Brain volumetric study of patients with Crouzon and Apert syndromes

879 

Abstract Submission 

Ombline Delassus^1,2,3, Lucas Chollet^1,3, Adèle Rohée-Traoré³, Quentin Beaufort⁴, Antonio Messina⁴, Maxime Taverne³, Giovanna Paternoster^5,6, Nathalie Boddaert⁴, Jeanne Amiel¹, Jean-François Mangin², Roman Hossein Khonsari^7,6,3, David Germanaud^8,9,10

¹Imagine Institute, Paris, France, ²Université Paris-Saclay, CEA, CNRS, Neurospin, Gif-sur-Yvette, France, ³Necker-Enfants Malades Hospital, Craniofacial Growth and Form Lab, Paris, France, ⁴Necker-Enfants Malades Hospital, Department of Radiology, Paris, France, ⁵Necker-Enfants Malades Hospital, Department of Pediatric Neurosurgery, Paris, France, ⁶Université Paris Cité, Paris, France, ⁷Necker-Enfants Malades Hospital, Department of Maxillofacial Surgery and Plastic Surgery, Paris, France, ⁸CEA Paris-Saclay, Institut Frederic Joliot, NeuroSpin, UNIACT, Gif-sur-Yvette, France, ⁹Université Paris Cité, Inserm, NeuroDiderot, inDEV, Paris, France, ¹⁰Service de génétique (CRMR DI-TND), AP-HP Hôpital Robert-Debré, Paris, France

Ombline Delassus  
Imagine Institute|Université Paris-Saclay, CEA, CNRS, Neurospin|Necker-Enfants Malades Hospital, Craniofacial Growth and Form Lab
Paris, France|Gif-sur-Yvette, France|Paris, France

Lucas Chollet  
Imagine Institute|Necker-Enfants Malades Hospital, Craniofacial Growth and Form Lab
Paris, France|Paris, France

Adèle Rohée-Traoré  
Necker-Enfants Malades Hospital, Craniofacial Growth and Form Lab
Paris, France

Quentin Beaufort  
Necker-Enfants Malades Hospital, Department of Radiology
Paris, France

Antonio Messina  
Necker-Enfants Malades Hospital, Department of Radiology
Paris, France

Maxime Taverne  
Necker-Enfants Malades Hospital, Craniofacial Growth and Form Lab
Paris, France

Giovanna Paternoster  
Necker-Enfants Malades Hospital, Department of Pediatric Neurosurgery|Université Paris Cité
Paris, France|Paris, France

Nathalie Boddaert  
Necker-Enfants Malades Hospital, Department of Radiology
Paris, France

Jeanne Amiel  
Imagine Institute
Paris, France

Jean-François Mangin  
Université Paris-Saclay, CEA, CNRS, Neurospin
Gif-sur-Yvette, France

Roman Hossein Khonsari  
Necker-Enfants Malades Hospital, Department of Maxillofacial Surgery and Plastic Surgery|Université Paris Cité|Necker-Enfants Malades Hospital, Craniofacial Growth and Form Lab
Paris, France|Paris, France|Paris, France

David Germanaud  
CEA Paris-Saclay, Institut Frederic Joliot, NeuroSpin, UNIACT|Université Paris Cité, Inserm, NeuroDiderot, inDEV|Service de génétique (CRMR DI-TND), AP-HP Hôpital Robert-Debré
Gif-sur-Yvette, France|Paris, France|Paris, France

Craniostenosis is a cranial malformation caused by premature closure of some sutures[Mathijssen] that may be syndromic origin, such as in the rare Crouzon (CS) and Apert (AS) syndromes (1/50 000-1/65 000 birth resp.[Levesque, Hilton]), caused by FGFR-2 mutations[Hilton], a gene involved in cranial and brain development. The neurological involvement is a complex clinical issue, but few quantitative studies have been carried out so far on the brain anatomy alone. We have taken advantage of a unique monocentric tertiary expertise on craniostenosis to propose a first quantitative insight into the large intracranial compartments and the global brain gyrification.

Genotyped patients imaged before surgery and typically developing controls, aged 1.5 to 18 years (y/o), were recruited from the clinical series of the Necker-Enfants Malades hospital between 2010 and 2023. 3D T1-weighted MRI were performed at 1.5T or 3T on 3 different scanners (4 different IR-prep ultrafast GE sequences) and resampled to exact millimetric isotropic resolution. Exclusion criteria were MRI insufficient resolution/quality and report of factors potentially damaging for brain development. The MRI dataset included 14 preoperative patients with CS (1,5-16y/o, avg 4.14y/o, 7 males), 3 with AS, and 75 controls (2-18y/o, avg 10y/o, 36 males). Four out-center patients with AS were added (final range 3-21y/o, avg 13y/o, 7 AS, 3 males) for secondary analyses. The data were automatically segmented with volBrain[Manjón] (Fig.1) and Morphologist (BrainVISA)[Fischer] to provide the volume of different large intracranial compartments and the hemispheric cortical and hull surfaces to compute the global gyrification index. Statistical analyses included OLS Multiple Linear Regression (age, gender, sequence and group effect), and a normative analysis based on growth modeling in controls (von Bertalanffy model) to provide 10th, 50th and 90th percentile (perc.) and test whether there was an excess of patients under or over these normative perc..

In the 1,5 to 7y/o range, multiple linear regression found a difference between CS and control groups only for the lateral ventricle volume. Intracranial, cerebral and cerebellar volumes were mainly affected by patient age(p<0.028), as was brainstem also impacted by gender. The MRI sequence had an impact on white matter and CSF volumes(p<0.032). Normative analysis based on growth modeling in controls showed no excess of patients with CS outside the 10th and 90th perc. except for the lateral ventricles volume (2 patients below the 10th, 4 for the 10th to the 50th, 2 for the 50th to the 90th and 6 above the 90th, p<0.01) (Fig.2). In AS patients, normative analyses showed intracranial and cerebellar volumes were higher than controls (5 patients above the 90th perc., p<0.006). For CSF and lateral ventricles, 6 patients were above the 90th of controls model(p=0.001), and 4 for the grey matter(p=0.02). For gyrification, all variables but the disease one had a significant influence in the multiple linear regression within the 1,5-7y/o range. However, in the normative analysis, 10 CS and 6 AS patients were for the 10th to the 90th perc. for both hemispheres and total gyrification, consistent with no major gyrification impact of the disease.

We propose a first comparison to typically developing controls of the volumes of the large compartment of the brain and its global gyrification in patients with AS or CS. Our CS patients showed volumes similar to controls except for larger lateral ventricles. However, our AS patients had much larger cerebral and cerebellar volumes than controls, aside with ventricular volume enlargement. Moreover, global gyration remained in the normal range in our 2 patient groups. Although relatively small and heterogeneous, our dataset remains rare and will enable us to further analyze brain anatomy in these two very rare conditions and provide insight into the poorly understood, but important, brain developmental involvement.

Neurogenetic Syndromes ¹

Early life, Adolescence, Aging ²

Neuroanatomy Other

STRUCTURAL MRI

Other - Craniosynostosis ; Gyrification ; Volumetry