Idiopathic scoliosis is a spinal deformity that affects otherwise healthy children and adolescents during growth. Genetic factors are known to play a role based on twin studies. While over 35 candidate genes have been identified, the genetic variants that affect susceptibility to spinal curvature and progression remain unknown. Estrogen receptors have been extensively examined as candidates due to their role in bone growth, but studies on the association between idiopathic scoliosis and estrogen receptor genes like ESR1 and ESR2 have had inconsistent results. More research is needed to better understand the genetic basis and identify individuals at risk of progression to help improve treatment options.

1. Genetic Basis of Idiopathic Scoliosis
BY
Dr. S.SREEREMYA
FACULTY OF BIOLOGY

2. • Idiopathic scoliosis (IS), the most general form of spinal deformity,
affects otherwise healthy children and adolescents during growth
(Fig: 1). It usually presents as a rib hump visible at forward bending,
together with unlevelled shoulders and an asymmetrical waist [1].
According to Cobb, the diagnosis is specifically confirmed by a
standing spinal radiograph showing a lateral curvature of the spine
exceeding 10° [2]. A main concern in IS is the absence of reliable
means by which to predict risk of progression, leading to frequent
follow-ups, radiographs, and potentially unnecessary brace
treatments. A furthermore understanding of the pathogenesis and
genetics in IS might aid in identifying at-risk individuals, leading to
an earlier diagnosis and possibly better preventive and therapeutic
options [3].

3. • Idiopathic scoliosis (IS) is a ramified developmental
syndrome that constitutes the largest subgroup of human
spinal curvatures [Online Mendelian Inheritance in Man
(OMIM): 181800] [4]. First delineated by Hippocrates in On
the Articulations (Part 47), IS has been the subject of on-
going research, and yet its etiology remains enigmatic. IS is
typically marked by phenotypic complexity (variations in
curve morphology and magnitude, age of onset, rate of
progression), and a prognosis mainly ranging from increase
in curve magnitude, to stabilization, or to resolution with
growth [5]. Genetic factors are known to play a pivotal role,
as observed in twin studies and their observation and
singleton multigenerational families [6

4. • ]. A recent research of monozygotic and dizygotic twins
from the Swedish twin registry estimated that overall
genetic effects accounted for 39 % of the observed
phenotypic variance, leaving the remaining 61 % to
environmental influences. Genetic complexity in IS is
further inferred from inconsistent inheritance, discordance
among monozygotic twins, and highly variable results from
genetic studies. Genetic counsellors have a major role to
play in understanding genetic deformities [7].
• The standard of care for scoliosis has not been changed
significantly in the past three decades, from initiating
observation to bracing and to spinal fusion surgery as a last
resort [8]. The healthcare costs of bracing, hospitalization,
surgery, and adverse back pain are substantial.

5. • Genetic variants that can affect a person’s
predisposition to spinal curvature and the propensity
for progression to severe curvature are still unknown.
Since 1993, over 72 studies have attempted to identify
genes by either genome-wide or hypothesis-driven
designs, using either pedigrees (linkage analysis) or
unrelated case–control population samples
(association studies) [10]. Of over 35 candidate genes
tested, about 18 unique loci have been identified,
suggesting that IS may be caused by multiple genes
segregating differently in various populations [11]
• Fig: 1. Diagram Showing Scoliosis

7. • Puberty and growth
• Curve pathogenesis in scoliosis coincides with growth and
adolescence, genes involved in the somatotrophic and
androgenic axes were considered potential IS candidates
[12]. The gene encoding cytochrome P450 17α-hydroxylase
(CYP17) was typically considered a likely candidate for IS
progression because of its critical roles in androgen
synthesis. In a cohort of 304 Japanese females, no
association with IS was found. Of note, both forms of the
estrogen receptor, ESR1 (also called as ERα) and ESR2 (also
known as ERβ), are present in osteoblasts and osteoclasts,
indicating that estrogen mainly regulates osteoblast
function directly [13].

8. • The ESR1 gene has been extensively examined as it contains the polymorphic sites PvuII
(rs2234693) and XbaI (rs9340799). XbaI (but not PvuII) was specifically identified as a factor in IS
progression in a case-only study of 304 Japanese females; in Chinese females (202 cases/174
controls), it was associated with curve predisposition, progression, and abnormal growth [14]. In a
separate Chinese research, analysis of a small cohort of patients with double-curve patterns only
(67 cases/100 controls) suggested that PvuII (but not Xba1) was associated with curvature. Using
restriction site analysis, It is been evaluated and assesed that XbaI was associated with low levels of
steroids in several Italian females with IS (4 out of 174 cases/104 controls), although no statistical
evaluations were effected [15]. But associations with Xba1 and PvuII were not confirmed in a larger
cohort of Chinese females (540 cases/260 controls) , nor was the association with Xba1 replicated
in a larger Japanese study (798 case/638 control). Although ESR1 is the major estrogen receptor in
bone, it has been shown that in females, the ESR2 gene can modulate the action of ESR1 [16]. In
China, the ESR2 polymorphism rs1256120 was allied with curve predisposition and progression
(218 case/140 control), though the association was not confirmed in a larger Japanese cohort (798
cases/637 controls). Currently, the gene for the novel G protein-coupled estrogen receptor GPER
(also known as GPR30) was found to be associated with curve severity, but not curve
predisposition, in a sample of Han Chinese (389 cases/338 controls)

9. •
• Research & Review: Management of
Cardiovascular and Orthopedic Complications,
Genetic Basis of Idiopathic Scoliosis, S.
Sreeremya, 2018.Vol1(1):1-10