A Rare Case of Lhermitte Duclos Disease Associated with Somatic PTEN and Germline SUFU Variants.

Lhermitte-Duclos disease (LDD) is a rare dysplastic gangliocytoma of the cerebellum, typically manifesting as a hamartomatous lesion in the posterior fossa. Currently, LDD has been only linked to PTEN pathogenic variants, with the PI3K/AKT/mTOR pathway acting as the primary signaling cascade responsible for its pathogenesis. We present a case of LDD in which a novel germline heterozygous splice site variant (c.183-2 A > G) in the SUFU gene and a somatic heterozygous missense variant (c.389 G > A) in the PTEN gene, identified from tumor tissue were detected by targeted next-generation sequencing (NGS). SUFU, a tumor suppressor gene, primarily inhibits the hedgehog (Hh) signaling pathway and furthermore influences the AKT/mTOR pathway. Pathogenic variants in SUFU have been linked to medulloblastoma, and their potential role in LDD remains under investigation. Given that both conditions involve granule cell progenitors and are influenced by impaired Hh signaling, they may share a similar developmental path. This is the first research indicating that SUFU may play a role in the etiology of LDD, despite SUFU variants being associated with several central nervous system malignancies. The SUFU variant was shown to disrupt splicing via Sanger sequencing and gel electrophoresis of RNA extracted from blood. Analysis of DNA from tumor tissue using the TWIST Exome 2.0 Panel revealed de novo pathogenic SUFU (c.183-2 A > G) and PTEN (c.389G > A) variants. This paper establishes an initial link between LDD and germline SUFU along with somatic PTEN variants identified from tumor tissue, providing novel insights into the molecular pathogenesis of this rare condition.