Neuroimaging abnormalities and genotype–phenotype correlations in Noonan syndrome: a multicenter cohort study
Year: 2026
Type: article
Study design: Observational Study
Abstract: CONTEXT: Neuroradiological findings in Noonan syndrome (NS) remain insufficiently characterized. OBJECTIVE: To characterize neuroimaging abnormalities in children with genetically confirmed NS and evaluate their associations with clinical phenotype. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter retrospective study, brain MRI scans and longitudinal clinical and genetic data were reviewed from children with genetically confirmed NS evaluated between 2008 and 2023 at seven pediatric endocrinology centers. MAIN OUTCOME MEASURES: Prevalence and spectrum of neuroimaging abnormalities and their associations with genotype and clinical features. RESULTS: The cohort included 130 individuals with NS (71 males; mean age at MRI, 9.7 years), most carrying PTPN11 variants (69.2%). Structural brain abnormalities were identified in 84.7% and included midbrain-hindbrain malformations (69.2%), callosal anomalies (52.3%), cortical malformations (50%), white matter abnormalities (48.4%), and cranio-cervical junction anomalies (40%). Brain tumors and Chiari I malformation were present in 12.3% and 10.7%, respectively. Seizures were associated with cortical tumors (p = 0.02) and callosal anomalies (p = 0.03), whereas developmental delay was associated with callosal anomalies (p = 0.02) and microcephaly (p < 0.01). Follow-up MRI, available in 41 patients over a mean duration of 6.3 years, showed interval changes in 48.7%, including tumor progression, progressive tonsillar descent, odontoid retroversion, and newly detected lesions. CONCLUSIONS: In this selected cohort of children with NS who underwent brain MRI as part of routine clinical care, structural brain abnormalities were frequent and were associated with neurological manifestations. These findings support a role for RAS/MAPK pathway dysregulation in brain development and highlight the clinical value of MRI in selected patients with NS.
Authors: Giuseppa Patti, Nadia Gabriella Maiorano, Francesca Piccoli, Alice Zucconi, Maria Grazia Calevo, Federica Tamburrino, Emanuela Scarano, Concetta Schiavariello, Cesare Rossi, Laura Mazzanti, Eleonora Orlandini, Gabriella Pozzobon, Martina Finamore, Cristina Baldoli, Anna Grandone, Mario Cirillo, Francesca Aiello, Domenico Corica, Malgorzata Wasniewska, Alessandro Cattoni, Paolo Remida, Donatella Capalbo, Fabio Tortora, Maria Carolina Salerno, Sara Azzolini, Mariam Mansour, Maria Felicia Faienza, Stefano Palladino, Domenico Tortora, Giulia Rosti, Francesca Faravelli, Cristina Venturino, Pasquale Capuozzo, Letizia De Mori, Paola Maietta, Anna Elsa Maria Allegri, Chiara Morreale, Alessia Angelelli, Flavia Napoli, Natascia Di Iorgi, Andrea Rossi, Mohamad Maghnie, Mariasavina Severino
Institutions: Istituto Giannina Gaslini, University of Genoa, Ospedale regionale di Lugano, IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola, University of Bologna, IRCCS Ospedale San Raffaele, University of Campania "Luigi Vanvitelli", University of Messina, Federico II University Hospital, University of Naples Federico II, Ospedale San Bortolo, University of Bari Aldo Moro, Ospedale Pediatrico Giovanni XXIII, University of Insubria
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,750
Funders: Ministero della Salute, Novo Nordisk
OpenAlex ID: W7204475739
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