Sotos Syndrome: Deep Neuroimaging Phenotyping Reveals a High Prevalence of Malformations of Cortical Development

Abstract

Background and purpose: Sotos syndrome is a rare autosomal dominant condition caused by pathogenic mutations in the NSD1 gene that presents with craniofacial dysmorphism, overgrowth, seizures, and neurodevelopmental delay. Macrocephaly, ventriculomegaly, and corpus callosal dysmorphism are typical neuroimaging features that have been described in the medical literature. The purpose of this study was to expand on the neuroimaging phenotype by detailed analysis of a large cohort of patients with genetically proved Sotos syndrome.

Materials and methods: This multicenter, multinational, retrospective observational cohort study systematically analyzed the clinical characteristics and neuroimaging features of 77 individuals with genetically diagnosed Sotos syndrome, via central consensus review with 3 pediatric neuroradiologists.

Results: In addition to previously described features, malformations of cortical development were identified in most patients (95.0%), typically dysgyria (92.2%) and polymicrogyria (22.1%), varying in location and distribution. Incomplete rotation of the hippocampus was observed in 50.6% of patients and was associated with other imaging findings, in particular with dysgyria (100% versus 84.2%, P = .012).

Conclusions: Our findings show a link between the genetic-biochemical basis and the neuroimaging features and aid in better understanding the underlying clinical manifestations and possible treatment options. These findings have yet to be described to this extent and correspond with recent studies that show that NSD1 participates in brain development and has interactions with other known relevant genetic pathways.

FIG 1.

Malformations of cortical development in 4 patients with Sotos syndrome (B–E). A, An 11-year-old healthy control. Axial, sagittal, and coronal T1WIs show a normal appearance of the cortex and sulcation pattern. B, A 15-year-old boy. Axial and coronal T1WIs show diffuse dysgyria (arrowheads), and sagittal T1WI shows undulating gyri in keeping with polymicrogyria (empty arrowheads). C, A 5.5-year-old girl. Axial T2WI and coronal T1 inversion recovery show frontal dysgyria with shallow sulci in disorganized orientation (arrowheads). Sagittal T1WI shows perisylvian dysgyria. D, A 3-year-old boy. Axial and coronal T1WI shows asymmetric, left-sided, frontal dysgyria (arrowheads). Sagittal T1WI shows perisylvian dysgyria (arrowheads). E, A 13-year-old girl. Axial, sagittal, and coronal T1WI shows polymicrogyria with regionally increased gyral/sulcal frequency and greater corticomedullary junction irregularity compared with dysgyria (empty arrowheads), accompanied by frontal dysgyria (arrowheads).

FIG 2.

Imaging characteristics of Sotos syndrome in 3 patients (A, C, and D). A, A 16-year-old girl. Sagittal T1WI shows midline abnormalities including a thin corpus callosum (white dashed arrow), a thin anterior commissure (white empty arrow), and brainstem dysmorphism, a shallow pontomedullary sulcus (white empty arrowhead). B, A 16-year-old girl, an age-matched healthy control. Sagittal T1WI shows a normal midline appearance of the corpus callosum (white dashed arrow), anterior commissure (white arrow), and a pontomedullary sulcus (white arrowhead). C, A 10-month-old boy. Axial T2WI shows reduced white matter volume in the posterior cerebrum with enlargement of the ventricular atria and occipital horns and enlarged perivascular spaces (black arrows). D, A 3-year-old boy. Coronal T2WI demonstrates enlarged CSF spaces (asterisks), bilateral incomplete hippocampal rotation (black dashed arrows), and ventriculomegaly (black arrowheads).

FIG 3.

A patient with Sotos syndrome. Fetal MR imaging at 32 weeks’ gestational age (A and B) and postnatal MR imaging at 1 year of age (C and D). A and B, Axial and coronal T2WI shows mild asymmetry of sulcation (arrowheads), mild ventriculomegaly, enlargement of the cavum septum pellucidum/vergae, and taller-than-wide hippocampal formations consistent with incomplete hippocampal rotation bilaterally (arrows). C and D, Axial T1WI and coronal T2WI show mild dysgyria in the frontal and perisylvian regions (empty arrowheads), ventriculomegaly, incomplete hippocampal rotation, and thinning of the corpus callosum. Distention of the cavum septum pellucidum/vergae has intervally resolved.