Hereditary central nervous system (CNS) tumour syndromes

CNS tumours are a histologically heterogeneous group of WHO-classified neoplasms. Clinical presentation is highly variable and reflects tumour site, size, and growth rate. Symptoms commonly include focal neurological deficits, raised intracranial pressure, seizures, or endocrine disturbance, depending on anatomical location. In paediatric oncology, CNS tumours represent the second most common malignancy. Hereditary forms are recognised across the age spectrum: paediatric onset is particularly enriched in cancer-predisposition contexts, while adult-onset hereditary forms also occur. The spectrum of hereditary CNS tumours includes gliomas, subependymal giant-cell astrocytomas, medulloblastomas, haemangioblastomas, schwannomas, and meningiomas. The pathological pattern guides clinical suspicion of an underlying predisposition syndrome and selection of confirmatory molecular testing.

Due to insufficient data, no reliable statement on prevalence can currently be made. In paediatric cohorts, 8.6% of CNS tumours were associated with a cancer-predisposition syndrome.

A large number of genes have been associated with CNS tumours. Hereditary CNS tumours often occur in the context of recognised cancer-predisposition syndromes such as (NF1), (TP53), (SDHA, SDHAF2, SDHB, SDHC and SDHD), rhabdoid tumor predisposition syndromes (SMARCA4 and SMARCB1) and (VHL).

The genetic conditions associated with CNS tumours follow heterogeneous inheritance patterns. Most recognised cancer-predisposition syndromes implicated in hereditary CNS tumours are inherited in an autosomal dominant manner, while a smaller subset follows an autosomal recessive pattern. De novo pathogenic variants are well-documented for several of the dominant syndromes.

• Where CNS tumours are suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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