PTEN – Proteus-like Syndrome

Proteus-like syndrome is a rare subset of PTEN hamartoma tumor syndrome (PHTS) characterized by asymmetric overgrowth, lipomas, and neurodevelopmental anomalies without the full spectrum of Proteus syndrome. Germline heterozygous variants in PTEN (HGNC:9588) have been repeatedly identified in individuals meeting clinical criteria for Proteus-like presentations, establishing a robust gene–disease relationship. The disease follows an autosomal dominant pattern consistent with other PHTS disorders.

Autosomal dominant inheritance of Proteus-like syndrome is supported by segregation of PTEN variants in multiplex families and de novo occurrences in sporadic cases. In one kindred, a novel PTEN c.402G>A (p.Met134Ile) variant was found in multiple affected relatives presenting with macrocephaly and mild learning disabilities without classical PHTS tumors ([PMID:23124040]). Across independent cohorts, germline PTEN mutations are detected in approximately 50% of Proteus-like syndrome cases, supporting strong genetic evidence ([PMID:12938083]).

The PTEN variant spectrum in Proteus-like syndrome encompasses missense mutations predominantly within the phosphatase domain, truncating variants leading to loss of function, and rare splicing defects. To date, over ten distinct germline variants have been reported, including recurrent changes at Met134, Cys124/Thr remodelling residues, and stop-gain mutations affecting the C2 domain. The prototypic c.402G>A (p.Met134Ile) variant exemplifies a missense change disrupting enzymatic activity and familial transmission dynamics.

Functional studies demonstrate that PTEN missense mutants abrogate lipid phosphatase activity and downstream AKT regulation, elucidating the mechanism of haploinsufficiency in PHTS. For example, the p.Gly129Glu variant sharply reduces inositol phospholipid dephosphorylation and fails to rescue PI3K/AKT–mediated cell growth assays, confirming concordant functional evidence ([PMID:9811831]). Animal and cellular models further recapitulate overgrowth phenotypes when PTEN is inactivated.

No conflicting reports have refuted the primary role of PTEN in Proteus-like syndrome; rather, genotype-phenotype correlations continue to refine variant pathogenicity and expressivity. Existing data exceed the threshold for maximum ClinGen scoring, underscoring a definitive association.

Key Take-home: Germline PTEN variants cause Proteus-like syndrome through loss of lipid phosphatase function, justifying PTEN testing in patients with asymmetric overgrowth and guiding surveillance akin to Cowden syndrome.

References

• Gene • 2013 • Novel PTEN germline mutation in a family with mild phenotype: difficulties in genetic counseling. PMID:23124040
• Human Mutation • 2003 • PTEN: one gene, many syndromes. PMID:12938083
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • The lipid phosphatase activity of PTEN is critical for its tumor supressor function. PMID:9811831

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