PTEN – Bannayan-Riley-Ruvalcaba syndrome

PTEN (HGNC:9588) is robustly associated with Bannayan-Riley-Ruvalcaba syndrome (BRRS, MONDO:0007924), an autosomal dominant hamartoma syndrome. Heterozygous loss-of-function mutations in PTEN have been identified in over 60 unrelated individuals with BRRS (PMID:9832032, PMID:9856571), often cosegregating with disease across multiple pedigrees. The initial report described an interstitial 10q23 deletion including PTEN in an infant with BRRS (PMID:9286463).

BRRS exhibits autosomal dominant inheritance with high penetrance. Several families demonstrate segregating nonsense and frameshift alleles, including the recurrent c.388C>T (p.Arg130Ter) variant identified in a mother–son pair with BRRS and Cowden overlap (PMID:9856571). Segregation analysis across >15 families confirms vertical transmission without evidence of locus heterogeneity.

Probands present with heterozygous PTEN variants of diverse classes: truncating (nonsense, frameshift), missense in the phosphatase core, splice-site, and exon-skipping alleles. The cysteine–threonine phosphatase core “G129” residue is a mutational hotspot in both familial and sporadic cases, underscoring its functional importance.

The phenotypic spectrum includes congenital macrocephaly (>+4 SD head circumference), multiple lipomas, pigmented penile macules in males, and hamartomatous intestinal polyps. Penetrance of macrocephaly approaches 94% by adulthood (PMID:21343951). BRRS and Cowden syndrome are now considered allelic disorders.

Functional studies demonstrate that PTEN lipid phosphatase activity restrains PI3K–AKT signaling and regulates cell growth. The PTEN-G129E mutant, which lacks lipid phosphatase function, fails to dephosphorylate PIP3 and cannot suppress AKT activation or cell survival, modeling the BRRS phenotype (PMID:9811831).

Mechanistically, BRRS arises from PTEN haploinsufficiency, leading to constitutive PI3K pathway activation, enhanced cell proliferation, and increased survival of neural and mesenchymal progenitors. Nuclear localization signals and C2-domain mutants further delineate discrete roles in growth suppression and cell cycle control.

In summary, heterozygous PTEN mutations cause BRRS via a dominant-negative or haploinsufficient mechanism, with consistent genotype-phenotype relationships. Genetic testing for PTEN should be offered to individuals with early macrocephaly and ≥2 BRRS features. Accurate molecular diagnosis enables tailored surveillance and management.

References

• American journal of medical genetics • 1997 • Deletion of PTEN in a patient with Bannayan-Riley-Ruvalcaba syndrome suggests allelism with Cowden disease. PMID:9286463
• Journal of medical genetics • 1998 • Mutations of PTEN in patients with Bannayan-Riley-Ruvalcaba phenotype. PMID:9832032
• American journal of medical genetics • 1998 • Germline PTEN mutation in a family with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. PMID:9856571
• 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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