characterized by the development of hundreds to thousands of colonic adenomas , 
                 classic familial adenomatous polyposis ( fap ) is one of the most common hereditary 
                 syndromes associated with an increased risk of colorectal cancer . fap occurs once in 
                 every 10,00030,000 live births,1 has a relatively equal worldwide distribution , 
                 and occurs equally among males and females . these patients are also at an 
                 increased risk for extra - colonic malignancies , such as duodenal ampullary cancer , 
                 follicular or papillary thyroid cancer , childhood hepatoblastoma , and 
                 medullablastoma . fap is inherited in an autosomal dominant fashion by germ line mutations in the 
                 adenomatous polyposis coli ( apc ) gene located on chromosome 5q2122.2 more than 800 mutations of the 
                 apc gene associated with fap have been described and the majority of these mutations 
                 involve frame shifts and premature stop codons , which results in truncated , 
                 non - functional apc gene products.3,4 in most fap 
                 patients , the expression of the apc mutation involves an inherited mutation of one 
                 apc allele , with a second hit  deletion of the other allele.5 several studies have attempted 
                 to correlate specific apc mutations with clinical phenotype.6 however , there is considerable variability in 
                 the expression of specific phenotypes within families and among individuals with 
                 identical mutations.7 we report a case of newly diagnosed fap in a patient without any family history of 
                 the syndrome or its associated malignancies . a 30 year - old hispanic female presented to the emergency department with a 2-week 
                 history of persistent , worsening , left lower quadrant abdominal pain with increasing 
                 constipation . there were no 1st , 2nd , or 3rd degree relatives with a history 
                 of colon cancer or any other malignancies . the patient s family had frequent 
                 follow - up medical care with adherence to current cancer screening guideline 
                 recommendations . on admission , physical exam revealed a soft , moderately distended abdomen with hypoactive bowel 
                 sounds and tenderness to palpation over the left lower quadrant . pertinent 
                 laboratory findings included white blood cell count 12.8  
                 10/l , hemoglobin 9.2 g / dl , hematocrit 29.5% , mean corpuscular 
                 volume 67.7 fl , red blood cell distribution width 17.9 , and carcinoembryonic antigen 
                 1.25 ng / ml . computed tomography of the abdomen and pelvis with oral and intravenous 
                 contrast revealed innumerable polypoid filling defects within the transverse and 
                 descending colon ( fig . sigmoidoscopy revealed innumerable polyps in the rectum and sigmoid colon with a 
                 large mass ( 5.0 cm by 2.0 cm ) in the sigmoid colon ( figs . 2 and 3 ) . 4b ) . immunohistochemistry staining revealed homogenous 
                 proliferative activity with ki-67 ( fig . the tumor cells were negative for msh2 
                 and positive for mlh1 , pms2 and msh6 by immunohistochemistry . the tumor was 
                 classified as msi - high , indicating a high probability of microsatellite instability . endoscopy revealed innumerable polyps and  coffee ground  blood in 
                 the fundus , body , and cardia of the stomach ( fig . the patient s hospital course 
                 was complicated by the development of a rapidly growing colonic abscess that was 
                 successfully drained . however , subsequent gene sequencing analysis of the exons and 
                 adjacent intrinsic regions of the apc gene revealed a germline apc mutation 
                 3927del5 , resulting in a premature truncation of the apc protein at amino acid 
                 position 1312 with the absence of a myh mutation . a definitive diagnosis of 
                 classical familial adenomatous polyposis was made and the patient underwent a total 
                 proctocolectomy . post - surgery , there was no evidence of tumor in 57 nodes reviewed . the patient tolerated the procedure well and plans were made for an ileal - pouch- 
                 anal anastomosis . the patient was also started on celoximib 400 mg twice per day to 
                 prevent both the recurrence of polyps in the ileal pouch and progression of duodenal 
                 adenomas . the patient s family underwent genetic counseling and although 
                 recommended , they refused genetic testing at the time . this case highlights many important genetic and clinical questions regarding a very 
                 rare condition . why did this patient with no family history of cancer present with a 
                 classically autosomal dominant condition what is the significance of mismatch 
                 repair genes and of this patient s specific genetic mutation ? what are the recommended 
                 screening procedures and treatments ? can genetic information be further incorporated 
                 into treatment ? our patient was classified as msi - high , indicating a high probability of 
                     microsatellite instability in her mismatch repair genes . these critical growth 
                     regulatory genes are responsible for correcting the nucleotide base mis - pairings 
                     that occur during dna replication.912 
                     several of these genes exist , including human muts homolog 1 , 2 , 3 , and 6 , and 
                     human post meiotic segregation 1 and 2 . a tumor is classified as msi - h when at 
                     least two of these genes are affected by instability.13 the prevalence and incidence of 
                     microsatellite instability in fap patients has not been defined . one study 
                     suggested that microsatellite instability was only detectable in a small 
                     proportion of fap adenocarcinomas and that these cases may constitute a distinct 
                     subgroup among fap neoplasms.14 the majority of patients with hereditary non - polyposis colorectal 
                     cancer ( hnpcc ) , another common hereditary syndrome , have msi - h tumors , whereas 
                     only approximately 15 percent of sporadic tumors are msi - h . in contrast to 
                     microsatellite - stable crcs , sporadic tumors with msi - h tend to occur in the 
                     proximal colon , have a greater mucinous component , contain lymphocytic 
                     infiltration , are more frequently poorly differentiated , and are associated with 
                     longer survival . most colon cancers arise when there is an inactivation of the apc gene and the 
                     regulation of adenoma epithelial renewal is disrupted . the normal apc protein 
                     prevents the accumulation of cytosolic and nuclear beta - catenin by mediating its 
                     phosphorylation and degradation . the majority of mutations in the apc gene ( both 
                     germline and somatic ) lead to premature truncation of the apc protein and loss 
                     of its beta - catenin regulatory domains . loss of functional apc results in the 
                     nuclear accumulation of beta - catenin , which activates the transcription factor 
                         tcf-4.1517 it is proposed that 
                     beta - catenin / tcf-4 acts as a switch controlling proliferation in the intestinal 
                     crypt epithelial cells18,19 and the 
                     activation of this pathway prevents cell differentiation and induces apoptosis 
                         resistance.20 the 
                     genetic events occurring after the apc gene mutation are dependent on the 
                     underlying genetic instability chromosomal instability , germ line 
                     mutations in dna mismatch repair enzymes , and cpg island hyper - methylation 
                     phenotype [ cimp+].21 the process of gene sequencing has become relatively simple with newer 
                         technologies.22 the 
                     process begins by breaking chromosomes into shorter pieces . these fragments , 
                     differing in length from each other by a single base , are used as templates to 
                     be identified . the fragments are then separated by gel electrophoresis and the 
                     final base at the end of each fragment is identified , recreating the original 
                     sequence of as , ts , cs , and gs for each short piece generated in the first step . automated sequencers analyze the data and the output consists of a four - color 
                     chromatogram showing peaks that represent each of the four dna bases . after the 
                     bases are  read ,  computers are used to analyze for errors , 
                     gene - coding regions , and other characteristics . it is hypothesized that new germline apc mutations account for approximately one 
                     third of fap patients who have no family history of the disease.23 our patient had a germ 
                     line apc mutation 3927del5 , resulting in premature truncation of the apc protein 
                     at amino acid position 1312 . in a review of 417 fap cases in the literature , the 
                     frequency of 3927del5 mutations was 8.9%.24,25 in a study by hadjisavvas et al , the most 
                     common apc gene mutation was 2307dela , followed by 1242 , and 3927del5.24 another study noted that 
                     the 3927del5 mutation was associated with a patient presentation of polyposis , 
                     but no family history of the disease.26,27 little is known about the function of specific apc mutations , including 3927del5 , 
                     and why certain mutations occur more frequently than others . however , several 
                     studies have attempted to correlate specific apc mutations with clinical 
                     phenotypes ( table 1 ) . mutations between codons 169 to 1578 were generally associated with the classic 
                     form of fap.6,7,28 mutations between codons 1445 and 1578 
                     were associated with desmoid tumors,2931 whereas mutations between codons 279 to 
                     1309 correlated with the development of duodenal polyposis.32 classical fap typically develops in the second or third decade of life and 
                     patients generally seek medical attention because of nonspecific abdominal 
                     complaints , anemia , or an established family history of fap . fap is 
                     traditionally diagnosed based on the presence of more than 100 adenomatous 
                     colorectal polyps . genetic testing is now standard for the diagnosis of 
                         fap.3336 attenuated fap ( afap ) is a variant of classical fap and is characterized by a 
                     widely variable presentation with fewer colonic adenomas ( 10 to 100 ) , a lower 
                     ( up to 80 percent ) lifetime risk of colon cancer , a more proximal distribution 
                     of adenomas , and a later age of diagnosis of both colonic polyps ( average age of 
                     40 to 45 ) and colon cancer ( average age of 50).3739 consideration of genetic testing for afap 
                     ( apc gene ) is recommended in patients with more than 10 to 20 cumulative colonic 
                     adenomas . approximately 10 to 30 percent of patients with classical fap , and 90 percent of 
                     individuals with attenuated fap do not have a detectable apc mutation.40 many of these individuals 
                     have mutyh associated polyposis ( map ) , an autosomal recessive polyposis syndrome 
                     caused by biallelic mutations in the mutyh gene.41 the two most common 
                         mutyh gene mutations found in map in the caucasian 
                     population are y179c and g396d.40 the clinical spectrum of map is variable , ranging from a clinical 
                     phenotype similar to afap42 to one of classic fap.43,44 a large - scale meta - analysis showed that 
                     map patients demonstrated a 28-fold increase in colon cancer , had a higher 
                     frequency of right sided tumors , and had a mean age of 45 at diagnosis.45 extra - colonic features 
                     associated with map include gastroduodenal polyps , duodenal carcinoma , osteomas , 
                     breast cancer in female carriers , congenital hypertrophy of the retinal pigment 
                     epithelium , dental cysts , and sebaceous gland tumors.46 map patients are also at increased risk 
                     for extra - intestinal cancers including ovarian , bladder , skin , and breast 
                         cancer.45,47 fundic gland polyps of the proximal stomach , present in 30 to 100 percent of fap 
                         patients,48,49 are thought to have a 
                     very low risk of progression to cancer , whereas duodenal polyps , present in 45 
                     to 90 percent of fap patients , are usually adenomatous and are more likely to 
                     progress to cancer . patients with fap have an approximately 4 to 12 percent 
                     lifetime risk of cancer of the duodenum or papilla of vater . adenomas in the 
                     distal small bowel and in the stomach occur in 20 to 40 percent of patients with 
                     fap , but have a much lower cancer risk than duodenal adenomas . cancer has been 
                     reported to occur in the ileostomy following colectomy.50,51 in a sample of 167 patients who were 
                     followed for up to 15 years following colectomy , the risk for developing one or 
                     more adenomas in the ileal pouch was 7 , 35 , and 75 percent at 5 , 10 , and 15 
                     years follow - up , respectively.51 fap patients are also at an increased risk for developing 
                     intra - abdominal desmoid tumors and have a lifetime prevalence of 20 percent with 
                     a peak incidence around 30 years of age.52 these tumors are benign , slowly growing 
                     fibroblastic neoplasms that tend to recur locally and destroy adjacent vital 
                     structures . screening of the upper gastrointestinal tract with upper endoscopy for gastric 
                     and duodenal polyps has been recommended , although the benefit has not been 
                     proven in clinical trials.5355 
                     it is recommended that fap gene carriers or high - risk family members engage in 
                     screening of the lower gastrointestinal tract with a flexible sigmoidoscopy or 
                     colonoscopy every 12 months from the age of 1012 until 3540 
                     years old if results are persistently negative . screening recommendations for 
                     extra - intestinal lesions in fap , including hepatoblastoma and thyroid cancer , 
                     include serum alpha - fetoprotein testing with abdominal palpation ( every six 
                     months until the age of six ) and annual palpation of the thyroid , 
                         respectively.56 colectomy near the time of initial diagnosis is strongly recommended in patients 
                     with multiple large adenomas or adenomas with villous histology and/or 
                     high - grade dysplasia . the preferred operation in classical fap patients is a 
                     total proctocolectomy with ileoanal anastomosis . a subtotal colectomy with 
                     ongoing surveillance or a total colectomy is reasonable in patients with 
                     attenuated adenomatous polyposis who have minor rectal involvement . one study 
                     suggested that the specific apc genotype may be useful in 
                     predicting which patients would be better suited for ileorectal anastomosis 
                     versus total proctocolectomy with ileal - pouch - anal anastomosis.57 various medical therapies 
                     have been researched as an adjuvant to surgery in order to decrease the overall 
                     gi tract polyp burden . celecoxib , a cyclooxygenase-2 inhibitor , has been shown 
                     to reduce the number of colonic polyps ( 2844 percent reduction ) in 
                     adults with fap.58,59 nsaids are also being 
                     used to slow the development of adenomas prior to colectomy and to delay new 
                     polyp formation in the rectum after subtotal colectomy.60 our patient was classified as msi - high , indicating a high probability of 
                     microsatellite instability in her mismatch repair genes . these critical growth 
                     regulatory genes are responsible for correcting the nucleotide base mis - pairings 
                     that occur during dna replication.912 
                     several of these genes exist , including human muts homolog 1 , 2 , 3 , and 6 , and 
                     human post meiotic segregation 1 and 2 . a tumor is classified as msi - h when at 
                     least two of these genes are affected by instability.13 the prevalence and incidence of 
                     microsatellite instability in fap patients has not been defined . one study 
                     suggested that microsatellite instability was only detectable in a small 
                     proportion of fap adenocarcinomas and that these cases may constitute a distinct 
                     subgroup among fap neoplasms.14 the majority of patients with hereditary non - polyposis colorectal 
                     cancer ( hnpcc ) , another common hereditary syndrome , have msi - h tumors , whereas 
                     only approximately 15 percent of sporadic tumors are msi - h . in contrast to 
                     microsatellite - stable crcs , sporadic tumors with msi - h tend to occur in the 
                     proximal colon , have a greater mucinous component , contain lymphocytic 
                     infiltration , are more frequently poorly differentiated , and are associated with 
                     longer survival . most colon cancers arise when there is an inactivation of the apc gene and the 
                     regulation of adenoma epithelial renewal is disrupted . the normal apc protein 
                     prevents the accumulation of cytosolic and nuclear beta - catenin by mediating its 
                     phosphorylation and degradation . the majority of mutations in the apc gene ( both 
                     germline and somatic ) lead to premature truncation of the apc protein and loss 
                     of its beta - catenin regulatory domains . loss of functional apc results in the 
                     nuclear accumulation of beta - catenin , which activates the transcription factor 
                         tcf-4.1517 it is proposed that 
                     beta - catenin / tcf-4 acts as a switch controlling proliferation in the intestinal 
                     crypt epithelial cells18,19 and the 
                     activation of this pathway prevents cell differentiation and induces apoptosis 
                         resistance.20 the 
                     genetic events occurring after the apc gene mutation are dependent on the 
                     underlying genetic instability chromosomal instability , germ line 
                     mutations in dna mismatch repair enzymes , and cpg island hyper - methylation 
                     phenotype [ cimp+].21 the process of gene sequencing has become relatively simple with newer 
                         technologies.22 the 
                     process begins by breaking chromosomes into shorter pieces . these fragments , 
                     differing in length from each other by a single base , are used as templates to 
                     be identified . the fragments are then separated by gel electrophoresis and the 
                     final base at the end of each fragment is identified , recreating the original 
                     sequence of as , ts , cs , and gs for each short piece generated in the first step . automated sequencers analyze the data and the output consists of a four - color 
                     chromatogram showing peaks that represent each of the four dna bases . after the 
                     bases are  read ,  computers are used to analyze for errors , 
                     gene - coding regions , and other characteristics . it is hypothesized that new germline apc mutations account for approximately one 
                     third of fap patients who have no family history of the disease.23 our patient had a germ 
                     line apc mutation 3927del5 , resulting in premature truncation of the apc protein 
                     at amino acid position 1312 . in a review of 417 fap cases in the literature , the 
                     frequency of 3927del5 mutations was 8.9%.24,25 in a study by hadjisavvas et al , the most 
                     common apc gene mutation was 2307dela , followed by 1242 , and 3927del5.24 another study noted that 
                     the 3927del5 mutation was associated with a patient presentation of polyposis , 
                     but no family history of the disease.26,27 little is known about the function of specific apc mutations , including 3927del5 , 
                     and why certain mutations occur more frequently than others . however , several 
                     studies have attempted to correlate specific apc mutations with clinical 
                     phenotypes ( table 1 ) . mutations between codons 169 to 1578 were generally associated with the classic 
                     form of fap.6,7,28 mutations between codons 1445 and 1578 
                     were associated with desmoid tumors,2931 whereas mutations between codons 279 to 
                     1309 correlated with the development of duodenal polyposis.32 classical fap typically develops in the second or third decade of life and 
                     patients generally seek medical attention because of nonspecific abdominal 
                     complaints , anemia , or an established family history of fap . fap is 
                     traditionally diagnosed based on the presence of more than 100 adenomatous 
                     colorectal polyps . attenuated fap ( afap ) is a variant of classical fap and is characterized by a 
                     widely variable presentation with fewer colonic adenomas ( 10 to 100 ) , a lower 
                     ( up to 80 percent ) lifetime risk of colon cancer , a more proximal distribution 
                     of adenomas , and a later age of diagnosis of both colonic polyps ( average age of 
                     40 to 45 ) and colon cancer ( average age of 50).3739 consideration of genetic testing for afap 
                     ( apc gene ) is recommended in patients with more than 10 to 20 cumulative colonic 
                     adenomas . approximately 10 to 30 percent of patients with classical fap , and 90 percent of 
                     individuals with attenuated fap do not have a detectable apc mutation.40 many of these individuals 
                     have mutyh associated polyposis ( map ) , an autosomal recessive polyposis syndrome 
                     caused by biallelic mutations in the mutyh gene.41 the two most common 
                         mutyh gene mutations found in map in the caucasian 
                     population are y179c and g396d.40 the clinical spectrum of map is variable , ranging from a clinical 
                     phenotype similar to afap42 to one of classic fap.43,44 a large - scale meta - analysis showed that 
                     map patients demonstrated a 28-fold increase in colon cancer , had a higher 
                     frequency of right sided tumors , and had a mean age of 45 at diagnosis.45 extra - colonic features 
                     associated with map include gastroduodenal polyps , duodenal carcinoma , osteomas , 
                     breast cancer in female carriers , congenital hypertrophy of the retinal pigment 
                     epithelium , dental cysts , and sebaceous gland tumors.46 map patients are also at increased risk 
                     for extra - intestinal cancers including ovarian , bladder , skin , and breast 
                         cancer.45,47 fundic gland polyps of the proximal stomach , present in 30 to 100 percent of fap 
                         patients,48,49 are thought to have a 
                     very low risk of progression to cancer , whereas duodenal polyps , present in 45 
                     to 90 percent of fap patients , are usually adenomatous and are more likely to 
                     progress to cancer . patients with fap have an approximately 4 to 12 percent 
                     lifetime risk of cancer of the duodenum or papilla of vater . adenomas in the 
                     distal small bowel and in the stomach occur in 20 to 40 percent of patients with 
                     fap , but have a much lower cancer risk than duodenal adenomas . cancer has been 
                     reported to occur in the ileostomy following colectomy.50,51 in a sample of 167 patients who were 
                     followed for up to 15 years following colectomy , the risk for developing one or 
                     more adenomas in the ileal pouch was 7 , 35 , and 75 percent at 5 , 10 , and 15 
                     years follow - up , respectively.51 fap patients are also at an increased risk for developing 
                     intra - abdominal desmoid tumors and have a lifetime prevalence of 20 percent with 
                     a peak incidence around 30 years of age.52 these tumors are benign , slowly growing 
                     fibroblastic neoplasms that tend to recur locally and destroy adjacent vital 
                     structures . screening of the upper gastrointestinal tract with upper endoscopy for gastric 
                     and duodenal polyps has been recommended , although the benefit has not been 
                     proven in clinical trials.5355 
                     it is recommended that fap gene carriers or high - risk family members engage in 
                     screening of the lower gastrointestinal tract with a flexible sigmoidoscopy or 
                     colonoscopy every 12 months from the age of 1012 until 3540 
                     years old if results are persistently negative . screening recommendations for 
                     extra - intestinal lesions in fap , including hepatoblastoma and thyroid cancer , 
                     include serum alpha - fetoprotein testing with abdominal palpation ( every six 
                     months until the age of six ) and annual palpation of the thyroid , 
                         respectively.56 colectomy near the time of initial diagnosis is strongly recommended in patients 
                     with multiple large adenomas or adenomas with villous histology and/or 
                     high - grade dysplasia . the preferred operation in classical fap patients is a 
                     total proctocolectomy with ileoanal anastomosis . a subtotal colectomy with 
                     ongoing surveillance or a total colectomy is reasonable in patients with 
                     attenuated adenomatous polyposis who have minor rectal involvement . one study 
                     suggested that the specific apc genotype may be useful in 
                     predicting which patients would be better suited for ileorectal anastomosis 
                     versus total proctocolectomy with ileal - pouch - anal anastomosis.57 various medical therapies 
                     have been researched as an adjuvant to surgery in order to decrease the overall 
                     gi tract polyp burden . celecoxib , a cyclooxygenase-2 inhibitor , has been shown 
                     to reduce the number of colonic polyps ( 2844 percent reduction ) in 
                     adults with fap.58,59 nsaids are also being 
                     used to slow the development of adenomas prior to colectomy and to delay new 
                     polyp formation in the rectum after subtotal colectomy.60 our case 
                 of a rare genetic condition highlights the importance of understanding sporadic 
                 mutations and how genetic mutations can have widely variable phenotypes . much more 
                 research and randomized clinical trials need to be conducted with fap patients in 
                 order to more definitively characterize random mutations . the hope is that one day 
                 it will be possible to risk stratify patients with fap and improve the screening , 
                 diagnosis , and treatment for this condition .
introduction 
 characterized by the development of hundreds to thousands of colonic 
                         adenomas , classic familial adenomatous polyposis ( fap ) is one of the most 
                         common hereditary syndromes associated with an increased risk of colorectal 
                         cancer . 
 several studies have attempted to correlate specific apc mutations 
                         with clinical phenotype.6 however , there is considerable variability in the expression 
                         of specific phenotypes within families and among individuals with identical 
                             mutations.7 


 case presentation 
 a 30 year - old hispanic female presented to the emergency department with a 
                         2-week history of persistent , worsening , left lower quadrant abdominal pain . 
 she had no family history of malignancy . 
 sigmoidoscopy revealed innumerable 
                         polyps in the rectum and sigmoid colon and a large mass in the sigmoid 
                         colon . 
 biopsy of the mass revealed a moderately differentiated 
                         adenocarcinoma invading the subserosa . 
 endoscopy revealed innumerable 
                         polyps . 
 genetic testing of the patient via southern blot revealed a germline 
                         apc mutation 3927del5 , resulting in a premature truncation of the apc 
                         protein at amino acid position 1312 . 
 conclusion 
 genetic information has only recently started being incorporated into 
                         clinical care . 
 more research and randomized clinical trials need to be 
                         conducted to definitively characterize random mutations . 
 once these 
                         mutations are further understood , fap patients may be able to be risk 
                         stratified and this may ultimately improve the screening , diagnosis , and 
                         treatment of this rare condition .