Etiology of Congenital Scoliosis

Frances A. Farley, MD
Congenital scoliosis may have an environmental or genetic etiology. Environmental etiologies have focused on maternal carbon monoxide exposure in mice early in gestation.
Genetic studies have focused on skeletal patterning genes in the human and the mouse.
Genetic mutations have been isolated in the related Jarcho-Levin syndrome.
Semin Spine Surg 22:110-112 2010 Elsevier Inc. All rights reserved.
KEYWORDS congenital scoliosis, environmental factors, genetic factors

ongenital scoliosis is lateral curvature of the spine

caused by defects in formation or segmentation of the
vertebrae or a combination of both.1 Numerous other congenital spine disorders produce similar malformations and
may have similar origins. Spondylothoracic dysostosis, also
known as Jarcho-Levin syndrome, is characterized by severe
spinal malformations, multiple rib fusions, and chest wall
deformities.2 In contrast, in spondylocostal dysostosis, the
ribs are not so severely affected and the life expectancy is
normal, but the trunk is shortened as the result of the multiple abnormal vertebrae.3 KlippelFeil syndrome, which is a
result of a defect in segmentation, is characterized by cervical
spine fusions. Congenital scoliosis and KlippelFeil syndrome are associated with congenital anomalies of other organ systems, including cardiac, auditory, genitourinary, and
the neural axis.4 The VACTRL (ie, V, vertebral anomalies/
dysgenesis, vascular anomalies; A, anal atresia; C, cardiac
anomalies; T, tracheo-esophageal [T-E] fistula; E, esophageal
atresia; R, renal anomalies, radial dysplasia; L, limb anomalies) association includes vertebral anomalies, anal atresias,
congenital cardiac anomalies, tracheal-esophageal fistulas,
renal anomalies, and radial aplasias.5 The exact causes of
these disorders are unknown.
The etiology of congenital scoliosis is believed to be related
to environmental and genetic factors. Either of these factors
appears to affect the human developing spine during week 6
in development.6 Segmentation of the spine occurs during
weeks 3 to 6 of gestation.7 Defects caused by failure of formation may occur earlier. Although both genetic and endoPediatric Orthopaedic Service, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI.
This work was supported by a Congenital Scoliosis Center Grant, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI.
Address reprint requests to Frances A. Farley, MD, Department of Orthopaedic Surgery, University of Michigan, 1500 East Medical Center
Dr., TC 2912, Ann Arbor, MI 48109. E-mail: fafarley@umich.edu

110

1040-7383/$-see front matter 2010 Elsevier Inc. All rights reserved.

doi:10.1053/j.semss.2010.03.001

crine factors have been associated with idiopathic scoliosis,

endocrine factors have not been implicated as an etiology for
congenital scoliosis.

Environmental Factors
Experimentally induced hypoxia in pregnant animals has
produced vertebral anomalies in the offspring similar to
those found in humans with congenital scoliosis. Maternal
hypoxia at 9.5 days of gestation in the mouse can induce
vertebral malformations.8-11 Overexposure of pregnant animals to carbon monoxide (CO) and maternal hypoxia are
associated with vertebral anomalies in the offspring.9,12-16
Studies investigating maternal CO exposure during somite
formation in the developing embryo produce vertebral and
other skeletal anomalies in the offspring of mice and rabbits.11,14,16,17
An animal model for congenital scoliosis was developed
with the use of maternal carbon coexposure in mice.12 The
first study used DBA/1-J mice and 200, 400, 600 parts per
million by volume (ppmv) CO and varied the exposure on
days 8.5 and 9.5, or 10.5. The highest percentage of anomalies occurred at 600 ppmv at day 9.5 of gestation (77%).
Anomalies were found throughout the spine.
The second study sought to produce a dose-response
curve for acute and chronic maternal CO exposure versus
vertebral anomalies in the offspring with the use of the CD-1
mouse breed.18 In the first phase, pregnant female mice were
exposed to an acute dose CO at day 9 of gestation. In a second
phase, pregnant female mice were exposed to chronic CO for
the first 11 days of gestation. In a third phase, pregnant
female mice were exposed to an acute dose of CO at gestation
day 8 and 9, or 10. A positive dose-response relationship of
acute maternal CO exposure and vertebral anomalies in the
offspring was produced (11% anomalies at 600 ppmv).
Chronic exposure of CO did not produce a significant num-

Etiology of congenital scoliosis

Figure 1 An anteroposterior microradiograph of a mouse spine with

congenital anomalies. This mouse was exposed to CO (600 ppmv)
on day 9 in utero. Image provided courtesy of Frances A. Farley.

ber of vertebral anomalies. Day 9 of gestation in this mouse

breed is the critical day for maternal exposure to CO. Anomalies were predominately in the thoracic spine. In these first 2
studies,12,18 the greatest number of anomalies was produced
with CO exposure of 600 ppmv on day 9.
The third study allowed the affected animals to grow to
maturity. All animals with congenital anomalies developed
measurable curves (Fig. 1).19 The congenital anomalies were
best measured by microcomputed tomography.19 Thirty percent had moderate-to-severe curves, indicating that our
mouse model has similar progression rates to those associated with congenital scoliosis in humans.19
The inbred DBA/1 J strain has a greater incidence of scoliosis in the offspring than the outbred CD-1 stock, or 50%
versus 10%.12,18,19 The strain-specific differences in incidence suggest that genes that vary functionally between
DBA/1 J and CD-1 either enhance or suppress the susceptibility to environmentally induced vertebral defects. Identification of these genes may provide insight into the genetic
factors involved in the development of congenital scoliosis.

Genetic Factors
Genetic factors involved in the developing spine are believed
to also play a role in congenital scoliosis. Patients with congenital scoliosis and no known syndrome were found to have
a significant number of renal and cardiac anomalies and a
family history of idiopathic scoliosis.20 Families of individuals with congenital scoliosis have a greater than random incidence of idiopathic scoliosis, indicating a genetic link between the 2 types of scoliosis. In 1 study of 237 children with
congenital scoliosis, 20% had a relative with a spinal defor-

111
mity, of which 17% had relatives with idiopathic scoliosis.
The authors assert that families with one type of spinal deformity may also be predisposed to having other spinal deformities.21 In another report, monozygotic twins were both found to
have congenital scoliosis presenting as a thoracic hemivertebrae.22 To perform a clinical genetic study, vertebral defects
were classified based on developmental etiology.23
Genetic studies have focused on the mutations of specific
genes. Mistakes in segmentation may result in hemivertebrae
and may be governed by a paired homeobox sequence.7 Mutations in the Notch 1 receptor and deltalike 3 ligand (DLL3)
cause disruptions in axial segmental patterning. Thirty percent of DLL3-Notch 1 double-heterozygous mutant mice exhibited localized spinal segmental anomalies and diminished
mandibular height. These mice model both congenital scoliosis and craniofacial disorders.24
Spondylocostal dysostosis type 1 is associated with a homozygous DLL3 mutation. Forty-six patients with congenital
scoliosis had the DLL3 gene sequenced. No previously described mutations were found. Four missense allelic mutations were found, but the functional significance is unknown.
DLL3 is unlikely to be a major cause of congenital scoliosis.20
In studying 12 patients from Puerto Rico with Jarcho-Levin
syndrome, the authors found mutations in the mesoderm
posterior 2 homolog (MESP2) gene, which suggests mutation
in the MESP2 gene as a major cause of the classical Puerto
Rican form of Jarcho-Levin Syndrome.25
Synteny analysis is the analysis of gene order conservation
between species. Mouse axial patterning genes can be related
to human axial patterning genes according to position on the
human genome. Mutations of these axial patterning genes
may cause congenital scoliosis. Synteny analysis of mouse
and human databases uses mouse clones that are ordered
according to their mapping onto the human genome to allow
the development of a list of candidate genes for congenital
scoliosis.26 A total of 100 mutants were found in the Mouse
Genomic Database, of which 66 were mapped. Forty-five loci
had phenotypes that included vertebral anomalies. Twentyseven had the comparative maps of linkages between mouse
and human used to identify human regions to which candidate genes were mapped.26
The link between genes that may cause neurological disorders of the spine, such as myelomeningocele, spinal dysraphism, and congenital scoliosis, is unclear. The mouse genome contains 2 Sim genes: Sim1 and Sim2. These Sim genes
are thought to be important in central nervous system development. Sim2 mutant mice die soon after birth from respiratory failure. The mutant mice have an abnormal chest cavity
and have congenital scoliosis. Sim2 may regulate chest and
spine growth.27

Conclusions
Environmental or genetic factors or both may play a role in
the etiology of congenital scoliosis. A mouse model for congenital scoliosis has been developed that uses high doses of
maternal CO exposure early in development of the offspring.
The incidence of congenital scoliosis in the offspring varies

112
depending on the species of mouse. Other models that rely
on maternal hypoxia rather than maternal CO exposure have
been developed. Genetic studies have focused on skeletal
patterning genes in the human and the mouse. Genetic mutations of the MESP2 gene have been isolated in the related
Jarcho-Levin syndrome. Studies on Deltalike 3 ligand and
Sim2 genes in the mouse and human are being investigated
for their relationship to congenital scoliosis.

Acknowledgments
The editorial assistance of Kristi Overgaard during the preparation of this manuscript is gratefully acknowledged.

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