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.

Intrauterine phenotypic features associated with 16p11.2 recurrent microdeletions

“…Skeletal malformations, particularly vertebral malformations, were the most common malformations observed in our cohort. Vertebral malformations have a prevalence of 0.5 to 1 per 1000 live births and may involve 1 or multiple vertebra . Vertebral malformations are common birth defects among newborns with 16p11.2 recurrent microdeletion.…”

Axial skeletogenesis in human autosomal aneuploidies: A radiographic study of 145 second trimester fetuses

“…In combination with other blastogenetic and non-blastogenetic malformations, costovertebral anomalies can be observed in dozens of syndromes, as recently reviewed for multiple vertebral segmentation defects [Giampietro et al, 2013]. Their origin is obscure in otherwise healthy subjects.…”

Diagnostic strategy in segmentation defect of the vertebrae: a retrospective study of 73 patients

“…Finally, it could also be due to an issue in data analysis, thus raising the hypothesis of a non-Mendelian model with multigenic and epigenetic factors. Indeed, environmental factors like hypoxia during gestation have been shown to increase the SDV rate when associated with fetal haploinsufficiency of HES7 , MESP2 , DLL1 or NOTCH1 ,21 or with maternal conditions in mice 11…”

“…Well-described syndromes are found in each category, notably with Klippel-Feil syndrome, which is associated with variants in GDF3 , GDF6 , MYO18B and MEOX1 8; spondylocarpotarsal synostosis syndrome, associated with variants in FLNB 9; and Currarino syndrome, associated with variants in MNX1 10. M-SDV can also be secondary to neuromuscular disorders and teratogenic exposure (alcohol, valproic acid, phenytoin…) 11. It has been shown that some environmental factors, like short-term gestational hypoxia, increase the penetrance and severity of SDV 12…”