Novel Mutation in APC Gene Associated with Multiple Osteomas in a Family and Review of Genotype-Phenotype Correlations of Extracolonic Manifestations in Gardner Syndrome

Gardner syndrome is a neoplasic disease that associates intestinal polyposis and colorectal adenocarcinoma with osteomas and soft tissue tumors determined by germline mutations in the APC gene. The early diagnosis and identification of high-risk individuals are important because patients have a 100% risk of colon cancer. We present the case of a family with Gardner syndrome. Cephalometric, panoramic X-rays and CBCT of the proband and her brother showed multiple osteomas affecting the skull bones, mandible and paranasal sinuses. The detailed family history showed an autosomal dominant transmission with the presence of the disease in the mother and maternal grandfather of the proband. Both had the typical signs of disease and died in the fourth decade of life. Based on these aspects the clinical diagnosis was Gardner syndrome. By gene sequencing, a novel pathogenic variant c.4609dup (p.Thr1537Asnfs*7) in heterozygous status was identified in the APC gene in both siblings. We reviewed literature data concerning the correlation between the localization of mutations in the APC gene and the extracolonic manifestations of familial adenomatous polyposis as well as their importance in early diagnosis and adequate oncological survey of patients and families based on abnormal genomic variants.

48-Year-Old Female MUTYH Carrier Presenting with Five Concurrent Primary Cancers.

Background: MUTYH-associated polyposis (MAP) is a rare, and only recently described disorder resulting from mutations in genes encoding enzymes involved in DNA mismatch repair. These mutations result in an increased susceptibility to colonic adenomatosis as well as a variety of cancers. In current literature, studies have examined the frequencies of extracolonic manifestations of this disorder. However, these manifestations typically occur alone concurrently, or temporally separate from an already diagnosed colorectal cancer in individuals with a bi-allelic mutation. Case Presentation: 48-year-old female with five distinct primary neoplasms presenting simultaneously in a patient mono-allelic for an MYH mutation, and only a single gastrointestinal polyp. Family history included colon, rectal, and lung cancer. Her past medical history included obesity and type 2 diabetes mellitus and a large ventral hernia was noted on examination. She initially presented with a several-month history of an enlarging pruritic labial mass found to represent a high grade squamous intraepithelial neoplasm for which a radical right partial vulvectomy was performed. Final pathology demonstrated a stage IB squamous cell carcinoma. At follow-up, the patient complained of fecal incontinence. To evaluate this, upper and lower endoscopies were performed which demonstrated a large rectal mass representing adenocarcinoma characterized by a low probability of microsatellite instability and an anal mass representing a second adenocarcinoma. An asymptomatic thyroid mass was discovered with pathology demonstrating papillary thyroid carcinoma. During her en bloc surgical resections of previously mentioned malignancies, a left ovarian serous implant of psammocarcinoma was identified. Scattered foci of low-grade serous carcinoma (psammomatous carcinoma) were found within the ventral hernia sac tissue.Conclusions: The disparate and aggressive presentation of this case serves two purposes; to highlight the importance of a thorough workup in patients with oncologic presentations suspicious for genetic aberration, and to highlight how variable expressivity can lead to unpredictable presentations necessitating a broad differential diagnosis.

Solid-pseudopapillary neoplasm of the pancreas in a patient with familial adenomatous polyposis: a case report

Background Familial adenomatous polyposis (FAP) is characterized by the presence of hundreds to thousands of colonic polyps, and extracolonic manifestations are likely to occur. Pancreatic tumors are rare extracolonic manifestations in patients with FAP, among which solid-pseudopapillary neoplasm (SPN) are extremely rare. We report here a patient with an SPN of the pancreas found during the follow-up of FAP. Case presentation A 20-year-old woman was diagnosed with FAP 3 years previously by colonoscopy which revealed less than 100 colonic polyps within the entire colon. She complained of left upper abdominal pain and a 10-cm solid and cystic pancreatic tumor was found by computed tomography scan. Solid and cystic components within the tumor were seen on abdominal magnetic resonance imaging. Simultaneous laparoscopic resection of the distal pancreas and subtotal colectomy was performed. Histopathological findings confirmed the pancreatic tumor as an SPN without malignancy. Abnormal staining of beta-catenin was observed by immunohistochemical study. Multiple polyps in the colorectum were not malignant. Molecular biological analysis from peripheral blood samples revealed a decrease in the copy number of the promoter 1A and 1B region of the APC gene, which resulted in decreased expression of the APC gene. Conclusions A rare association of SPN with FAP is reported. The genetic background with relation to beta-catenin abnormalities is interesting to consider tumor development. So far, there are few reports of SPN in a patient with FAP. Both lesions were treated simultaneously by laparoscopic resection.

Molecular basis of familial adenomatous polyposis in the southeast of Brazil: identification of six novel mutations

Background: The goal of this study was to screen point mutations and deletions in APC and MUTYH genes in patients suspected of familial adenomatous polyposis (FAP) in a Brazilian cohort. Methods: We used high-resolution melting, Sanger direct sequencing and multiplex ligation-dependent probe association (MLPA) assays to identify point mutations, and large genomic variations within the coding regions of APC and MUTYH genes. Results: We identified 19 causative mutations in 40 Brazilian patients from 20 different families. Four novel mutations were identified in the APC gene and two in the MUTYH gene. We also found a high intra- and inter-familial diversity regarding extracolonic manifestations, and gastric polyps were the most common manifestation found in our cohort. Conclusion: We believe that the FAP mutational spectrum can be population-specific and screening FAP patients in different populations can improve pre-clinical diagnosis and improve clinical conduct.

Giant adrenal cavernous hemangioma in a patient with familial adenomatous polyposis

Adrenal hemangioma is an uncommon benign vascular tumor that is often discovered incidentally. It has never been reported in association with familial adenomatous polyposis. We report a case of a 60-year old man with a history of familial adenomatous polyposis, in whom a huge retroperitoneal cyst of 18×17 cm was discovered during routine radiologic evaluation. Because of the impossibility of ruling out the presence of malignancy, surgical cystectomy was performed, associated to a scheduled total colectomy. Pathological examination revealed that the cyst corresponded to an adrenal cavernous hemangioma. Colonic adenomas did not show signs of degeneration. Screening for adenomatous polyposis coli (<em>APC</em>) gene mutation was not carried out. As familial adenomatous polyposis is known to involve a variety of extracolonic manifestations, this finding raises the suspicion of a possible variant of this syndrome including adrenal hemangioma. An extensive study based on a larger patient series with genetic exploration is necessary.

Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis

Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli ( APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1+) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1+ cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.