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Gastrointestinal polyps in children: Advances in molecular genetics, diagnosis, and management

2001; Elsevier BV; Volume: 138; Issue: 5 Linguagem: Inglês

10.1067/mpd.2001.113619

1097-6833

Julissa Corredor, Jennifer Wambach, John Barnard,

Colorectal Cancer Screening and Detection

See related article, p 629. Gastrointestinal polyps are common during childhood and are almost always benign lesions. However, pediatricians must be aware that occasionally children with polyps may have an underlying genetic abnormality resulting in a predisposition to colorectal cancer or other neoplasms. In recent years, major progress has been made in understanding the molecular pathogenesis of genetic polyposis syndromes. These basic advances have led to improved methods of detection and screening of at-risk individuals. Herein, we review clinical features of the common juvenile polyp and the molecular genetics of less common polyposis syndromes that may present during the first 2 decades of life. Dilemmas in the approach to children with multiple juvenile polyps are also discussed. The interested reader is referred to www3.ncbi.nlm.nih.gov/Omim and www.geneclinics.org for more exhaustive, regularly updated, clinical and genetic information. A fundamental property of normal cellular growth regulation is the delicate counterbalance of growth promotion and growth inhibition. In the broadest sense, a gastrointestinal polyp results from a defect in this highly regulated process. This may occur by either aberrant "gain-of-function" in a growth-promoting protein (oncogene) or "loss-of-function" in a growth inhibitory protein (tumor suppressor gene). Oncogenes are most often activated , and tumor suppressor genes are most often inactivated , although additional molecular and cellular mechanisms favoring polyp formation may occur. The genetic gastrointestinal polyposis syndromes most often result from a germline (inherited) inactivating mutation of a tumor suppressor gene. Eventual somatic mutation of the normal remaining allele results in loss of normal growth constraint and creates a selective growth advantage, unchecked growth and polyp formation. Progression of a polyp to gastrointestinal cancer requires the sequential acquisition of additional genetic defects. Recognition of this "adenoma-to-carcinoma" sequence has been a major advance in the biology of gastrointestinal neoplasia.1Kinzler KW Vogelstein B. Lessons from hereditary colorectal cancer.Cell. 1996; 87: 159-170Abstract Full Text Full Text PDF PubMed Scopus (4307) Google Scholar By far the most frequent type of polyp encountered in pediatric practice is the common juvenile polyp, a term used to describe histologically distinctive colorectal polyps occurring during childhood (Table).Tabled 1Table. Gastrointestinal polyps in childrenSyndromeGene defectHistologyFrequencyGastrointestinal cancer riskCommon juvenile polypsUnknownHamartoma1:100 to 1:50None*FAP coli (including Gardner's and Turcot's variants)APCAdenoma1:17,000 to 1:5000100%PJSLKB1 (STK11); ? othersHamartoma1:120,000IncreasedCSPTEN; ? othersHamartomaRareUncertainBRRSPTEN; ? othersHamartomaRareNoneJuvenile polyposisSmad4; ?PTEN ? othersHamartomaRare50%*If solitary.FAP, Familial adematous polyposis; APC, adenomatous polyposis coli; PJS, Peutz-Jeghers syndrome; CS, Cowden syndrome; BRRS, Bannayan-Riley-Ruvalcaba syndrome; PTEN, protein tyrosine phosphatase and tensin homolog. Open table in a new tab It has been estimated that 1% to 2% of asymptomatic children have juvenile polyps,2Horrileno EG Eckert C Ackerman LV. Polyps of the rectum and colon in children.Cancer. 1957; 10: 1210-1220Crossref PubMed Scopus (95) Google Scholar, 3Gonzalez-Peralta R Andres J. Polyps and polyposis Syndromes.in: Pediatric gastrointestinal disease: pathophysiology, diagnosis, and management. WB Saunders, Philadelphia1999: 443-453Google Scholar which are diagnosed most often in the first decade of life, and the peak incidence occurs between 2 and 5 years of age.4Mazier WP MacKeigan JM Billingham RP Dignan RD. Juvenile polyps of the colon and rectum.Surg Gynecol Obstet. 1982; 154: 829-832PubMed Google Scholar, 5Mestre JR. The changing pattern of juvenile polyps.Am J Gastroenterol. 1986; 81: 312-314PubMed Google Scholar Polyps in infants less than 12 months of age are exceedingly unusual. The most frequent presenting complaint is painless rectal bleeding, which occurs in virtually all patients. Less common complaints include a prolapsing rectal mass, mucopurulent stools, and abdominal pain. Colocolic intussusception occurs rarely.6Arthur AL Garrer R Vaness DG. Colocolic intussusception in a three-year-old child caused by a colonic polyp.Conn Med. 1990; 54: 492-494PubMed Google Scholar Iron deficiency anemia is found in as many as one third of cases.7Cynamon HA Milov DE Andres JM. Diagnosis and management of colonic polyps in children.J Pediatr. 1989; 114: 593-596Abstract Full Text PDF PubMed Scopus (58) Google Scholar FAP, Familial adematous polyposis; APC, adenomatous polyposis coli; PJS, Peutz-Jeghers syndrome; CS, Cowden syndrome; BRRS, Bannayan-Riley-Ruvalcaba syndrome; PTEN, protein tyrosine phosphatase and tensin homolog. The differential diagnosis of rectal bleeding between 1 and 10 years of age includes Meckel's diverticulum, hemorrhoids, vascular lesions, intussusception, infectious diarrhea, anal fissure, lymphonodular hyperplasia, hemolytic uremic syndrome, Schölein-Henoch purpura, inflammatory bowel disease, and polyps. In the absence of diarrhea, constipation, significant abdominal pain, vomiting, large-volume bleeding, fever, weight loss, other systemic symptoms, and an abdominal mass or an anal fissure, the clinician may reasonably suspect the presence of a juvenile polyp and proceed to definitive diagnosis and treatment in the majority of cases. Colonoscopy is preferred over contrast enema examination in almost all children because it is both diagnostic and therapeutic. In the era of facile pediatric colonoscopy, a pan-colonoscopic examination is indicated, and polypectomy can be safely performed. Although pedunculated polyps may "auto-amputate," there is no objective evidence supporting the commonly held belief that polyps will ultimately naturally outgrow their blood supply and auto-amputate. Approximately 50% of children with polyps have more than one,5Mestre JR. The changing pattern of juvenile polyps.Am J Gastroenterol. 1986; 81: 312-314PubMed Google Scholar, 7Cynamon HA Milov DE Andres JM. Diagnosis and management of colonic polyps in children.J Pediatr. 1989; 114: 593-596Abstract Full Text PDF PubMed Scopus (58) Google Scholar and up to 25% of polyps may be proximal to the transverse colon. In a review of patients at Vanderbilt Children's Hospital, 18% of children undergoing pan-colonoscopic examination for juvenile polyps had 5 or more lesions (Fig 1).Definition of the number of juvenile polyps and their histology may carry implications for colorectal carcinoma risk and the need for subsequent screening examinations, an assertion that is developed more rigorously below. Histologically, the typical juvenile polyp is a hamartoma with a distinctive cystic architecture, mucus-filled glands, a prominent lamina propria, and dense infiltration with inflammatory cells. These findings have led to overlapping terminology, including inflammatory polyp s, retention polyp s, and hyperplastic polyps , depending on the dominant histologic finding. The etiology of the common juvenile polyp is not known. The large number of inflammatory cells suggests a contribution from inflammatory mediators. Genetic alterations commonly found in colorectal adenomas and carcinomas, such as mutations in Ras, the p53 tumor suppressor gene, the adenomatous polyposis coli tumor suppressor gene, and aneuploidy have not been detected in sporadic juvenile polyps.8Hoffenberg EJ Sauaia A Maltzman T Knoll K Ahnen D. Symptomatic colonic polyps in childhood: not so benign.J Pediatr Gastroenterol Nutr. 1999; 28: 175-181Crossref PubMed Scopus (55) Google Scholar, 9Wu T Rezai B Rashid A Michael CL Cayouette MC Kim C et al.Genetic alterations and epithelial dysplasia in juvenile polyposis syndrome and sporadic juvenile polyps.Am J Pathol. 1997; 150: 939-947PubMed Google Scholar Activity of ornithine decarboxylase, an enzyme associated with cellular proliferation, is increased in juvenile polyps, an indirect reflection of an underlying proliferative stimulus.10Elitsur Y Koh SJG Moshier JA Dosescu J Tureaud J Majumdar APN. Ornithine decarboxylase and tyrosine kinase activity in juvenile polyps of childhood.Pediatr Res. 1995; 38: 574-578Crossref PubMed Scopus (4) Google Scholar Familial adenomatous polyposis (OMIM 175100) is the most common genetic polyposis syndrome with an estimated prevalence between 1:17,000 and 1:5000.11Rustgi AK. Hereditary gastrointestinal polyposis and nonpolyposis syndromes.N Engl J Med. 1994; 331: 1694-1702Crossref PubMed Scopus (241) Google Scholar Inheritance is autosomal dominant, although spontaneous mutations account for approximately 30% of cases. Affected patients may have only a few adenomatous polyps, but ultimately hundreds or thousands of polyps are diffusely distributed in the rectum and colon. The average age at the onset of adenomatous polyps is 16 years, although there are isolated reports of adenomatous polyps and carcinoma before age 10.12Disante S Nasioulas S Somers GR Cameron DJS Young MA Forrest SM et al.Familial adenomatous polyposis in a 5 year old child: a clinical pathological and a molecular genetic study.J Med Genet. 1996; 33: 157-160Crossref PubMed Scopus (37) Google Scholar The occurrence of upper gastrointestinal adenomas confers a statistically increased risk of duodenal and periampullary carcinomas.13Offerhaus GJA Giardiello FM Krush AJ Booker SV Tersmette AC Kelley C et al.The risk of upper gastrointestinal cancer in familial adenomatous polyposis.Gastroenterology. 1992; 102: 1980-1982PubMed Google Scholar Progression to neoplasia is considered inevitable by the fifth decade in patients with FAP. Extra-intestinal manifestations of FAP include desmoid tumors, epidermoid cysts, osteomas, congenital hypertrophy of the retinal pigment epithelium, fibromas, and lipomas—all of which are benign but may signal the presence of FAP in at-risk patients. The presence of congenital hypertrophy of the retinal pigment epithelium in an at-risk individual is predictive of FAP,14Traboulsi EI Krush AL Gardner EJ Booker SV Offerhaus JA Yardley JH et al.Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome.N Engl J Med. 1987; 316: 661-667Crossref PubMed Scopus (206) Google Scholar, 15Romania A Zakov N Church J Jagelman DG. Retinal pigment epithelium lesions as a biomarker of disease in patients with familial adenomatous polyposis.Ophthalmology. 1992; 99: 911-913Abstract Full Text PDF PubMed Scopus (16) Google Scholar but use of this examination as a screening approach has largely been supplanted by the availability of genetic testing. Gardner's syndrome is a phenotypic variant of FAP, which includes desmoid tumors, exostoses, and the other extra-colonic manifestations enumerated above. The occurrence of brain tumors and FAP is known as Turcot's syndrome. Hepatoblastoma occurs in 1.6% of children born to a parent with FAP, a relative risk approximately 850 times that of the general population, leading some to recommend annual α-fetoprotein measurement and perhaps hepatic sonography in at-risk children between 0 and 6 years of age.16King J Dozois RR Lindor NM Ahlquist DA. Care of patients and their families with familial adenomatous polyposis.Mayo Clin Proc. 2000; 75: 57-67Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 17Giardiello FM Offerhaus JA. Phenotype and cancer risk of various polyposis syndromes.Eur J Cancer. 1995; 31A: 1085-1087Abstract Full Text PDF PubMed Scopus (52) Google Scholar An increased risk of pancreatic adenocarcinoma, cholangiocarcinoma, and thyroid carcinoma has also been reported. The genetic abnormality in FAP is germline defect in APC , a tumor suppressor gene that maps to chromosome 5q21.18Groden J Thliveris A Samowitz W Carlson M Gelbert L Albertsen H et al.Identification and characterization of the familial adenomatous polyposis coli gene.Cell. 1991; 66: 589-600Abstract Full Text PDF PubMed Scopus (2420) Google Scholar APC is a cytoplasmic protein that binds and regulates the degradation of β-catenin, a protein with multiple functions, including regulation of cytoskeletal organization, organization of tissue architecture, cell migration and adhesion, intracellular signaling, and gene transcription.19O'Sullivan MJ McCarthy T Doyle C Familial adenomatous polyposis: from bedside to benchside.Am J Clin Pathol. 1998; 109: 521-526PubMed Google Scholar Although more than 400 APC mutations have been found, most occur in a mutation cluster region located upstream of domains responsible for β-catenin degradation. Thus accumulation of unregulated β-catenin is the likely cellular event leading to tumor development20Chung DC. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis.Gastroenterology. 2000; 119: 854-865Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar (Fig 2).Correlations exist between the location of mutations in the APC gene and the clinical presentation of FAP. For example, attenuated familial adenomatous polyposis coli occurs when a truncating mutation occurs in the extreme 5′ portion of the APC gene. Attenuated familial adenomatous polyposis coli is usually associated with the late onset of fewer than 100 adenomas.21Giardiello FM Brensinger JD Luce MC Petersen GM Cayouette MC Krush AJ et al.Phenotypic expression of disease in families that have mutations in the 5' region of the adenomatous polyposis coli gene.Ann Intern Med. 1997; 126: 514-519Crossref PubMed Scopus (82) Google Scholar Conversely, mutations between codons 1250 and 1464 are associated with a profuse distribution and earlier onset of gastrointestinal polyps.22Gayther SA Wells D SenGupta SB Chapman P Neale K Tsioupra K et al.Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli.Hum Mol Genet. 1994; 3: 53-56Crossref PubMed Scopus (108) Google Scholar APC mutations can be directly detected in peripheral blood lymphocytes by commercially available in vitro protein truncation assays.23Powell SM Petersen GM Krush AJ Booker S Jen J Giardiello FM et al.Molecular diagnosis of familial adenomatous polyposis.N Engl J Med. 1993; 329: 1982-1987Crossref PubMed Scopus (636) Google Scholar These assays detect an APC mutation in more than 80% to 90% of affected families. A negative result in the remaining 10% to 20% may lead to errors in genetic advice if experienced counseling is not utilized.24Giardiello FM Brensinger JD Petersen GM Luce MC Hylind LM Bacon JA et al.The use and interpretation of commercial APC gene testing for familial adenomatous polyposis.N Engl J Med. 1997; 336: 823-837Crossref PubMed Scopus (416) Google Scholar It must be emphasized that results of the protein truncation assay cannot be considered truly negative unless an affected family member has had a positive result. Once a mutation is detected in a kindred, genetic testing of first-degree relatives may discriminate affected from unaffected individuals with virtual certainty.16King J Dozois RR Lindor NM Ahlquist DA. Care of patients and their families with familial adenomatous polyposis.Mayo Clin Proc. 2000; 75: 57-67Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 25Soravia C Berk T Cohen Z. Genetic testing and surgical decision making in hereditary colorectal cancer.Int J Colorectal Dis. 2000; 15: 21-28Crossref PubMed Scopus (27) Google Scholar Early diagnosis of FAP is essential because of the inevitable risk of colorectal carcinoma. Before the availability of genetic testing, screening for the appearance of multiple colorectal polyps by annual or biannual colonoscopic examination in at-risk individuals was suggested beginning at the age of 10 years. Currently, genetic testing is the recommended approach. This strategy is more cost-effective than repeated endoscopic screening.26Bapat B Noorani H Cohen Z Berk T Mitri A Gallie B et al.Cost comparison of predictive genetic testing versus conventional clinical screening for familial adenomatous polyposis.Gut. 1999; 44: 698-703Crossref PubMed Scopus (47) Google Scholar Identification of an APC mutation merits genetic counseling and testing of first-degree relatives. Annual flexible sigmoidoscopy should be performed in persons with a mutant allele. Individuals with negative genetic test results but a family member with an identified APC mutation can be relieved of the burden of annual examinations. In this circumstance, the cancer risk is equivalent to that of the general population, although most experts advocate continued screening by flexible sigmoidoscopy at least every decade, beginning in adolescence.16King J Dozois RR Lindor NM Ahlquist DA. Care of patients and their families with familial adenomatous polyposis.Mayo Clin Proc. 2000; 75: 57-67Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 27Berk T Cohen Z Bapat B Gallinger S. Negative genetic test result in familial adenomatous polyposis: clinical screening implications.Dis Colon Rectum. 1999; 42: 307-312Crossref PubMed Google Scholar Endoscopic screening of the upper gastrointestinal tract should begin whenever colonic adenomas are identified.16King J Dozois RR Lindor NM Ahlquist DA. Care of patients and their families with familial adenomatous polyposis.Mayo Clin Proc. 2000; 75: 57-67Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 25Soravia C Berk T Cohen Z. Genetic testing and surgical decision making in hereditary colorectal cancer.Int J Colorectal Dis. 2000; 15: 21-28Crossref PubMed Scopus (27) Google Scholar Formal recommendations for the timing of genetic testing in children have not been proposed. It seems prudent to apply the "rule of earliest onset," which states that genetic testing should be done at an age no earlier than the age of first possible onset of cancer.28Kodish ED. Testing children for cancer genes: the rule of earliest onset.J Pediatr. 1999; 135: 390-395Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Thus screening of at-risk children should occur at approximately age 8 to 10 years to avoid early stigmatization, discrimination, and the introduction of grief into the parent-child relationship at a time when there is no benefit to the child. Prophylactic total proctocolectomy remains the preferred treatment for patients with FAP. Most experts suggest colectomy soon after polyps are identified.25Soravia C Berk T Cohen Z. Genetic testing and surgical decision making in hereditary colorectal cancer.Int J Colorectal Dis. 2000; 15: 21-28Crossref PubMed Scopus (27) Google Scholar Administration of the nonsteroidal anti-inflammatory drug sulindac has been shown to be effective in reducing the size and number of colonic and rectal polyps in patients with FAP; however, the approach remains investigational because a reduction in cancer risk has not been proven.29Giardello F Hamilton S Krush A Piantadosi S Hylind L Celano P et al.Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis.N Engl J Med. 1993; 328: 1313-1316Crossref PubMed Scopus (1566) Google Scholar Celecoxib, a selective cyclooxygenase-2 (prostaglandin synthetase) inhibitor, reduces by 28% the mean number of polyps in adult patients with FAP.30Steinbach G Lynch PM Phillips RK Wallace MH Hawk E Gordon GB et al.The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.N Engl J Med. 2000; 29 (1946-52): 342Google Scholar The potential use of this class of drugs as chemopreventive and therapeutic agents is the subject of intense current investigation.31Lipsky PE. The clinical potential of cyclooxygenase-2-specific inhibitors.Am J Med. 1999; 106: 51S-57SAbstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Peutz-Jeghers syndrome (OMIM 175200) is an autosomal dominant disorder characterized by mucocutaneous pigmentation and hamartomatous gastrointestinal polyps.32Westerman AM Entius MM de Baar E Boor PPC Koole R Van Velthuysen MLF et al.Peutz-Jeghers syndrome: 78-year follow-up of the original family.Lancet. 1999; 353: 1211-1215Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar The most distinctive clinical feature is dark-brown to blue pigmentation in the lips and buccal mucosa, a finding observed in more than 95% of patients. Pigmentation may be noted early in infancy, long before polyps are diagnosed. Polyps are found in the small intestine (70%-90%), in the colon (50%), and in the stomach. Less commonly, polyps may be located in mucosal surfaces outside the gastrointestinal tract.33McGarrity TJ Kulin HE Zaino RJ. Peutz-Jeghers syndrome.Am J Gastroenterol. 2000; 95: 596-604Crossref PubMed Google Scholar Symptoms such as rectal bleeding, rectal prolapse, and colicky pain caused by recurrent intussusception may begin as early as the first few years of life.34Seara MJ Soto MI Lorenzo JR Trabazo S Gamborino E Vila JF. Peutz-Jeghers syndrome in a neonate.J Pediatr. 1995; 126: 965-967Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Polyps in PJS are benign, hamartomatous lesions with a unique histopathology characterized by a prominent "frond-like" core of stromal tissue and smooth muscle surrounded by a normal-appearing intestinal epithelium. Long-term analysis of 31 patients with PJS demonstrated a 48% incidence of neoplasia, most of which occurred outside the gastrointestinal tract. The relative risk of cancer at any site was estimated to be 18 times that of the general population.35Giardiello FM Welsh SB Hamilton SR Offerhaus GJ Gittelsohn AM Booker SV et al.Increased risk of cancer in Peutz-Jeghers syndrome.N Engl J Med. 1987; 316: 1511-1514Crossref PubMed Scopus (741) Google Scholar Biannual surveillance for small intestinal polyps by small bowel follow-through and upper endoscopy, beginning at age 10, is recommended.25Soravia C Berk T Cohen Z. Genetic testing and surgical decision making in hereditary colorectal cancer.Int J Colorectal Dis. 2000; 15: 21-28Crossref PubMed Scopus (27) Google Scholar, 36Burt RW. Colon cancer screening.Gastroenterology. 2000; 119: 837-853Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar Colonoscopy has been recommended at least every 3 years, beginning in late adolescence. Aggressive annual screening for non-gastrointestinal neoplasia is recommended, beginning in the third decade of life. The defective gene, in at least some cases of PJS, is LKB1 (also termed STK11 ), a serine/threonine kinase located on chromosome 19p13.3.37Wang ZJ Churchman M Avizienyte E McKeown C Davies S Evans DGR et al.Germline mutations of the LKB1 (STK11) gene in Peutz-Jeghers patients.J Med Genet. 1999; 36: 365-368PubMed Google Scholar Although germline mutations were initially reported in 50% to 75% of patients, in a more recent report, LKB1 mutations were found in only 6 of 33 cases,38Boardman LA Couch FJ Burgart LJ Schwartz D Berry R McConnell SK et al.Genetic heterogeneity in Peutz-Jeghers syndrome.Hum Mutat. 2000; 16: 23-30Crossref PubMed Scopus (114) Google Scholar indicating more genetic heterogeneity than originally believed. Most mutations result in frameshifts and production of a truncated, kinase-inactive protein. Although mutational activation of a cellular kinase activity resulting in tumorigenesis is well described, PJS is the first syndrome in which inactivation of a cellular kinase has been found. The cellular function of LKB1 is uncertain, although restoration of normal LKB1 activity in deficient cells results in G1 cell cycle arrest and growth suppression.39Tiainen M Ylikorkala Y Makela TP. Growth suppression by Lkb1 is mediated by a G1 cell cycle arrest.Proc Natl Acad Sci USA. 1999; 96: 9248-9251Crossref PubMed Scopus (265) Google Scholar Cowden syndrome (OMIM 158350) and Bannayan-Riley-Ruvalcaba syndrome (OMIM 174900) are rare disorders characterized by multiple phenotypic abnormalities, hamartomas in the intestine and other tissues, and an autosomal dominant pattern of inheritance.40Hannssen AMN Fryns JP. Cowden syndrome.J Med Genet. 1995; 32: 117-119Crossref PubMed Scopus (161) Google Scholar, 41Fargnoli MC Orlow SJ SemelConcepcion J Bolognia JL. Clinicopathologic findings in the Bannayan-Riley-Ruvalcaba syndrome.Arch Dermatol. 1996; 132: 1214-1217Crossref PubMed Google Scholar Recent genetic studies indicate that the same defective gene causes both syndromes and clinical differences are due to allelic variation. Furthermore, many of the reported cases of familial juvenile polyposis (see below) probably include cases of CS and BRRS. Eng and Ji42Eng C Ji H. Molecular classification of the inherited hamartoma polyposis syndromes: clearing the muddied waters.Am J Hum Genet. 1998; 62: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar emphasized the importance of a detailed evaluation of family history and phenotypic features by physicians who have extensive experience with polyposis syndromes, especially because signs and symptoms may be subtle. Molecular approaches will ultimately allow more concise classification of these phenotypically related syndromes. A mutation in the tumor suppressor gene termed protein tyrosine phosphatase and tensin homologue (PTEN), located on chromosome 10q23,43Tsuchiya KD Wiesner G Cassidy SB Limwongse C Boyle JT Schwartz S. Deletion 10q23.2-q23.33 in a patient with gastrointestinal juvenile polyposis and other features of a Cowden-like syndrome.Genes Chromosomes Cancer. 1998; 21: 113-118Crossref PubMed Scopus (57) Google Scholar accounts for between 10% and 80% of cases.42Eng C Ji H. Molecular classification of the inherited hamartoma polyposis syndromes: clearing the muddied waters.Am J Hum Genet. 1998; 62: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 44Marsh DJ Dahia PLM Caron S Kum JB Frayling IM Tomlinson IPM et al.Germline PTEN mutations in Cowden syndrome-like families.J Med Genet. 1998; 35: 881-885Crossref PubMed Scopus (132) Google Scholar, 45Marsh DJ Dahia PLM Sheng Z Liau D Parsons R Gorlin RJ et al.Germline mutations in PTEN are present in Bannayan-Zonana syndrome.Nat Genet. 1997; 16: 333-334Crossref PubMed Scopus (575) Google Scholar This wide divergence likely represents variation in criteria used for diagnosis.42Eng C Ji H. Molecular classification of the inherited hamartoma polyposis syndromes: clearing the muddied waters.Am J Hum Genet. 1998; 62: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Both the CS and BRRS phenotypes have been found in the context of a PTEN mutation within a single family.46Celebi JT Tsou HC Chen FF Zhang H Ping XL Lebwohl MG. Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family associated with a single germline mutation in PTEN.J Med Genet. 1999; 36: 360-364PubMed Google Scholar The PTEN phosphatase activity appears to regulate cellular growth by inhibition of key growth signaling intermediates such as phosphoinositol 3-kinase. CS is characterized by hamartomas in multiple sites including the skin, breast, thyroid gland, oral mucosa, brain, and gastrointestinal tract. Oral papillomas and facial trichilemmomas are common and highly characteristic. Lipomas, fibromas, and hemangiomas may be observed. Progressive macrocephaly with normal ventricular size may be seen in the first 2 years of life, and mild to moderate mental retardation is seen in about 10% of cases.40Hannssen AMN Fryns JP. Cowden syndrome.J Med Genet. 1995; 32: 117-119Crossref PubMed Scopus (161) Google Scholar The primary cancer risk is carcinoma of the breast and thyroid gland. A gastrointestinal hamartoma is considered a minor criterion in the extensive set of formal criteria required for the diagnosis of CS proposed by the International Cowden Consortium.44Marsh DJ Dahia PLM Caron S Kum JB Frayling IM Tomlinson IPM et al.Germline PTEN mutations in Cowden syndrome-like families.J Med Genet. 1998; 35: 881-885Crossref PubMed Scopus (132) Google Scholar Gastrointestinal polyps may be found in 40% to 60% of patients with CS. These may be typical juvenile polyps, lipomas, ganglioneuromas, adenomas, and prominent lymphoid nodules. The risk of gastrointestinal neoplasia is uncertain, and no recommendations for gastrointestinal screening have been proposed. BRRS, also referred to as Bannayan-Zonana, Riley-Smith, or Ruvalcaba-Myhre-Smith syndrome , is characterized by intestinal hamartomatous polyps, macrocephaly with normal ventricle size, subcutaneous and visceral lipomas, and hemangiomas, pseudopapilledema, cognitive and motor developmental delay, lipid storage myopathy, hypotonia, seizures, and pigmented macules on the penis.41Fargnoli MC Orlow SJ SemelConcepcion J Bolognia JL. Clinicopathologic findings in the Bannayan-Riley-Ruvalcaba syndrome.Arch Dermatol. 1996; 132: 1214-1217Crossref PubMed Google Scholar Approximately one half of patients have intestinal hamartomas. Unlike CS, malignant transformation has not been found in patients with BRRS. Juvenile polyposis (OMIM 174900) is a rare autosomal dominant condition characterized by multiple gastrointestinal hamartomatous polyps in the colon. Patients generally come to medical attention late in childhood or early adolescence with rectal bleeding. In rare cases, large numbers of polyps are distributed throughout the gastrointestinal tract resulting in failure to thrive, anemia, hypoalbuminemia, and abdominal pain early in life (including infancy).47Stiff GJ Alwafi A Jenkins H Lari J. Management of infantile polyposis syndrome.Arch Dis Child. 1995; 73: 253-254Crossref PubMed Scopus (7) Google Scholar Localized involvement in the stomach has also been reported.48Watanabe