A novel association of campomelic dysplasia and hydrocephalus with an unbalanced chromosomal translocation upstream of SOX9

Abstract

Campomelic dysplasia is a rare skeletal dysplasia characterized by Pierre Robin sequence, craniofacial dysmorphism, shortening and angulation of long bones, tracheobronchomalacia, and occasionally sex reversal. The disease is due to mutations in SOX9 or chromosomal rearrangements involving the long arm of Chromosome 17 harboring the SOX9 locus. SOX9, a transcription factor, is indispensible in establishing and maintaining neural stem cells in the central nervous system. We present a patient with angulation of long bones and external female genitalia on prenatal ultrasound who was subsequently found to harbor the chromosomal abnormality 46, XY, t(6;17) (p21.1;q24.3) on prenatal genetic testing. Comparative genomic hybridization revealed deletions at 6p21.1 and 17q24.3, the latter being 2.3 Mb upstream of SOX9. Whole-exome sequencing did not identify pathogenic variants in SOX9, suggesting that the 17q24.3 deletion represents a translocation breakpoint farther upstream of SOX9 than previously identified. At 2 mo of age the patient developed progressive communicating ventriculomegaly and thinning of the cortical mantle without clinical signs of increased intracranial pressure. This case suggests ventriculomegaly in some cases represents not a primary impairment of cerebrospinal fluid dynamics, but an epiphenomenon driven by a genetic dysregulation of neural progenitor cell fate.

SOX9-COL9A3–dependent regulation of choroid plexus epithelial polarity governs blood–cerebrospinal fluid barrier integrity

“…SOX9 mutations in human neonates commonly manifest hydrocephalus accompanied by ventriculomegaly, but the mechanistic linkage is unclear ( 13 – 15 ). Hydrocephalus can be caused by dysfunction of ependymal cells lining the ventricles, impairment of CSF dynamics, or overabundance of CSF proteins ( 6 , 36 , 37 ).…”

“…SOX9 is a member of the high-mobility group transcription factor family that plays diverse roles in development ( 12 ). In humans, SOX9 mutations are commonly associated with congenital CNS anomalies, including ventriculomegaly and hydrocephalus, but the pathological mechanisms are unknown ( 13 – 15 ). Previous studies in mice suggest that Sox9 is essential for cell fate specification and differentiation in the neuroepithelium of neocortex, retina, and spinal cord during embryogenesis ( 16 – 18 ).…”

Environmentally relevant uptake, elimination, and metabolic changes following early embryonic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish

“…These mechanistic findings derived from model organism studies make important contributions to our understanding of how human exposure to TCDD may disrupt human development and health. In humans, dysregulation of SOX9, the human paralog of sox9b, is known to cause skeletal, central nervous system, heart malformations, phenotypes which mirror those observed in model organisms exposed to TCDD ( Houston et al, 1983 ; Castori et al, 2016 ; Sanchez-Castro et al, 2013 ; Antwi et al, 2018 ; Wu et al, 2019a ). The proposed human ortholog of slincR, LINC00673, was identified in the human genome, allowing for the possibility that a conserved mechanism mediates TCDD-induced toxicity in both zebrafish and humans ( Garcia et al, 2018 ).…”

High-resolution mass spectrometry reveals environmentally relevant uptake, elimination, and metabolic alterations following early embryonic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish

“…These mechanistic findings derived from model organism studies make important contributions to our understanding of how human exposure to TCDD may disrupt human development and health. In humans, dysregulation of SOX9, the human paralog of sox9b, is known to cause skeletal, central nervous system, heart malformations, phenotypes which mirror those observed in model organisms exposed to TCDD (29)(30)(31)(32)(33). The proposed human ortholog of slincR, LINC00673, was identified in the human genome, allowing for the possibility that a conserved mechanism mediates TCDD-induced toxicity in both zebrafish and humans (27).…”