PTEN – PTEN Hamartoma Tumor Syndrome

The association between PTEN and PTEN hamartoma tumor syndrome is classified as Definitive. This conclusion is based on the identification of 368 germline PTEN mutation carriers across multiple cohorts (PMID:22252256) with segregation in 131 families (PMID:22595938) and extensive concordant functional studies in both cellular and mouse models.

Genetic Evidence

Inheritance of PTEN hamartoma tumor syndrome is autosomal dominant, with de novo mutations accounting for at least 10.7% of cases and the remainder inherited from an affected parent (PMID:22595938). Segregation analysis demonstrates co-segregation of PTEN variants in 131 additional affected relatives. Case series encompass 368 probands harboring a spectrum of variant classes, including missense (e.g., c.406T>C (p.Cys136Arg)), truncating, splice-site, and frameshift mutations. Macrocephaly is a hallmark, observed in 94% of mutation-positive individuals (mean OFC +4.9 SD) (PMID:21343951).

Functional Evidence

PTEN pathogenic variants lead to loss of lipid phosphatase activity with consequent up-regulation of PI3K/AKT signaling. In vitro phosphoinositide phosphatase assays show >90% reduction of activity for missense mutations in the catalytic domain (PMID:10866302). Mouse models with Pten missense alleles recapitulate megencephaly and tumor predisposition, and reconstitution of wild-type PTEN in PTEN-null tumor cells restores G1 arrest and suppresses angiogenesis in orthotopic models.

Conflicting Evidence

No studies have convincingly refuted the PTEN–PHTS association. Low-level mosaicism may obscure mutation detection in blood but does not alter the established pathogenic link.

Integration and Conclusion

Genetic and experimental findings converge on PTEN haploinsufficiency as the mechanism underlying PHTS. Deep intronic and promoter variants further expand the mutational spectrum beyond coding exons. Early recognition of macrocephaly and mucocutaneous features should prompt PTEN testing to enable cancer surveillance and tailored management.

Key Take-home: PTEN genetic analysis is essential for diagnosing PHTS, guiding surveillance for high lifetime cancer risks, and informing family counseling.

References

• Clinical Cancer Research • 2012 • Lifetime cancer risks in individuals with germline PTEN mutations. PMID:22252256
• Genetics in Medicine • 2012 • Estimate of de novo mutation frequency in probands with PTEN hamartoma tumor syndrome. PMID:22595938
• European Journal of Human Genetics • 2011 • Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model. PMID:21343951
• Cancer Research • 2000 • Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. PMID:10866302

Evidence Based Scoring (AI generated)