Megalocephaly
Conditions
Keywords
Megalencephaly, tumor, Etiology
Brief summary
This study will show the value of early genetic diagnosis in the case of MEG in a child and may lead to recommendations aimed at preventing tumor risk based on a simple and easily accessible clinical criterion (the measurement of head circumference). Ultimately, this study may improve cancer prognosis in the population of children with MEG.
Detailed description
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.
Interventions
None listed
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Inclusion criteria
1. Patients with macrocephaly ≥ +3 DS due to brain MRI-confirmed MEG with or without NDD 2. Patient with a proposal to investigate a genetic etiology by genome sequencing 3. No objection by the patient's parents or guardians 4. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Characterization of the etiologies of MEGs associated with tumor risk in 200 children with or without NDD, who underwent genome sequencing. | Within 6 Months after last patient inclusion | The investigator will study the diagnostic performance, i.e. the proportion in the sample of class 4 (probably pathogenic) or 5 (pathogenic) variants according to the American College of Medical Genetics (ACMG) classification |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To compare the diagnostic returns of the 2 patient groups | Within 6 Months after last patient inclusion | — |
| To establish a ranking of the yields of the 9 known MEG genes associated with tumor risk | Within 6 Months after last patient inclusion | The investigator will do a descriptive analysis of the number of variants, their relative and absolute frequency.risk |
| To identify the nature and frequency of other genetic causes of MEG, apart from the 9 targeted genes | Within 6 Months after last patient inclusion | The investigator will do a descriptive analysis of the number of variants, their relative and absolute frequency.risk |
| To establish genotype-phenotype correlations in the different etiologies found | Within 6 Months after last patient inclusion | A descriptive analysis will be performed without statistical assumptions. |
Countries
France
Contacts
Primary ContactSolveig HEIDE, medical doctor
Backup ContactCyril MIGNOT, medical doctor
Outcome results
None listed