PTEN – Cowden Disease

Cowden disease is an autosomal dominant hamartoma-tumor syndrome characterized by mucocutaneous lesions, macrocephaly and elevated risks of breast, thyroid and endometrial carcinomas. Germline variants in PTEN underlie most cases of Cowden disease, establishing PTEN as the principal causal gene (PMID:9140396).

PTEN-related Cowden disease follows an autosomal dominant inheritance pattern with both familial and de novo mutations. Initial linkage and mutational analyses in five pedigrees identified germline truncating and missense mutations in four families (PMID:9140396), and subsequent screens confirmed PTEN mutations in over 70% of classic Cowden syndrome patients (PMID:9832031).

Genetic evidence includes >200 unrelated probands with diverse PTEN variant classes—missense, nonsense, frameshift, splice-site and intragenic deletions—with recurrent hotspots and de novo events. Notable examples include c.386G>T (p.Gly129Val) in exon 5. Segregation across multiple pedigrees demonstrates co-segregation in at least 19 affected relatives.

Functional assays of PTEN missense mutants confirm loss of lipid phosphatase activity and failure to regulate the PI3K/AKT pathway. The Gly129Glu change abolishes PIP₃ dephosphorylation, fails to suppress PKB/Akt and does not induce G₁ arrest in vitro (PMID:9811831; PMID:10051603).

In vivo, reconstitution of wild-type PTEN into PTEN-null tumor models reduces tumor growth and angiogenesis, whereas lipid phosphatase-deficient mutants lack this effect, underscoring the necessity of PTEN catalytic function for tumor suppression in Cowden disease.

Collectively, extensive familial segregation, a broad variant spectrum and concordant functional data meet ClinGen criteria for a Definitive gene–disease association. No substantive conflicting evidence has been reported.

Key Take-home: Germline PTEN testing is essential for individuals with Cowden disease features to enable tailored surveillance and proactive risk-reduction strategies.

References

• Nature Genetics • 1997 • Germline mutations of the PTEN gene in Cowden disease PMID:9140396
• Journal of Medical Genetics • 1998 • Germline PTEN mutations in Cowden syndrome–like families PMID:9832031
• Experimental Dermatology • 1999 • Identification of PTEN mutations in five families with Bannayan-Zonana syndrome PMID:10232405
• Proceedings of the National Academy of Sciences • 1998 • The lipid phosphatase activity of PTEN is critical for its tumor supressor function PMID:9811831
• Proceedings of the National Academy of Sciences • 1999 • Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway PMID:10051603

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