Neurologic, Neuropsychologic, and Neuroradiologic Features of EBF3-Related Syndrome

Abstract

Background and objectives: Heterozygous mutations or deletions of the EBF3 gene are known to cause a syndrome characterized by intellectual disability, neurodevelopmental disorders, facial dysmorphisms, hypotonia, and ataxia; the latter is quite common despite in most patients brain MRI is reported to be normal. Despite the predominant neurologic involvement of EBF3-related syndrome, a systematic definition of neurologic, cognitive/behavioral, and neuroradiologic features is lacking.

Methods: We report on 6 patients (2 females and 4 males, age range 2-12 years), of whom 4 carrying a heterozygous point mutation of the EBF3 gene and 2 with 10q26 deletion encompassing the gene, diagnosed at Carlo Besta Neurologic Institute of Milan, Italy. Clinical evaluation was performed by a pediatric neurologist and pediatric dysmorphologist; ataxia severity was rated by Scale for the Assessment and Rating of Ataxia (SARA); brain MRIs were reviewed by expert neuroradiologists; general quotient levels were obtained through standardized Griffiths Mental Development Scales. Patients carrying a 10q26.3 deletion were diagnosed by array-CGH, whereas EBF3 variants were detected by whole exome sequencing.

Results: Phenotype was consistent in all patients, but with wide variability in severity. Developmental milestones were invariably delayed and resulted in an extremely variable cognitive impairment. All patients showed ataxic signs, as confirmed by SARA scores, often associated with hypotonia. Brain MRI revealed in all children a cerebellar malformation with vermis hypoplasia and a peculiar foliation anomaly characterized by a radial disposition of cerebellar folia (dandelion sign). Neurophysiologic examinations were unremarkable.

Discussion: EBF3-related syndrome has been so far described as a neurodevelopmental condition with dysmorphic traits, with limited emphasis on the neurologic features; we highlight the predominant neurologic involvement of these patients, which can be explained at least in part by the underlying cerebellar malformation. We therefore propose that EBF3-related syndrome should be classified and treated as a congenital, nonprogressive ataxia.

Figure 1. Brain MRIs

Top row sagittal images; middle row axial T2W images; bottom row coronal T2W images. Left column a subject harboring a mutation in EBF3; central column a subject with a deletion in the same gene; right column a normal patient. (A) Radial shape of cerebellar folia (dandelion sign), vermis is hypoplastic, and lack the normal lobules subdivision; these features are less evident in deleted patient (B). (D) Axial image shows blurred and wavy boundaries of the folia (subtler in deleted patient E). (G, H) Coronal view demonstrate the facing cerebellar hemispheres and the flattened course of the folia white matter stem. EBF3 = early B cell factor 3.

Figure 2. EEG Registration of Patient 6

During drowsiness (A) and nonREM sleep (B, C), note the occurrence of spikes on vertex and right centroparietal region.

Figure 3. Phenotype Evolution Over Time

Patient 3 at the age of 4 months (A, B), 1 year and 3 months (C, D), and 10 years (E, F): Infraorbital creases, large and bulbous nasal ridge, flat philtrum, thin upper lip, retrognathia, and low-set ears; note as all features, besides infraorbital creases, become more apparent over the years.