3.42 and 2,784 per million person‐years, respectively. The majority of FAP patients developed desmoid‐type fibromatoses after the diagnosis of FAP. Having FAP was associated with male gender [odds ratio (OR) 2.0, p = 0.034], desmoid diagnosis at an earlier age (mean 36 vs. 42 years, p = 0.031), and desmoid localization intra‐abdominally (OR 18.9, p ≤ 0.001) or in the abdominal wall (OR 4.8, p ≤ 0.001), compared to extra‐abdominal desmoid localization. In conclusion, patients with desmoid‐type fibromatoses are at risk of underlying FAP. Especially cases with desmoid localization intra‐abdominal or in the abdominal wall, and all patients younger than 60 years, have a substantial increased risk and should be referred for colonoscopy.     

Psychological distress and use of psychosocial support in familial adenomatous polyposis

Objective: Familial adenomatous polyposis (FAP) is characterized by multiple adenomas in the colorectum with a high risk to develop colorectal cancer. It is unclear whether individuals at risk of FAP experience distress due to this potentially life‐threatening disease. This nationwide study assessed: (1) the prevalence of psychological distress; and (2) the need for and use of specialized professional psychosocial support. Methods: In this cross‐sectional study, all individuals from families at high risk for FAP registered at the Netherlands Foundation for the Detection of Hereditary Tumours were invited to complete a questionnaire assessing, among other issues, generalized, cancer‐specific and FAP‐specific distress. Results: In total, 525 individuals completed the questionnaire. Approximately 20% of the respondents had moderate to severe levels of FAP‐specific distress. Levels of generalized distress were comparable to the general Dutch population. Significantly more individuals with a FAP diagnosis had frequent cancer worries than those at risk of FAP or non‐carriers (p=0.02). Distress levels were more strongly associated with psychosocial variables (e.g. perceived cancer risk), than with sociodemographic or clinical variables. Up to 43% of the variance in distress could be explained by all variables combined. Of those moderately to severely distressed, 26% had received specialized professional psychosocial support, while 30% of those did not receive the support they wanted. Conclusions: A substantial minority of individuals reported moderate to severe distress levels associated with FAP. However, only one‐third of those received specialized professional psychosocial support. We recommend the use of a screening questionnaire to identify individuals in need of such support. Copyright © 2009 John Wiley & Sons, Ltd.     

APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis

Correlations between germline APC mutation sites and colorectal pathophenotypes, as evaluated by the direct count of adenomas at colectomy, were investigated analysing colectomy specimens from 29 FAP patients carrying one mis-sense (codon 208) and 14 frame-shift or non-sense APC mutations (codons 232, 367, 437, 623, 876, 995, 1061, 1068, 1075, 1112, 1114, 1309, 1324, 1556). The mis-sense mutation at codon 208 was associated with a relatively mild colorectal pathophenotype. The mutation at codon 367, subject to alternative splicing, was associated with attenuated FAP. The mutation at codon 1309 was associated with the profuse colorectal adenomatosis. For 13 mutations, predicted to result in null alleles or truncated APC proteins, we correlated density and distribution of colorectal adenomas with the predicted functional effects of the mutation. The most severe colorectal pathophenotype was significantly associated with the truncating mutation at codon 1309, which is located downstream to the I beta-catenin binding domain but upstream II beta-catenin-binding domain. Mutations between codons 867 and 1114, which affect the I beta-catenin binding domain, as well as mutations occurring in exons 6 and 9, predicted to result in null alleles, were associated with a less severe colorectal pathophenotype. Overall, the highest number of adenomas was detected in the right colon, followed by the left colon, transverse colon sigma and rectum. However, the highest density of adenomas was observed in the left colon, followed by the right colon, sigma, transverse colon and rectum. Colorectal carcinomas, observed in only five patients, were all in the left colon.