The Great Escape: A Case Series on DDX3X Craniofacial Phenotypes in Females

IntroductionDDX3X-related neurodevelopmental disorder (DDX3X-NDD) is a rare genetic condition that primarily affects females, leading to developmental delays and intellectual disability. DDX3X variants, primarily de novo, 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 DescriptionCase 1. 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 de novo pathogenic missense variant in the DDX3X gene, DDX3X c.1039G > T (p.Asp347Tyr). Developmentally, the patient is progressing gradually-can sit unassisted, but remains nonverbal.Case 2. The patient is a 4-year-old female, born full-term, with a history of right hemifacial microsomia and DDX3X-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 de novo DDX3X 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 DDX3X-NDD, craniofacial findings such as hemifacial microsomia and CLP have been minimally reported in the literature. Given the association between DDX3X variants and craniofacial findings, plastic surgeons and their multidisciplinary team should be aware of this genetic condition.