Severe hypotonia and developmental delay due to an EBF3 pathogenic variant: Clinical implications of a molecular defect and narrative review

Abstract

Hypotonia Ataxia and Delayed Development Syndrome (HADDS) is a neurodevelopmental syndrome due to missense pathogenic variants of the EBF3 gene, located on chromosome 10q26.3. In most cases, these variants appear de novo and the transmission is autosomal dominant. HADDS would affect about 200 people worldwide and is characterized by a high clinical variability in the expression of these different symptoms : severe hypotonia, failure to thrive, psychomotor delay, digestive and feeding disorders, vesicoureteral anomalies, strabismus, and moderate facial dysmorphia. Although our knowledge is still limited, the significance of these symptoms seems to depend upon the EBF3 expression during embryogenesis. Animal studies suggest that EBF3 plays a critical role in neuronal migration and differentiation and interacts with CDKN1A, NeuroD, and ARX regulation pathways. With respect to diaphragmatic and vesicoureteral dysfunction and hypotonia, EBF3 appears to be involved in myocyte calcium metabolism. In addition, EBF3 has recently been identified as a novel tumor suppressor gene in some cancers. Further research on the EBF3 gene and the associated pathological pathways is needed to improve our understanding of HADDS and to provide appropriate care for such rare diseases.