AXIN2 – Oligodontia-Cancer Predisposition Syndrome

Heterozygous pathogenic variants in AXIN2 are implicated in oligodontia-cancer predisposition syndrome (ODCRCS), a disorder marked by congenitally missing teeth and increased colorectal cancer risk, often accompanied by sparse hair, ectodermal dysplasia features, and in cases of de novo variation, developmental anomalies. Initial reports linked truncating AXIN2 mutations to autosomal dominant oligodontia with variable colorectal polyposis and early-onset carcinomas, while recent precision animal modeling has expanded the phenotypic spectrum to include microcephaly, global developmental delay, and limb and ophthalmologic abnormalities.

Genetic studies have identified four unrelated individuals with de novo missense variants in the tankyrase-binding domain of AXIN2: c.196G>A (p.Glu66Lys) and c.199G>A (p.Gly67Arg), each disrupting Axin2:tankyrase interaction and WNT signaling (PMID:39677486). In addition, a multi-generation family segregates an autosomal dominant truncating variant c.1989G>A (p.Trp663Ter) with oligodontia, colorectal polyposis, gastric and breast neoplasms in multiple affected members (PMID:21416598).

Inheritance follows an autosomal dominant pattern, with at least five unrelated probands (four de novo, one familial) and segregation in a family with four additional affected relatives ([PMID:39677486]; [PMID:21416598]). The variant spectrum includes recurrent truncating alleles in the DIX domain and missense changes within the tankyrase-binding region. Phenotypic mapping encompasses oligodontia (HP:0000688), colorectal cancer predisposition (HP:0009509), microcephaly (HP:0000252), global developmental delay (HP:0001263), limb anomalies (HP:0040064), and ophthalmologic abnormalities (HP:0000478).

Functional assays demonstrate that p.Glu66Lys and p.Gly67Arg variants lead to context-dependent WNT pathway dysregulation: structural modeling predicts disrupted AXIN2:tankyrase binding, prime editing in mice yields perinatal lethality with craniofacial and skeletal defects, and Drosophila models reveal dual gain- and loss-of-function effects on Wnt signaling ([PMID:39677486]). The p.Trp663Ter truncation abolishes the DIX domain, leading to loss of inhibitory control over β-catenin in cell-based reporter assays.

No conflicting evidence has been reported to date. The convergence of de novo and familial genetic findings, together with concordant functional modeling in human, mouse, and fly, supports a strong clinical validity for AXIN2 in ODCRCS.

Key Take-home: AXIN2 should be included in genetic testing panels for patients with familial or sporadic oligodontia and colorectal cancer predisposition, as pathogenic variants inform diagnosis, surveillance, and family counseling.

References

• American Journal of Medical Genetics Part A • 2011 • AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome PMID:21416598
• medRxiv • 2025 • Uncovering Phenotypic Expansion in AXIN2-Related Disorders through Precision Animal Modeling PMID:39677486

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