General description

Lhermitte–Duclos disease (LDD), also known as dysplastic cerebellar gangliocytoma, is a rare, benign hamartomatous overgrowth of cerebellar ganglion cells most often driven by germline PTEN mutations. Mutations in the tumor suppressor gene PTEN on chromosome 10q23 are identified in a substantial subset of patients with LDD. Loss of PTEN function disinhibits the PI3K–AKT–mTOR signaling cascade, resulting in uncontrolled cell proliferation and aberrant neuronal migration within the cerebellar cortex. These germline mutations often occur in the context of PTEN hamartoma tumor syndrome, which includes Cowden syndrome; up to 30% of LDD cases coexist with Cowden syndrome.

Clinical manifestations

Symptoms vary with lesion size, location, and mass effect but commonly include:

• Headache, nausea, vomiting due to increased intracranial pressure from posterior fossa mass effect and obstructive hydrocephalus.
• Cerebellar signs: Ataxia, dysmetria, dysdiadochokinesia, vertigo, and gait disturbances.
• Cranial nerve deficits: Diplopia, facial numbness, or nystagmus when lesions impinge on adjacent brainstem or cranial nerve root entry zones.
• Macrocephaly may be present, particularly in pediatric cases associated with Cowden syndrome.
• Onset is most frequent in the third to fourth decades, but pediatric and late-adult presentations occur.

Cowden syndrome

The pathophysiology of Cowden syndrome is characterized by the development of multiple hamartomas—benign, disorganized overgrowths of tissue native to the organ of origin—in various organs, including the skin, breast, thyroid, gastrointestinal tract, and central nervous system (including Lhermitte-Duclos disease). These hamartomas reflect the underlying disruption in cell cycle regulation and tissue architecture due to PTEN dysfunction. The syndrome is also associated with a markedly increased risk of developing malignancies, particularly of the breast, thyroid, and endometrium. Macrocephaly and other developmental abnormalities are frequently observed, especially in patients with more destabilizing PTEN mutations.

Abnormalities in Cowden Syndrome

• Macrocephaly: 84%
• Benign mucocutaneous lesions: 77%
• Lipomas: 47%
• Penile pigmentation: 47% (male)
• Gastrointestinal lesions: 40%
• Benign breast tumors: 38%
• Goiter: 38%
• Breast cancer: 32% (female)
• Uterine fibroids: 20% (female)
• Intellectual disability: 17%
• Endometrial cancer: 13% (female)
• Thyroid cancer: 8%
• Renal/gastrointestinal cancers, Lhermitte-Duclos disease: 3%

References

1. Monjarás-Romo, Gonzalo, et al. "Lhermitte-Duclos disease: a case series." Cureus 15.8 (2023).
2. Pilarski, Robert, et al. "Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome clinical features." Journal of medical genetics 48.8 (2011): 505-512.