PTEN – Lhermitte-Duclos Disease

PTEN encodes a dual-specificity phosphatase that negatively regulates the PI3K/AKT/mTOR pathway, acting as a tumor suppressor in multiple tissues. Loss-of-function germline variants in PTEN underlie Cowden syndrome and are also found in Lhermitte-Duclos disease (LDD), a dysplastic cerebellar gangliocytoma presenting with ataxia, macrocephaly, and hydrocephalus. LDD has a characteristic "tiger stripe" appearance on MRI and can manifest sporadically or in the context of PTEN-related hamartoma syndromes.

Genetic evidence supports an autosomal dominant inheritance of LDD due to heterozygous PTEN variants. A three-generation family demonstrated co-segregation of a nonsense PTEN variant with LDD and Cowden features (2 additional affected relatives) (PMID:8071972). In a cohort of 18 unrelated adult-onset LDD cases, 15 (83%) harbored germline PTEN mutations, all predicted to disrupt phosphatase function (PMID:14566704). Additional series and case reports have identified both recurrent and unique PTEN missense (e.g., c.335T>C (p.Leu112Pro)) and truncating variants (e.g., c.469G>T (p.Glu157Ter)).

Segregation in multiple pedigrees and the diversity of variant classes—including nonsense, frameshift, splice, and missense—fulfill strong genetic criteria. Recurrent founder alleles are not evident, but hot-spot exons 5 and 8 frequently yield catalytic core mutations. Penetrance for LDD among PTEN mutation carriers is high in adulthood, with variable expressivity of cerebellar symptoms and intracranial hypertension.

Functional studies demonstrate that loss of PTEN lipid phosphatase activity leads to AKT hyperactivation and mTOR pathway-driven cerebellar granule cell hypertrophy. Immunohistochemistry of LDD lesions shows elevated phospho-AKT and phospho-S6 in dysplastic gangliocytes, paralleling models in which Pten deletion in murine cerebellum recapitulates LDD pathology (PMID:15835270). In vitro assays confirm that PTEN variants such as p.Gly129Glu abrogate lipid phosphatase function and fail to inhibit cell proliferation (PMID:9811831).

Although rare sporadic LDD cases lack detectable PTEN mutations—particularly in pediatric-onset forms—the preponderance of adult LDD with PTEN variants and concordant functional data supports a causative role. No robust conflicting evidence has been reported, but isolated early-onset LDD may represent alternate genetic mechanisms or mosaicism.

In summary, germline PTEN haploinsufficiency is a definitive mechanism for Lhermitte-Duclos disease in the context of Cowden syndrome. Clinical genetic testing for PTEN should be pursued in all adult LDD patients, guiding surveillance for associated neoplasms. Key Take-home: PTEN mutation analysis is clinically actionable for diagnosis, family counseling, and targeted monitoring in LDD.

References

• Journal of medical genetics • 1994 • Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy? PMID:8071972
• American journal of human genetics • 2003 • Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults. PMID:14566704
• Nature genetics • 1997 • Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. PMID:9140396
• Journal of neuropathology and experimental neurology • 2005 • Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway. PMID:15835270
• 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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