Neuroimaging Abnormalities and Genotype-Phenotype Correlations in Noonan Syndrome: A Multicenter Cohort Study

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.

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Journal
The Journal of Clinical Endocrinology & Metabolism
Published
2026-08-27
DOI
https://doi.org/10.1210/clinem/dgag352
Primary Topic
Protein Tyrosine Phosphatases
Type
article
Field-Weighted Citation Impact
0.00

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article

Neuroimaging Abnormalities and Genotype-Phenotype Correlations in Noonan Syndrome: A Multicenter Cohort Study

Anna Elsa Maria Allegri, Domenico Corica, Domenico Tortora, Mohamad Maghnie et al.
The Journal of Clinical Endocrinology & Metabolism
Protein Tyrosine Phosphatases
article

Neuroimaging Abnormalities and Genotype-Phenotype Correlations in Noonan Syndrome: A Multicenter Cohort Study

Anna Elsa Maria Allegri, Domenico Corica, Domenico Tortora, Mohamad Maghnie, Eleonora Orlandini, Cristina Baldoli, Alessia Angelelli, Natascia Di Iorgi, Sara Azzolini, Concetta Schiavariello, Maria Felicia Faienza, Giulia Rosti, Paolo Remida, Stefano Palladino, Maria Carolina Salerno, Maria Grazia Calevo, Pasquale Capuozzo, Flavia Napoli, Alessandro Cattoni, Mariasavina Severino, Chiara Morreale, Emanuela Scarano, Cesare Rossi, Giuseppa Patti, Laura Mazzanti, Mario Cirillo, Anna Grandone, Mariam Mansour, Donatella Capalbo, Andrea Rossi, Cristina Venturino, Nadia Gabriella Maiorano, Francesca Faravelli, Letizia Mori, A. Zucconi, Paola Maietta, Gabriella Pozzobon, Francesca Aiello, Federica Tamburrino, Martina Finamore, Fabio Tortora, Francesca Piccoli, Malgorzata Wasniewska
article en

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.

The Journal of Clinical Endocrinology & Metabolism
University of Messina (IT), University of Insubria (IT), Vita-Salute San Raffaele University (IT), Istituto Giannina Gaslini (IT), San Raffaele University of Rome (IT), Ospedale regionale di Lugano (CH), Azienda Ospedaliera San Gerardo (IT), Azienda USL di Bologna (IT), University of Campania "Luigi Vanvitelli" (IT), Ospedale Pediatrico Giovanni XXIII (IT), Ospedale San Bortolo (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Bari Aldo Moro (IT), University of Naples Federico II (IT), University of Genoa (IT), University of Bologna (IT)
Ministero della Salute, Novo Nordisk
Good health and well-being
Openalex Percentile: Top 17%
Protein Tyrosine Phosphatases
DOIOpen Access PDFOpenAlex
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