Unusual features in a child with Marshall-Smith syndrome due to a novel NFIX variant: Evidence for an abnormal protein function

Marshall-Smith syndrome (MSS) is a rare genetic condition characterized by different clinical features, such as accelerated skeletal maturation, growth retardation, neuropsychomotor delay, and characteristic facial abnormalities. This study describes a 2-year-old boy presenting longiline appearance, macrocephalus with trigonocephaly, prominent eyes with bluish sclera, middle face hypoplasia, micrognathia, dysplastic ears, hirsutism, narrow and asymmetrical thorax, hypoplastic scrotal sac, cryptorchidism, joint laxity, hypoplastic toenails, and large sacral dimple with prominent coccyx. Abdominal ultrasonography showed an enlarged left ectopic kidney and skull computed tomography revealed signs of early closure of the metopic suture. High-resolution GTG banding karyotype and high-density CytoScan HD array did not identify abnormalities associated to the patient clinical findings. NFIX sequencing revealed a de novo variant consisted of a seven nucleotides duplication in exon 8. We suggest that some clinical findings, as glaucoma, trigonocephaly and ectopic kidney are underestimated and should be considered within the clinical spectrum of the syndrome. In addition, the NFIX variant identified in our patient is unusual among patients with MSS and has not yet been described in the literature. We present some mechanisms that could be involved in the impairment of proper NFIX protein function.