The Great Escape: A Case Series on <i>DDX3X</i> Craniofacial Phenotypes in Females

Introduction<i>DDX3X</i>-related neurodevelopmental disorder (<i>DDX3X</i>-NDD) is a rare genetic condition that primarily affects females, leading to developmental delays and intellectual disability. <i>DDX3X</i> variants, primarily <i>de novo</i>, account for an estimated 1% to 3% of females with unknown causes of intellectual disability. Affected males have also been reported, often with the variant being inherited from an asymptomatic or mildly symptomatic mother.Case Description<i>Case 1</i>. The patient is a 22-month-old female, born full-term, with a history of developmental delay and complete bilateral cleft lip and palate (CLP). Whole exome sequencing (WES) identified a <i>de novo</i> pathogenic missense variant in the <i>DDX3X</i> gene, <i>DDX3X</i> c.1039G > T (p.Asp347Tyr). Developmentally, the patient is progressing gradually-can sit unassisted, but remains nonverbal.<i>Case 2</i>. The patient is a 4-year-old female, born full-term, with a history of right hemifacial microsomia and <i>DDX3X</i>-NDD, and no known family history. The patient has global developmental delay, but is able to speak in 3- to 4-word sentences. WES identified a <i>de novo</i> <i>DDX3X</i> frameshift variant, c.841_842delC>A (p.Gln281AspfsX13). Facial features include right-sided hemifacial microsomia, with right enophthalmos, microtia, mandibular hypoplasia, and bilateral facial nerve weakness. The patient is well-managed at home and receives regular care from neurology and speech therapy at school.DiscussionAlthough there have been numerous reports on the neurodevelopmental aspects of <i>DDX3X</i>-NDD, craniofacial findings such as hemifacial microsomia and CLP have been minimally reported in the literature. Given the association between <i>DDX3X</i> variants and craniofacial findings, plastic surgeons and their multidisciplinary team should be aware of this genetic condition.