Familial Adenomatous Polyposis Syndrome Research Articles

Early Detection of CHRPE and Subsequent Familial Adenomatous Polyposis Syndrome by Ultra-Wide Field Retinal Laser Scanning Technology

Introduction: Congenital hypertrophy of the retinal pigment epithelium (CHRPE) has been associated with familial adenomatous polyposis (FAP) and may be the first presenting feature of the disease process. This case presents the diagnosis of CHRPE by ultra-wide field retinal laser scanning technology. A 68-year-old male who was seen in the outpatient ophthalmologic care setting for post-op follow-up 1 month after photorefractive keratectomy (PRK) of OU in both eyes and correction of retinal detachment (RD) of the (OS) left eye. This patient has also previously tolerated phacoemulsification (PE) and intraocular lens placement (IOL), with open capsule for a cataract and Lasik surgery of OU without complication. Patient came in with complaints of his distance vision not being as clear as before the RD. Near is closer in the OS than before. Post-op follow up included ultra-wide field retinal laser scanning that reveal an OS peripheral CHRPE, and vitelliform dystrophy. We recommended IOL and referred the patient to oncology and gastrotroenterology, where he was diagnosed and treated as a new incident case of FAP. The most common and very first extracolonic manifestation is CHRPE, with reports of expression in 36-90% of FAP kindred, and with a specificity of 95% for being a carrier of the APC tumor suppressor gene deletion that leads to FAP. This tumor suppressor gene was identified at the long arm of chromosome 5 (5q21). Guidelines using older technology recommended that patients with more than 3 CHRPE in 1 eye or bilateral CHRPE, as well as patients with a positive family history and 1 unilateral CHRPE require further gastroenterological evaluation. In the future, the use of ultra-wide field retinal laser technology may detect CHRPE earlier than standard diagnostics, and subsequently lead to timely care for FAP.Figure 1

Molecular analysis of the APC gene in Sicilian patients with familial adenomatous polyposis (F.A.P.)

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome, caused by germline mutations in the adenomatous polyposis coli (APC) suppressor gene. Patients with colorectal polyps are more likely to develop a malignant condition with poor prognosis. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extra-colonic manifestations; an attenuated form of polyposis (AFAP), presenting less than 100 adenomas and later onset, has been reported.In this study we have examined five Sicilian families affected by FAP syndrome, in order to provide predictive genetic testing for the affected families, as well as to contribute to mutation catalog enrichment.We have detected different APC mutations in these five pedigrees, confirming the remarkable heterogeneity of the mutational spectrum in FAP.

Sporadic giant mesenteric fibromatosis.

Mesenteric fibromatosis is an uncommon tumour which is locally aggressive without any metastatic potential and can occur as a sporadic event or in association with familial adenomatous polyposis syndrome. Giant mesenteric fibromatosis is very rare and is a diagnostic and therapeutic challenge. This is a case report of a rare presentation of deep fibromatosis as a sporadic giant intrabdominal mesenteric tumour in a 29year old male managed by surgical excision and definitive diagnosis made on the basis of immunohistochemical findings.

Familial Adenomatous Polyposis–Associated, Cribriform Morular Variant of Papillary Thyroid Carcinoma Harboring a K-RAS Mutation: Case Presentation and Review of Molecular Mechanisms

The cribriform morular variant of papillary thyroid carcinoma (CMVPTC) is a rare subtype of papillary thyroid cancer that occurs most often in association with the familial adenomatous polyposis (FAP) syndrome. A 18-year-old woman presented with recurrence of PTC in her neck. She had a prior diagnosis of FAP syndrome. Review of her original pathology slides reclassified the case as a CMVPTC. The tumor was examined for the four most common mutations found in PTC: BRAF, RET/PTC, RAS, and PAX/PPARγ. The molecular alterations associated with CMVPTC involve the WNT signaling pathway but are incompletely understood. When CMVPTC is associated with the FAP syndrome, a germline adenomatous polyposis coli (APC) gene mutation is almost always detected. For the initiation of oncogenesis however, one or more additional molecular alterations must occur, such as a new somatic mutation in the APC gene (biallelic inactivation), somatic mutations in the β-catenin (CTNNB1) gene, or gene-gene interaction (epistasis). To date, of the mutations commonly associated with PTC, only RET/PTC mutations have been reported in CMVPTC. We report a FAP-associated CMVPTC tumor with atypically aggressive features harboring a RAS mutation and review the molecular mechanisms associated with this interesting PTC subtype. The literature was reviewed using MEDLINE (included case presentations, original research, and reviews). We report here the first RAS mutation detected in an FAP-associated CMVPTC tumor.

Tu1893 MUTYH Mutations and Variants in Jews of North-African Origin With or Without Minimal Colorectal Adenomatous Polyposis

Background: Israeli-Jews of North-African origin are ~ 1/6 of the Israeli population, and have been considered as a low-risk population for colorectal cancer (CRC). In recent years CRC risk has been increased in this population. However, the contributing genetic susceptibility is currently unknown. Mutations in the MUTYH gene, which cause multiple colorectal adenomas and early onset colon cancer, might play a role in their increased CRC risk. Objectives: Evaluate frequency and types of MUTYH mutations and variants in a population of Jews fromNorth-African origin having colorectal adenomas and early onset CRC. Methods: The study population included North-African Jews having colonoscopy between 2007-12, having ≥3 colorectal adenomas and/or CRC, and were matched to controls having normal colonoscopy. Germ-line DNA was tested for a panel of 6 MUTYH mutations or variants and Sanger sequencing of the entire MUTYH gene for heterozygotes. Familial Adenomatous Polyposis (FAP) and Lynch Syndrome were excluded in the relevant cases. Results: 99 subjects, 69 with adenomas had MUTYH analysis; 19 (27.5%) had mutations or variants identified. In adenoma patients there were eight homozygotes or compound heterozygotes to either Y179C or G396D mutations: all had >10 adenomas and 5 had familial neoplasia. Six others were heterozygotes to only one mutation: 4 with 10 adenomas; 5 had familial neoplasia and 3 a neoplasm. Four subjects found as S512F heterozygotes: two had 10 adenomas. Two heterozygotes had the Q324H variant. In 23 non-adenoma controls: 1 had the S512F another the L417M variant, another the R509C variant and 16 the Q324H variant. Conclusions: MUTYH mutations are prevalent among Jews of North-African origin having colonic adenomas and/or early onset CRC. The clinical phenotype can be associated with only few adenoma and with family and personal history of cancer similar to sporadic CRC. The S512F mutation appears to be pathogenic, the Q324H a frequent variant that was not found to be associated with adenomas. The findings suggest MUTYH evaluation in these patients with even few adenomas, and need to follow-up heterozygotes carriers for CRC.

A potential life-saving diagnosis—recognizing Turcot syndrome

A previously healthy 9-year-old girl presented with ataxia, headaches, and nausea of 1 month's duration. Magnetic resonance imaging demonstrated a large posterior fossa mass. Posterior segment examination revealed pigmented ocular fundus lesions (POFLs), which included cometoid dark lesions with depigmented tails and smaller, dark midperipheral lesions. The patient underwent resection for a medulloblastoma. Because of these specific retinal lesions in combination with her medullobastoma, a diagnosis of Turcot syndrome was made and subsequently confirmed by genetic testing. Turcot syndrome is one of the familial adenomatous polyposis (FAP) syndromes. This diagnosis may be life-saving because 100% of FAP patients develop colon cancer that can be cured only early with timely colectomy.

Recurrences are common after endoscopic ampullectomy for adenoma in the familial adenomatous polyposis (FAP) syndrome

Endoscopic ampullectomy is increasingly performed in patients with familial adenomatous polyposis (FAP)-associated ampullary adenomas. We sought to define the procedure-associated morbidities and long-term outcomes. We performed a retrospective chart review of patients with FAP who underwent endoscopic ampullectomy at two tertiary institutions between 1999 and 2010. The severity of duodenal polyposis was classified according to Spigelman's classification. Of 26 FAP patients who underwent endoscopic ampullectomy, 21 arose in the setting of Spigelman's stage II duodenal polyposis. Adverse events associated with endoscopic ampullectomy included acute pancreatitis (19.2%), abdominal pain (7.6%), and bleeding (3.8%). The mean resected adenoma size was 0.99 ± 0.34 cm. Three adenomas (12.0%) contained foci of high-grade dysplasia. Follow-up data were available for 24 patients. The mean follow-up duration was 84.5 ± 36.2 months. Adenoma recurrence was observed in 14 patients (58.3%; 14/24) at a mean of 38.3 months after initial ampullectomy. Adenomas ≥10 mm recurred more frequently than smaller adenomas (76.9 vs. 36.4%; p = 0.002). Positive margins were not associated with higher recurrence rates. No cancers were observed during long-term follow-up. Three patients underwent a Whipple procedure, but none was performed for a recurrent ampullary adenoma. Endoscopic ampullectomy in FAP can be performed safely. Because ampullary adenomas frequently recur after endoscopic ampullectomy, close surveillance is essential. Smaller tumors are less likely to recur, suggesting a benefit for early recognition of these lesions.

Microsatellite Instability Testing in Colorectal Carcinoma: A Practical Guide

In this month’s “Road Ahead” article, we continue last month’s theme that focused on the role of pathology in the care of our GI patients. Many gastroenterologists have successfully incorporated pathology into their core practices either within a business infrastructure or as part of a larger health care system. Dr Gibson and her colleagues at Yale University School of Medicine have helped inform us about a particularly difficult management problem: how to handle the genetically high-risk patients we see frequently in our hospitals and endoscopy units. New comprehensive practice guidelines concerning management of hereditary colon cancer syndromes are in development, but this short article provides a clear and concise guide for the practicing gastroenterologist.

Early gastric adenocarcinoma arising from a gastric adenoma in a patient with familial adenomatous polyposis syndrome

Familial adenomatous polyposis (FAP) is a rare hereditary syndrome characterized by multiple colorectal polyps and early development of colorectal cancer. Although FAP uniformly involves the large bowel, it may also produce lesions in the stomach and upper intestinal tract. Management of the risk of development of upper gastrointestinal cancer is one of the greatest challenges faced by clinicians involved in the care of polyposis families. We present the case of a 45-year-old woman with FAP who developed gastric cancer early post proctocolectomy. A gastric adenoma with moderate atypia was detected during the upper gastrointestinal endoscopic screening performed prior to the colorectomy. However, 14 months later, the gastric adenoma had progressed to early gastric cancer. In FAP patients living in East Asia, gastric adenoma is a high risk factor for gastric cancer and shows rapid progression. Therefore, it is important in FAP patients detected to have gastric adenomas, to perform upper gastrointestinal endoscopy in the short term and to resect any gastric adenomas, regardless of their tissue grade.

Intestinal flora of FAP patients containing APC-like sequences.

Colorectal cancer mortality is one of the most common cause of cancer-related mortality. A multiple risk factors are associated with colorectal cancer, including hereditary, enviromental and inflammatory syndromes affecting the gastrointestinal tract. Familial adenomatous polyposis (FAP) is characterized by the emergence of hundreds to thousands of colorectal adenomatous polyps and FAP syndrome is caused by mutations within the adenomatous polyposis coli (APC) tumor suppressor gene. We analyzed 21 rectal bacterial subclones isolated from FAP patient 41-1 with confirmed 5bp ACAAA deletion within codons 1060-1063 for the presence of APC-like sequences in longest exon 15. The studied section was defined by primers 15Efor-15Erev, what correlates with mutation cluster region (MCR) in which the 75% of all APC germline mutations were detected. More than 90% homology was showed by sequencing and subsequent software comparison. The expression of APC-like sequences was demostrated by Western blot analysis using monoclonal and polyclonal antibodies against APC protein. To study missing link between the DNA analysis (PCR, DNA sequencing) and protein expresion experiments (Western blotting) we analyzed bacterial transcripts containing the 15Efor-15Erev sequence of APC gene by reverse transcription-PCR, what indicated that an APC gene derived fragment may be produced. We observed 97-100 % homology after computer comparison of cDNA PCR products. Our results suggest that presence of APC-like sequences in intestinal/rectal bacteria is enrichment of bacterial genetic information in which horizontal gene transfer between humans and microflora play an important role.

Genetics of thyroid lesions updated

Advances in research into molecular biology of thyroid cancers have made exciting progress in the understanding of genetic pathways of the cancers. Despite the huge amount of genetic information of thyroid cancers, only a few genetic changes are of clinical value in the current settings. The best known genetic change is the roles of RET mutation in the diagnosis of the familial form of medullary thyroid carcinoma. The other important mutation of some clinical use is the detection of BRAF mutation in papillary thyroid carcinoma. BRAF mutation is associated with aggressive pathological parameters, radioiodine-refractory and increased cancer mortality. Other than these genetic changes in thyroid cancer, familial predisposition of non-medullary thyroid carcinoma is beginning to emerge. This includes a group that is syndromic which is characterized by predominance of non-thyroidal tumours such as familial adenomatous polyposis and PTEN hamartoma syndromes. The other group non-medullary thyroid carcinoma includes familial syndromes of thyroid cancers. Greater than 85% of these are papillary thyroid carcinoma. Overall, new genetic information continues to emerge in thyroid cancers and applications of the information would be expected in the diagnosis, prognosis and molecular target therapies.

Identification of an APC Variant in a Patient with Clinical Attenuated Familial Adenomatous Polyposis.

Introduction. The objective of this case report is to discuss an unclassified germline variant of the adenomatous polyposis coli (APC) gene identified in an older patient with attenuated familial adenomatous polyposis syndrome (AFAP). Methods. We present a case report of a 66-year-old man diagnosed with AFAP. Colonoscopy found multiple polyps and invasive adenocarcinoma arising in the transverse colon. Samples were tested for mutations in the APC gene. Results. DNA sequencing of germline DNA identified a cytosine (C) to thymine (T) transition at nucleotide 1240, heterozygous. The C to T transition at codon 414 is predicted to convert an arginine residue to a cysteine that is possibly pathogenic. Analysis of the patient's colon tumor DNA indicated that the tumor had lost the mutant variant allele and retained only the normal allele, suggesting that the variant may not be significant. Conclusions. The p.R414C variant has been described previously as a germline mutation of probable pathogenicity. This substitution should be considered an unclassified variant and possibly not pathogenic. These findings support the need for further genetic testing of tissue, as well as for developing a mechanism for testing all variants, as this could significantly impact the lives of patients and their family members.

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)

Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis is manifested as colonic polyposis caused by mutations in the APC gene and is also inherited in an autosomal dominant manner. Finally, MYH-associated polyposis is caused by mutations in the MUTYH gene and is inherited in an autosomal recessive manner but may or may not be associated with polyps. There are variants of both familial adenomatous polyposis (Gardner syndrome--with extracolonic features--and Turcot syndrome, which features medulloblastoma) and Lynch syndrome (Muir-Torre syndrome features sebaceous skin carcinomas, and Turcot syndrome features glioblastomas). Although a clinical diagnosis of familial adenomatous polyposis can be made using colonoscopy, genetic testing is needed to inform at-risk relatives. Because of the overlapping phenotypes between attenuated familial adenomatous polyposis, MYH-associated polyposis, and Lynch syndrome, genetic testing is needed to distinguish among these conditions. This distinction is important, especially for women with Lynch syndrome, who are at increased risk for gynecological cancers. Clinical testing for these genes has progressed rapidly in the past few years with advances in technologies and the lower cost of reagents, especially for sequencing. To assist clinical laboratories in developing and validating testing for this group of inherited colorectal cancers, the American College of Medical Genetics and Genomics has developed the following technical standards and guidelines. An algorithm for testing is also proposed.

Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome

The British Society of Gastroenterology recommends that all familial adenomatous polyposis (FAP) and Lynch syndrome (LS) families are screened in the context of a registry. This systematic review was performed to appraise the published evidence for registration and screening in relation to colorectal cancer (CRC) incidence and mortality. Five electronic databases were searched using a combination of medical subject heading terms and free-text keywords. Titles and abstracts were scrutinized by two independent reviewers. Inclusion criteria were English-language studies describing CRC incidence and/or mortality in patients with FAP or LS, with comparison of either: screened and unscreened patients, or time periods before and after establishment of the registry. Of 4668 abstracts identified, 185 full-text articles were selected; 43 studies fulfilled the inclusion criteria. No randomized clinical trial evidence was identified. For FAP, 33 of 33 studies described a significant reduction of CRC incidence and mortality with registration and screening. For LS, nine of ten studies described a reduction of CRC incidence and mortality with registration and screening. Five studies (FAP, 2; LS, 3) provided evidence for complete prevention of CRC-related deaths during surveillance. Clinical and statistical heterogeneity prevented pooling of data for meta-analysis. Studies consistently report that registration and screening result in a reduction of CRC incidence and mortality in patients with FAP and LS (level 2a evidence, grade B recommendation). Funding and managerial support for hereditary CRC registries should be made available.

The natural history of familial adenomatous polyposis syndrome: A 24 year review of a single center experience in screening, diagnosis, and outcomes

PurposeUnderstanding the natural history of Familial Adenomatous Polyposis (FAP) will guide screening and aid clinical management. MethodsPatients with FAP, age ≤20years presenting between 1987 and 2011, were reviewed for presentation, diagnosis, extraintestinal manifestations, polyp burden, family history, histology, gene mutation, surgical intervention, and outcome. ResultsOne hundred sixty-three FAP patients were identified. Diagnosis was made by colonoscopy (69%) or genetic screening (25%) at mean age of 12.5years. Most children (58%) were asymptomatic and diagnosed via screening due to family history. Rectal bleeding was the most common (37%) symptom prompting evaluation. Colon polyps appeared by mean age of 13.4years with >50 polyps at the time of diagnosis in 60%. Cancer was found in 1 colonoscopy biopsy and 5 colectomy specimens. Family history of FAP was known in 85%. 53% had genetic testing, which confirmed APC mutation in 88%. Extraintestinal manifestations included congenital hypertrophy of the retinal pigment epithelium (11.3%), desmoids (10.6%), osteomas (6.7%), epidermal cysts (5.5%), extranumerary teeth (3.7%), papillary thyroid cancer (3.1%), and hepatoblastoma (2.5%). Six patients died secondary to FAP. ConclusionsClinical presentation and manifestations in pediatric FAP are variable. We suggest an individualized patient-oriented screening algorithm that allows for earlier screening and appropriate management.

Giant Inflammatory Pseudopolyp of the Duodenum

Purpose: Duodenal polyps are an uncommon finding. Typically, duodenal polyps are frequently seen in patients with genetic syndromes such as familial adenomatous polyposis syndrome, but also may occur sporadically. Unless large enough to cause symptoms, duodenal polyps are often discovered incidentally on upper endoscopy. Once discovered, therapeutic management depends on patient symptoms, histology, and/or size of the polyp. Management may include observation, endoscopic removal, or surgery. Here, we present a case of an unusually large duodenal pseudopolyp with unique histological features. We describe the management and course of the polyp over a 3-year time period. A 59-year-old male with a past medical history significant for prior myocardial infarction, diabetes and hyperlipidemia was referred by his gastroenterologist for evaluation of a large 4 cm duodenal polyp (not involving the ampulla) that encompassed one half the circumference of his duodenal lumen. Approximately 2 weeks prior, he underwent an upper endoscopy for an upper gastrointestinal bleed (attributed to a small gastric vessel) at which time this large polyp was incidentally discovered. Review of outside pathology reports were concerning for an adenomatous polyp with low-grade dysplasia. Upon review of the biopsy specimen by a pathologist at our institution, the polyp was found to consist of benign small bowel mucosa with non-specific inflammatory and reactive epithelial atypia with no definitive dysplasia. Due to the concerning size of this duodenal polyp, the patient subsequently underwent an MRI and upper endoscopy. MRI revealed no extra duodenal involvement and once again, biopsy revealed benign duodenal mucosa with chronic inflammation and reactive changes with no dysplasia. Following these investigational tests, general surgery was subsequently consulted for recommendations concerning surgical management. Due to the benign histology of the polyp, conservative measures with close observation were recommended. Thus, a follow up EGD with EUS was performed 8 weeks later. EUS demonstrated slight involvement of the submucosa and histology revealed reactive and regenerative changes with no malignancy. The patient continued to have regular surveillance with five upper endoscopies over the past 3 years. His most recent endoscopy has revealed a significant reduction in polyp size with biopsy showing benign mucosa, normal villous architecture and no active inflammation. There has been no progression to dysplasia or malignancy. This case highlights an unusual finding of a giant inflammatory pseudopolyp with unique histological features and the role of conservative management.

Adolescent and Young Adult Colorectal Cancer

Although the overall incidence of colorectal cancer (CRC) in adolescents and young adults (AYAs) is low, it has seen an increase over the past 2 to 3 decades, which contrasts with the trend of decreased incidence in the older population. This phenomenon is conceivably caused by a lack of routine CRC screening in the young population and lifestyle issues, including the obesity epidemic and dietary factors. Hereditary genetic syndromes (eg, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer syndrome) and known predisposing medical conditions (eg, inflammatory bowel disease) account for only a minority of CRC cases in AYA. Younger patients with CRC commonly present with more advanced disease at diagnosis and exhibit specific molecular and clinical characteristics associated with a distinct biologic phenotype of CRC compared with older individuals. Matched for stage, however, the prognosis of patients with young-onset CRC is similar to or better than that for older patients. A surprising paucity of data exists on outcomes associated with modern systemic cytotoxic and biologic therapy specifically in young patients with CRC. The toxicity pattern of these treatments, however, differs between young and older patients, partly because of the lower rate of pertinent comorbidities in younger adults. Issues regarding surgical management in the setting of hereditary syndromes and fertility preservation while on therapy are of particular importance to the younger patient population. Future studies should seek to increase understanding of the distinct tumor biology of AYA patients with CRC and the consequences of treatment interventions to optimize outcomes for this population.

Malignant Intraductal Papillary Mucinous Neoplasms of the Pancreas in Two Identical Twins

Context Intraductal papillary mucinous neoplasm (IPMN) is a rare pancreatic tumor defined as intraductal mucin-producing neoplasm with tall, columnar, mucin-producing epithelium. IPMNs have already been described in association with inherited genetic disorder including familial adenomatous polyposis and Peutz-Jeghers syndrome. However, description of familial history of IPMN is very rarely reported. We present two cases of malignant IPMN in identical twins. Case report A 54-year-old woman was admitted in August 2010 with epigastric pain and high serum levels of amylase and lipase. Abdominal CT revealed dilation of main pancreatic duct (5 mm) with multiple cysts in the head of the pancreas. Serum CA 19-9 was in the normal range, and positron emission tomography with CT acquisition (PET/CT) was negative. A diagnosis of mixed type IPMN was made, and the patient underwent pancreatico­duodenectomy. Pathologic examination showed a tubular, poorly differentiated adenocarcinoma, tubular type, in combined type IPMN (pancreatico-biliary type) of the head of the pancreas with high grade dysplasia (pT3N0M0 G3). Postoperative course was uneventful, and the patient underwent adjuvant chemo-radiotherapy. Three years after surgery, there was no evidence of tumor relapse. Her sister, a 57-year-old woman, was admitted in February 2013 for obstructive jaundice and weight loss. Serum CA 19-9 was 86.2 U/mL. Magnetic resonance of the abdomen showed a 4.8 cm, pluricystic mass of the head of the pancreas, with marked dilation (10 mm) of the main pancreatic duct. FNAC under EUS examination showed mucinous epithelial cells with low-moderate dysplasia. PET/CT revealed a pathologic uptake of the radiotracer in the pancreatic head and in the right colon. Colonoscopy did not show colonic lesions. In March 2013 the patient underwent pylorus-preserving pancreaticoduodenectomy. Pathologic examination showed a colloid, poorly differentiated adenocarcinoma in main duct IPMN (intestinal type) of the head of the pancreas (pT3N0M0G3). Adjuvant therapy with gemcitabine was started, and the patient is alive 3 months after operation, without tumor relapse. Conclusion Although rare, the coexistence of IPMN reported here in two identical twins, suggests that it is due to a genetic inherited factor that remains to be elucidated. Physicians should carefully study the familial history of patients with IPMN.

A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia

Truncating mutations in the AXIN2 gene, a key regulator of β-catenin degradation in the Wnt pathway, have been reported in three families with gastrointestinal adenomatous polyposis and features of ectodermal dysplasia. However, the role of AXIN2 in familial adenomatous polyposis (FAP) syndrome is not completely understood. We performed an in-depth study of APC and MUTYH, and ruled out their implication in 23 FAP families. We then investigated the role of other genes involved in the Wnt pathway, including AXIN2, and identified a novel missense variant in AXIN2 in one family with attenuated FAP. Carriers of the variant exhibited a variable number of polyps but none showed any sign of ectodermal dysplasia. We have demonstrated the pathogenicity of this novel variant by establishing its low frequency in controls as well as by LOH analysis, a segregation study, and immunofluorescent staining of AXIN2 and β-catenin proteins. This report expands the phenotype known to be related to AXIN2 alterations and raises the question of whether to screen AXIN2 in FAP cases negative for alterations in APC and MUTYH.

Multifocal Hepatic Neoplasia in 3 Children With APC Gene Mutation

Hepatoblastoma (HB), the most common hepatic neoplasm in children is associated with germline mutations in adenomatous polyposis coli tumor-suppressor gene that cause familial adenomatous polyposis syndrome. Individuals with familial adenomatous polyposis have a 750 to 7500× the risk of developing HB. We report 3 children with APC gene mutation, who underwent resection or liver transplant for HB. In addition to HB, all 3 patients had multiple independent adenoma-like nodules lacking qualities of intrahepatic metastases. Twenty-five nodules were subjected to immunohistochemical analysis using a panel of antibodies including glypican-3 (GPC3), β-catenin, cytokeratin AE1/AE3, CD34, Ki-67, glutamine synthetase (GS), and fatty acid binding protein. The nodules were round, ranged in size from 0.2 to 1.5 cm, and paler than the background liver. All lacked the chemotherapy effect. The nodules were circumscribed but nonencapsulated and composed of well-differentiated hepatocytes with occasional minor atypical features and absent or rare portal tracts. One lesion displayed a "nodule-within-nodule" pattern. The nodules demonstrated diffuse GS overexpression. Nine (36%) nodules were focally reactive for GPC3, and 1 (4%) displayed focal nuclear β-catenin expression. The associated HB showed diffuse expression of GS, GPC3, and β-catenin nuclear staining. We interpret these nodules as neoplastic with most being adenomas (GPC3 negative) that show features of independent origin and represent early stages of carcinogenesis, implying potential to progress to HB or hepatocellular carcinoma. To our knowledge, this is the first report of multifocal neoplasms in patients with HB and APC gene mutation.