Facial and ocular manifestations of male patients affected by the HUWE1-related intellectual developmental disorder.

Abstract

Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a rare neurodevelopmental disorder. MRXST is caused by pathogenic variants in the HUWE1 gene on chromosome Xp11.22. The HUWE1 gene encodes a ubiquitin ligase, which has downstream effects on the n-MYC protein and DLL3 Notch ligand, ultimately affecting neuronal differentiation. In addition to intellectual disability and developmental delay, other clinical features such as absent or delayed speech, skeletal abnormalities, abnormalities in hands or feet, seizures, and hypotonia have been described in case reports. Facial dysmorphic features and eye manifestations have been reported in patients with MRXST, but have not been identified as distinctive to this condition. We report two cases of individuals affected by HUWE1-Related Intellectual Developmental Disorder and present a review of literature of male patients affected by this disorder. Based on the literature review and findings in our two patients, it is our observation that patients with MRXST present with distinctive features, which include broad nasal tip, root, or prominent nose (39%), blepharophimosis (27%), epicanthic folds (25%), ear abnormalities (25%), thin upper lip (23%), and deep set eyes (23%). Furthermore, we note that oculofacial abnormalities are seen more frequently in patients with missense variants than patients with duplications in the HUWE1 gene. The findings noted in this paper may help clinicians suspect a diagnosis of MRXST when presented with these distinctive ocular and facial features.