Polymnia Galiatsatos

Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is an autosomal-dominant colorectal cancer syndrome, caused by a germline mutation in the adenomatous polyposis coli (APC) gene, on chromosome 5q21. It is characterized by hundreds of adenomatous colorectal polyps, with an almost inevitable progression to colorectal cancer at an average age of 35 to 40 yr. Associated features include upper gastrointestinal tract polyps, congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and other extracolonic malignancies. Gardner syndrome is more of a historical subdivision of FAP, characterized by osteomas, dental anomalies, epidermal cysts, and soft tissue tumors. Other specified variants include Turcot syndrome (associated with central nervous system malignancies) and hereditary desmoid disease. Several genotype–phenotype correlations have been observed. Attenuated FAP is a phenotypically distinct entity, presenting with fewer than 100 adenomas. Multiple colorectal adenomas can also be caused by mutations in the human MutY homologue (MYH) gene, in an autosomal recessive condition referred to as MYH associated polyposis (MAP). Endoscopic screening of FAP probands and relatives is advocated as early as the ages of 10–12 yr, with the objective of reducing the occurrence of colorectal cancer. Colectomy remains the optimal prophylactic treatment, while the choice of procedure (subtotal vs proctocolectomy) is still controversial. Along with identifying better chemopreventive agents, optimizing screening of extracolonic cancers and applying new radiological and endoscopic technology to the diagnosis and management of extracolonic features are the major challenges for the future.

Meta-analysis of Outcome of Cytomegalovirus Colitis in Immunocompetent Hosts

There are only a few anecdotal reports of cytomegalovirus (CMV) colitis in immunocompetent hosts. The impact of the disease in this patient population remains poorly understood. The aim of this study was to perform a meta-analysis using individual patient data to determine outcomes of CMV colitis in immunocompetent patients and identify risk factors that might influence prognosis. A literature search was performed from 1980 to 2003 looking for immunocompetent patients with CMV colitis. Immunocompetence was defined as absence of congenital or acquired immune deficiency, transplant, or immunosuppressive medication. Patients were divided by age (< 55 versus ≥55) and grouped according to coexisting illnesses. Kaplan–Meier curves were plotted to assess survival. Variables included age, sex, site of acquisition of infection, extent of disease, coexisting illnesses, and treatment modality. A total of 44 patients were identified, with an average age of 61.1. Only 10 were free of any comorbidity. The mean follow-up was 13.4 months. Spontaneous remission occurred in 31.8%, mostly individuals < 55 years old. Fourteen deaths occurred, all of which were in patients ≥55. There was a higher mortality rate among male patients ≥55 (56.9%; P = 0.08), patients with immune-modulating diseases (75.2%; P = 0.10), and those having a colectomy (68.9%; P = 0.09). This analysis underlines the rarity of CMV colitis in patients with an intact immune system. Advanced age, male gender, presence of immune-modulating comorbidities, and need for surgical intervention are factors negatively influencing survival. Conversely, young healthy patients have a good prognosis with no intervention.

Autistic enterocolitis: fact or fiction?

Autism spectrum disorder refers to syndromes of varying severity, typified by impaired social interactions, communicative delays and restricted, repetitive behaviours and interests. The prevalence of autism spectrum disorders has been on the rise, while the etiology remains unclear and most likely multifactorial. There have been several reports of a link between autism and chronic gastrointestinal symptoms. Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia and focally enhanced gastritis compared with controls. Postulated mechanisms include aberrant immune responses to some dietary proteins, abnormal intestinal permeability and unfavourable gut microflora. Two autism spectrum disorder patients with chronic intestinal symptoms and abnormal endoscopic findings are described, followed by a review of this controversial topic.

High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families.

Lynch syndrome is one of the most common autosomal dominantly inherited cancer syndromes. Mutations in MLH1, MSH2, MSH6, and PMS2 account for greater than 98% of reported mutations in Lynch syndrome families. It has been reported that large genomic deletions in MLH1 and MSH2 are a frequent cause of Lynch syndrome in certain populations. Using a multimodal approach, we have identified mutations in MLH1, MSH2, and MSH6 in French Canadian families fulfilling the Amsterdam criteria for Lynch syndrome and who displayed abnormal staining for at least one of the Lynch syndrome proteins. Mutations were identified in 28 of our 29 French Canadian probands (97%). A total of 18 distinct mutations (nine in MLH1, seven in MSH2, two in MSH6) were identified, of which six (33%) were genomic exon deletions. Another four (22%) resulted in exon deletions in cDNA alone. Three (17%) are novel mutations. Five of these 18 mutations were detected in more than one distinct family (four in MLH1, one in MSH2) and haplotype analysis suggests the possibility of founder effects. Fifteen of the 29 (52%) families carried one of these five putative founder mutations. These findings may simplify genetic testing for Lynch syndrome in French Canadians.

Acinic cell carcinoma of the retromolar trigone region: expanding the tumor phenotype in Cowden syndrome?

ABSTRACTCowden syndrome (CS) is a cancer predisposition syndrome caused by germline mutations in the PTEN tumor suppressor gene. It is associated with an increased risk of thyroid, breast and endometrial cancer but many manifestations can be found in the head and neck region, some of which are pathognomonic. Here we report a 35-year-old male referred by his dentist for evaluation of a lesion located near the retromolar trigone. Comprehensive clinical examination revealed papillomatous skin lesions, macrocephaly and gingival hypertrophy. Histopathological examination of the lesion showed an acinic cell carcinoma (ACC) of minor salivary gland origin. Analysis of the PTEN gene identified a germline R130Q mutation in exon 5, confirming the diagnosis of CS, but no loss of heterozygosity was seen in DNA extracted from tumor tissue. This is to our knowledge the first case describing an association of ACC of the minor salivary gland with a PTEN-gene related disorder. It emphasizes the importance of head and neck examination in these patients.

Multiple primary malignancies in a patient with situs ambiguus

To the Editor: Mrs D. is a 59 years old white female, with multiple metachronous cancers. She was initially diagnosed with stage I adenocarcinoma of the sigmoid colon at age 41. Over subsequent years, she had roughly 30 additional villous and tubulovillous adenomas, excised endoscopically and surgically. At 57, she had a second focally invasive adenocarcinoma of the transverse colon, treated by subtotal colectomy. There were no hyperplastic or hamartomatous colorectal polyps. Aside from gastrointestinal neoplasms, Mrs D. was also diagnosed with bladder (transitional cell) cancer at 47, a benign meningioma of the frontal lobe and a basal cell carcinoma of the right cheek at 48, a moderately differentiated squamous cell carcinoma of unknown primary affecting a cervical lymph node at 55 and a stage I invasive ductal carcinoma of the right breast (ER/PR positive, HER2/neu negative) at the age of 58 years. The patient’s past medical history included hypertension, dyslipidaemia, intradermal nevi and multiple seborrheic keratoses. At age 49, an incidental diagnosis of abdominal heterotaxia was made, on a CT scan performed to evaluate post-operative pain. The findings included a centrally placed liver, with a right-sided stomach, as well as multiple right-sided spleens. The heart was noted to be in its usual left-sided position. There was no extensive family history of cancer or laterality disorders, aside from her father who had gastric cancer at 53, and a maternal aunt with breast cancer at 70. Immunohistochemistry of both colonic cancers and several colonic polyps revealed no loss of expression of MLH1, MSH2, MSH6 or PMS2 gene products, implicated in the hereditary non-polyposis colorectal cancer syndrome (HNPCC). Protein truncation testing (PTT) of stored blood RNA also failed to identify any truncating mutations in MLH1, MSH2, or MSH6 genes. No adenomatous polyposis coli (APC) gene mutations were found by PTT or DNA sequencing. Full sequencing of the MYH gene, associated with multiple colorectal adenomas, also failed to identify mutations. Karyotyping using G and Q-banding was normal (46, XX). There were no disease-causing BRCA1 or BRCA2 mutations (Myriad Genetics Laboratory). TP53 is currently under investigation.

A Case of Mistaken Lipoma

Question: A 52-year-oldwoman with no past medical history presented for further evaluation of a 2-year history of intermittent melena. She initially presented to her primary physician 2 years prior with pica and fatigue and was found to have iron-deficiency anemia. Evaluation had included upper endoscopy with small bowel biopsy, colonoscopy, and abdominal comuted tomography (CT), which were unrevealing. She was placed on oral iron supplementation and did well for a short period of time; owever, the episodes of melena increased. A small-bowel-follow-through and a capsule endoscopy were performed and were normal. Her nemia became transfusion dependent and she was referred to our clinic. Physical examination was unremarkable except for conjunctival allor. CT enterography showed a 2-cm enhancing mass in the jejunum (Figure A, arrow). The patient underwent laparoscopic jejunal esection at which time a pedunculated polyp was removed (Figure B). What is the cause of her obscure gastrointestinal (GI) bleeding and what historical information is important for the future care f this patient? Look on page 1533 for the answer and see the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information n submitting your favorite image to Clinical Challenges and Images in GI. Conflicts of interest: The authors disclose no conflicts.

Low yield of gastroscopy in patients with Lynch syndrome

BACKGROUND/AIMS Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in mismatch-repair genes. Besides a lifetime risk of colorectal cancer averaging 70%-80%, there is an increased risk of extracolonic tumors including gastric cancer. The utility of screening gastroscopy in Lynch syndrome has long been debated. This study aimed to determine the proportion of abnormal gastroscopies among patients screened, including the incidence of gastric cancer and prevalence of precursor lesions. MATERIALS AND METHODS Charts of patients with mutation-proven Lynch syndrome between January 1, 2004, and December 31, 2014, from the Genetics clinic and Hereditary Gastrointestinal Cancer Clinic of our institution were retrospectively reviewed. RESULTS A total of 66 Lynch syndrome patients were identified. Thirty-two gastroscopies were performed in 21 (32%) of them. No gastric cancers were found. The prevalence of precursor lesions (Helicobacter pylori gastritis, atrophic gastritis, and gastric intestinal metaplasia) was 19.05%. A family history of gastric cancer was associated with a non-significant increased risk of abnormal gastroscopy, while sex and specific gene involved did not affect the abnormality rate. CONCLUSION Gastric screening in asymptomatic individuals with Lynch syndrome is probably best reserved for high-risk individuals, based on the family history and perhaps ethnicity as suggested by several governing bodies. Larger studies are required to achieve the statistical power necessary to address this controversial issue.

Colonic manifestation of a haematologic disorder

A 32year-old female presenting with right lower quadrant pain was found to have caecal varices. Extensive work-up revealed underlying protein C deficiency.

Using a family history questionnaire to identify adult patients with increased genetic risk for sarcoma.

BACKGROUND Sarcomas in adults can be associated with hereditary cancer syndromes characterized by early-onset predisposition to numerous types of cancer. Because of variability in familial presentation and the largely unexplained genetic basis of sarcomas, ascertainment of patients for whom a genetics evaluation is most indicated poses challenges. We assessed the utility of a Sarcoma Clinic Genetic Screening (scgs) questionnaire in facilitating that task. METHODS Between 2008 and 2012, 169 patients (median age: 53 years; range: 17-88 years) completed a self-administered scgs questionnaire. A retrospective chart review was completed for all respondents, and descriptive statistics were reported. Probands were divided into two groups depending on whether they did or did not report a family history of Li-Fraumeni syndrome-type cancers. RESULTS A family history of cancer (as far as 3rd-degree relatives) was reported in 113 of 163 sarcoma patients (69%). Eeles Li-Fraumeni-like (lfl) criteria were fulfilled in 46 probands (28%), Chompret lfl in 21 (13%), Birch lfl in 8 (5%), and classic Li-Fraumeni in none. In the 10 probands tested for TP53 mutations, 1 pathogenic mutation was found. Further investigation of selected families led to the discovery of germline mutations in MLH1, MSH2, and APC genes in 3 individuals. CONCLUSIONS The scgs questionnaire was useful for ascertaining probands with sarcoma who could benefit from a genetic assessment. The tool allowed us to identify high-risk families fitting the criteria for lfl and, surprisingly, other hereditary cancer syndromes. Similar questionnaires could be used in other cancer-specific clinics to increase awareness of the genetic component of these cancers.