Quantitative Assessment of the Etiologies of Megalencephaly Associated With a Detectable Tumor Risk

During paediatric follow-up, head circumference (CP) measurement can detect severe macrocephaly (CP ≥ +3 SD) in 1% of the population, in individuals with or without neurodevelopmental disorder (NDD). After prescribing brain imaging showing excess brain growth or megalencephaly (MEG), pediatricians can refer patients to expert centers (Rare Disease Reference Centers) for an etiologic search for MEG. Genome sequencing is then prescribed by pediatric neurologists or geneticists as part of the "cerebral malformations" pre-indication (Plan France Genomic Medicine 2025).

In the literature, more than 70 genetic causes of MEG have been identified, 9 of which are responsible for pathologies associated with a sufficiently high tumor risk (>5%) to justify recommendations for regular screening, specific to each pathology ((Cowden, Simpson-Golabi-Behmel syndrome, Gorlin syndrome, neurofibromatosis type 1, variant in the DICER1 gene).

These genetic diseases are inconsistently associated with NDD (about 50%) and require specific follow-up to improve the oncological prognosis. The absence of an etiological diagnosis in these patients is potentially damaging and represents a theoretical loss of opportunity with regard to tumor risk. There are no large studies investigating the etiologies of MEGs, so the incidence of pathologies with tumor risk in this population remains unknown, with the exception of PTEN gene mutations, identified in 10% of patients with TND and MEG. This study will indicate the incidence of mutations in genes with tumor risk, which may eventually justify modifying current paediatric practice by recommending early etiological testing for MEGs.

Inclusion criteria

• Patients with macrocephaly ≥ +3 DS due to brain MRI-confirmed MEG with or without NDD
• Patient with a proposal to investigate a genetic etiology by genome sequencing
• No objection by the patient's parents or guardians
• Patients affiliated to a social security scheme

Exclusion criteria

• Patients with an etiological diagnosis of its MEG
• Patients who have previously undergone genetic testing as part of their MEG, with or without a diagnosis
• Patients who have not received the standard-of-care genetic analysis, specifically whole genome sequencing