Concurrent Scoliosis and Dentofacial Anomaly: A Case Report

The relationship between scoliosis, dentofacial anomaly, and malocclusion is poorly understood. We report a novel and complex pediatric case of concurrent juvenile scoliosis, dentofacial anomaly, and malocclusion, successfully treated and managed by an interdisciplinary hospital team over a 15-year period. The degree of severity of the scoliosis and dentofacial anomaly necessitates surgical intervention. Successful orthopedic surgical procedures have improved the patient’s quality of life. Future surgical correction of the dentofacial anomaly and malocclusion is necessary to improve the patient’s condition from psychosocial, aesthetic, and functional standpoints. The patient’s condition is characterized by multiple congenital abnormalities, developmental delay, seizure disorder, juvenile scoliosis, and dentofacial anomaly with malocclusion. Intriguingly, a unifying diagnosis for the patient’s condition could not be confirmed despite the indication of a syndromic cause. The collection of characteristics is suggestive of the chromosome 22q11.2 deletion syndromes (including velocardiofacial syndrome [VCFS] or DiGeorge syndrome) as possible genetic causes. Clinical genetics testing was unable to establish a diagnosis of chromosome 22q11.2 deletion, VCFS or DiGeorge syndrome. Further investigation of the genotype-phenotype relationships of scoliosis, dentofacial anomaly, and malocclusion is required to improve medical knowledge, diagnostic capability, and patient care, specifically relating to cases of undiagnosed diseases. Future research utilizing next-generation sequencing techniques is necessary to aim for precise genetic diagnosis, including knowledge of the underlying cellular and molecular mechanisms, for the development of the potential of therapeutic approaches targeting gene repair.

Loss of the Reissner Fiber and increased URP neuropeptide signaling underlie scoliosis in a zebrafish ciliopathy mutant

SUMMARYCilia-driven movements of the cerebrospinal fluid (CSF) are involved in zebrafish axis straightness, both in embryos and juveniles [1, 2]. In embryos, axis straightness requires cilia-dependent assembly of the Reissner fiber (RF), a SCO-spondin polymer running down the brain and spinal cord CSF-filled cavities [3]. Reduced expression levels of the urp1 and urp2 genes encoding neuropeptides of the Urotensin II family in CSF-contacting neurons (CSF-cNs) also underlie embryonic ventral curvature of several cilia motility mutants [4]. Moreover, mutants for scospondin and uts2r3 (a Urotensin II peptide family receptor gene) develop scoliosis at juvenile stages [3, 4]. However, whether RF maintenance and URP signaling are perturbed in juvenile scoliotic ciliary mutants and how these perturbations are linked to scoliosis is unknown. Here we produced mutants in the zebrafish ortholog of the human RPGRIP1L ciliopathy gene encoding a transition zone protein [5–7]. rpgrip1l-/- zebrafish had normal embryogenesis and developed 3D spine torsions in juveniles. Cilia lining the CNS cavities were normal in rpgrip1l-/- embryos but sparse and malformed in juveniles and adults. Hindbrain ventricle dilations were present at scoliosis onset, suggesting defects in CSF flow. Immunostaining showed a secondary loss of RF correlating with juvenile scoliosis. Surprisingly, transcriptome analysis of rgprip1l mutants at scoliosis onset uncovered increased levels of urp1 and urp2 expression. Overexpressing urp2 in foxj1-expressing cells triggered scoliosis in rpgrip1l heterozygotes. Thus, our results demonstrate that increased URP signaling drives scoliosis onset in a ciliopathy mutant. We propose that imbalanced levels of URP neuropeptides in CSF-cNs may be an initial trigger of scoliosis.