Prominent and Regressive Brain Developmental Disorders Associated with Nance-Horan Syndrome

Abstract

Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder caused mainly by loss of function variants in the NHS gene. NHS is characterized by congenital cataracts, dental anomalies, and distinctive facial features, and a proportion of the affected individuals also present intellectual disability and congenital cardiopathies. Despite identification of at least 40 distinct hemizygous variants leading to NHS, genotype-phenotype correlations remain largely elusive. In this study, we describe a Sicilian family affected with congenital cataracts and dental anomalies and diagnosed with NHS by whole-exome sequencing (WES). The affected boy from this family presented a late regression of cognitive, motor, language, and adaptive skills, as well as broad behavioral anomalies. Furthermore, brain imaging showed corpus callosum anomalies and periventricular leukoencephalopathy. We expand the phenotypic and mutational NHS spectrum and review potential disease mechanisms underlying the central neurological anomalies and the potential neurodevelopmental features associated with NHS.

Keywords: Nance-Horan syndrome; congenital cataracts; dental anomalies; genotype; motor impairment; next-generation sequencing; pediatric age.

Figure 1

(A) Pedigree of the family. (B) Dental anomalies of the patient, including notching of incisors and supernumerary teeth (right and left panel). (C) Note the mild dyschromia of sub-ungual space. (D) Schematic representation of the NHS gene with the p.C125X hemizygous variant identified in the exon 1 of the gene.

Figure 2

(A) Axial T2 turbo-spin echo (TSE) and (B) axial T2 fluid attenuated inversion recovery (FLAIR) brain MRI images showing bilateral crystalline lens thinning (white arrows in (A)) and circumscribed outpouching along the posterior aspect of the ocular bulbs, temporal to the optic disc (red arrows in (A,B)). Note a well circumscribed left temporo-polar arachnoid cyst (* in (A,B)). (C) Sagittal T2 FLAIR and (D) Coronal T2 FLAIR brain MRI images showing thinning of posterior trunk of corpus callosum (red short arrow in (C)) and bilateral deep paratrigonal white matter hyperintensity due to periventricular leukoencephalopathy (red arrows in (D)).

Figure 3

Summary of NHS gene expression in human (A) and mouse (B) brain.

Figure 4

General protein–protein network showing different interactions of candidate genes with the NHS protein.