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

Abstract

Background and ObjectivesHeterozygous mutations or deletions of theEBF3gene 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 ofEBF3-related syndrome, a systematic definition of neurologic, cognitive/behavioral, and neuroradiologic features is lacking.MethodsWe report on 6 patients (2 females and 4 males, age range 2–12 years), of whom 4 carrying a heterozygous point mutation of theEBF3gene 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, whereasEBF3variants were detected by whole exome sequencing.ResultsPhenotype 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.DiscussionEBF3-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 thatEBF3-related syndrome should be classified and treated as a congenital, nonprogressive ataxia.