A novel pathogenic frameshift variant in AXIN2 in a man with polyposis and hypodontia.

BACKGROUND: WNT signaling is pivotal in embryogenesis and tissue homeostasis. Aberrant WNT signaling, due to mutations in components of this pathway, contributes to the development and progression of human cancers, including colorectal cancer. AXIN2, encoded by the AXIN2 gene, is a key negative regulator and target of the canonical WNT signaling pathway. Germline mutations in AXIN2 are associated with absence of permanent teeth (hypo- and oligodontia) and predisposition to gastrointestinal polyps and cancer. The limited number of patients makes an accurate genotype-phenotype analysis currently challenging. CASE PRESENTATION: We present the case of a 55-year-old male with colorectal polyposis and hypodontia. Genetic testing confirmed a novel frameshift germline mutation in exon 8 of the AXIN2 gene. In addition, we provide an updated overview of germline AXIN2 mutations reported in literature. CONCLUSIONS: Although the number of missing teeth is less severe in our patient than in some previously reported cases, our findings provide additional evidence that missing teeth and gastrointestinal neoplasia are associated with rare pathogenic AXIN2 germline mutations.

Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome.

INTRODUCTION: Hyperplastic polyposis syndrome (HPS) is characterised by the presence of multiple colorectal hyperplastic polyps and is associated with an increased colorectal cancer (CRC) risk. For first-degree relatives of HPS patients (FDRs) this has not been adequately quantified. Reliable evidence concerning the magnitude of a possible excess risk is necessary to determine whether preventive measures, like screening colonoscopies, in FDRs are justified. AIMS AND METHODS: We analysed the incidence rate of CRC in FDRs and compared this with the general population through person-year analysis after adjustment for demographic characteristics. Population-based incidence data from the Eindhoven Cancer Registry during the period 1970-2006 were used to compare observed numbers of CRC cases in FDRs with expected numbers based on the incidence in the general population. RESULTS: A total of 347 FDRs (41% male) from 57 pedigrees were included, contributing 11 053 person-years of follow-up. During the study period, a total of 27 CRC cases occurred among FDRs compared to five expected CRC cases (p<0.001). The RR of CRC in FDRs compared to the general population was 5.4 (95% CI 3.7 to 7.8). Four FDRs satisfied the criteria for HPS. Based on the estimated HPS prevalence of 1:3000 in the general population the projected RR of HPS in FDRs was 39 (95% CI 13 to 121). CONCLUSIONS: FDRs of HPS patients have an increased risk for both CRC and HPS compared to the general population. Hence, as long as no genetic substrate has been identified, screening colonoscopies for FDRs seem justified but this needs to be prospectively evaluated.