Clinical, genetic and environmental factors associated with congenital vertebral malformations

Abstract

Congenital vertebral malformations (CVM) pose a significant health problem because they can be associated with spinal deformities, such as congenital scoliosis and kyphosis, in addition to various syndromes and other congenital malformations. Additional information remains to be learned regarding the natural history of congenital scoliosis and related health problems. Although significant progress has been made in understanding the process of somite formation, which gives rise to vertebral bodies, there is a wide gap in our understanding of how genetic factors contribute to CVM development. Maternal diabetes during pregnancy most commonly contributes to the occurrence of CVM, followed by other factors such as hypoxia and anticonvulsant medications. This review highlights several emerging clinical issues related to CVM, including pulmonary and orthopedic outcome in congenital scoliosis. Recent breakthroughs in genetics related to gene and environment interactions associated with CVM development are discussed. The Klippel-Feil syndrome which is associated with cervical segmentation abnormalities is illustrated as an example in which animal models, such as the zebrafish, can be utilized to provide functional evidence of pathogenicity of identified mutations.

Keywords: Congenital vertebral malformation; Hemifacial microsomia; Klippel-Feil syndrome; Maternal diabetes; Spondylocostal dysostosis; Spondylothoracic dysostosis; Thoracic insufficiency syndrome; VACTERL syndrome.

Fig. 1

Schematic diagram of spine illustrating defects of formation (wedge and hemivertebrae) and segmentation (vertebral bar and block vertebrae). Reprinted with permission from Michael J. McMaster, MD [J R Coll Surg Edinb 2002;47:475–480].

Fig. 2

Illustration of the process of somite formation from the presomitic mesoderm (PSM) in the chick embryo. a Paired somites are formed in a periodic fashion every 90 minutes. b A molecular clocked linked to segmentation is identified by dynamic and periodic expression of the cyclic genes in the PSM. Top: The expression of Lunatic Fringe mRNA appears as a wave sweeping across the whole PSM once during each somite formation as illustrated by in situ hybridization in this 17-somite-old chick embryo. PSM cells as illustrated by the dot undergo a phase of upregulation of the cycling genes followed by a phase of downregulation of these genes each time a somite forms. Bottom: As shown in this schematic representation of the progression of somitogenesis in the embryo, the cycles of expression of the cyclic genes will last while the cells remain in the PSM, which corresponds approximately to the time to form 12 somites in the chick embryo. These PSM cells undergo 12 oscillations of the expression of the cycling genes. Reproduced with permission from Giampietro et al., 2008.

Fig. 3

Schematic algorithm for International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) congenital vertebral malformation classification. Reproduced with permission from Giampietro et al., 2008.

Fig. 4

Radiograph illustrating contiguous vertebral malformations with asymmetric rib malformations, characteristic of spondylocostal dysostosis. Photograph courtesy of Peter D. Turnpenney, MD, Royal Devon and Exeter Hospital.

Fig. 5

Radiograph illustrating contiguous vertebral malformations with symmetric posterior rib fusion, indicative of spondylothoracic dysostosis. Reproduced with permission [Expert Opin Med Diagn 2008;2:1107–1121].