Intrinsic back shape asymmetry (Figure 2, Table 4)
The girls and boys in the sitting FB position show a similar magnitude of severe TAs with significantly more TAs on the right (Figure 2). The relative frequency of severe TAs is significantly higher in girls than boys for each of the right thoracic and thoracolumbar regions (Figure 2). There is little or no difference in the magnitude of severe TAs between boys and girls (Table 5).
Body mass index (BMI) in children screened for scoliosis
Our findings confirm that BMI is normal in children screened for scoliosis (Figure 3) [7, 16, 23–25]. BMI is reported to be normal before scoliosis develops [24, 25]. While in general use as an indicator of adiposity and readily calculated, BMI needs further evaluation .
Relatively earlier menarche with relatively higher BMIs
The earlier menarche of the higher relative to the lower BMI subset confirms findings for scoliosis screening referrals . Several studies of normal girls show a relationship between BMI and measures of pubertal onset, and girls with relatively higher BMI are more likely to have earlier menarche [58, 59]. Our findings are consistent with knowledge of a link between body fat and the timing of puberty with (1) leptin playing a permissive role [58, 59], and (2) kisspeptin providing a critical metabolic signal initiating puberty through pulsatile GnRH secretion [59–62] by activating the G-protein coupled receptor-54 . BMI in girls is said to be a good although imperfect surrogate measure of body fat . In boys, few studies have found a link between body fat and earlier puberty . We have no puberty maturity data for boys by which to asses whether puberty was earlier in their higher BMI subset.
How may the lower BMI subset of girls with later menarche be related to the excess of severe TAs in the sitting FB position?
The girls with relatively lower BMI
are associated statistically with each of (1) significantly later menarche, (2) excess of premenarcheal girls, and (3) significant excess of severe TA (Figures 8
). Smaller BMIs are associated with more severe TAs
after correcting for age (Table 6
). The linkage of lower BMI with TA has not been reported, but it extends observations on girls with AIS and relatively lower BMI
, namely [23
girls with right thoracic AIS show statistically significant associations of each of Cobb angle and apical vertebral rotation with upper limb length asymmetry (upper arms); and
preoperative girls show upper arm length asymmetry significantly greater than in screened and normal girls.
These observations and other evidence from screened and normal girls suggested that girls with AIS have a dysfunctional energy balance involving the hypothalamus [23, 27–30]. Bodily energy reserves are managed actively by powerful and unconscious complex systems that regulate food intake, substrate partitioning, and energy expenditure . The complex systems include white adipose tissue, the adipose-tissue derived hormone leptin (and other cytokine-hormones), hypothalamus, and neuroendocrine axes including the sympathetic nervous system [63, 64]. Energy balance (bioenergetics) is known to influence bone formation, resorption and bone growth in mice [64–66], and there is evidence suggesting it does so in children [23, 30, 67].
We apply the hypothesis of pathogenesis proposed for girls with AIS [23, 30] to girls and boys with severe TAs, namely: TAs are caused by a genetically-determined selectively increased hypothalamic sensitivity (up-regulation) to lepti n with asymmetry as an adverse response (LHS concept). This hypothalamic functional asymmetry is expressed bilaterally via the sympathetic nervous system mainly to the growing trunk to produce left-right asymmetry in ribs and/or vertebrae leading to severe TAs, when beyond the capacity of postural mechanisms of the somatic nervous system to control the shape distortion in the trunk (neuro-osseous escalator concept) .
The evidence of Qiu et al  confirmed by Moreau (Dr A Moreau personal communication), suggests that the lower BMI subsets of the girls and boys in our study had relatively lower circulating leptin levels than those with relatively higher BMIs. If so, the lower circulating leptin levels may have exacerbated the hypothalamic processes including asymmetry leading to the excess of severe TA in the lower BMI subsets.
We suggest that the majority of girls and boys with TA who do not progress to AIS , may have less severe involvement of their autonomic and somatic nervous systems. They may also lack hormonal changes  and osteopenia [69, 70] posited to contribute to the curve severity of preoperative girls with AIS  in the biomechanical spinal growth modulation of progressive AIS [71–73].
LHS concept, melatonin-signaling pathway dysfunction, osteopontin and sCD44
In progressive AIS, Moreau and colleagues [74
] reported melatonin-signaling transduction to be impaired in osteoblasts, myoblasts and lymphocytes, caused by the dysfunction of G inhibitory (Gi) proteins. This mechanism does not appear to explain:
the association of an excess of severe TA with relatively lower BMI suggesting a link with energy homeostasis (this paper); and
disturbance in the autonomic nervous system regulating blood flow to the anterior chest wall in girls with right thoracic AIS [76–79] – unless the sympathetic nervous system also has Gi-signaling defect, or induces a Gi-signaling defect in growth plates and bone (see below).
Most recently, Moreau et al [80, 81] report mean plasma osteopontin (OPN) levels are increased in patients with (1) idiopathic scoliosis, correlating significantly with curve severity, and in (2) "an asymptomatic at-risk group" (offspring born from at least one scoliotic parent). In contrast, mean plasma levels of soluble CD44 receptor (sCD44) are significantly lower in patients with Cobb angles of 45 degrees or more [80, 81]. No OPN or sCD44 data are published for non-familial TA with or without spinal deformity.
Age at which severe TA become detectable in girls and boys
TAs in normal children become evident in juvenility, earlier in girls than boys . Normal juveniles are more symmetric in back shape than are adolescents with girls more symmetric than boys. Increase in TA takes place in girls at 6–7 and 8–9 years and in boys at 8–9 years . We suggest this developing TA involves energy balance controlled by the hypothalamus starting its preparations for puberty.
The greater susceptibility of girls than boys to progressive AIS is attributed to a greater down-regulation (i.e. central resistance) to leptin of the female hypothalamus established in hominin evolution [28, 30]. Hence, hypothalamic up-regulation (i.e central sensitivity) with its asymmetries contributing to AIS should be greater in girls than boys. Consistent with this prediction is finding that the relative frequency of severe TAs is significantly higher in girls than boys for the right thoracic and thoracolumbar regions [Figure 2 and Table 4 where right relative to left ATIs outside 2 SDs in both boys (p = 0.020) and girls (p = 0.009)], but the girls' severe TAs are not more severe than those of the boys (Table 5).
Musculo-skeletal mechanisms in the trunk that may determine TAs in normal girls and boys
Mechanical factors involving ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine  and contribute to its sagittal spinal shape alterations [82–84]. The musculo-skeletal mechanisms that may initiate TAs – thoracic, thoracolumbar and lumbar of normal adolescents are unknown. It is improbable that either relative anterior spinal overgrowth [82–86] or asynchronous spinal neuro-osseous growth [26, 87–89] could determine TAs. Possibilities include dorsal shear forces, with axial vertebral rotation [44, 52, 53] and neuromuscular mechanisms acting dysfunctionally on vertebral and rib growth. More likely are growth processes involving ribs [9, 90] with the rib cage deformity preceding the spinal deformity . In the normal adult, pre-existing thoracic axial vertebral rotation, usually to the right, has been demonstrated and accounted for by asymmetrical anatomy of thoracic organs . This axial vertebral rotation may be contributed to by asymmetrical growth in one or more neurocentral synchondroses [90–94], vertebral body torsion [95, 96] and/or ribs [9, 47, 48, 76, 90, 97–100].
Thoraco-spinal pathogenetic concept for right thoracic (RT) AIS in girls
The LHS concept extends, and provides a wider scientific framework for, the thoraco-spinal pathogenetic concept for right thoracic (RT) AIS of girls [76, 97, 98]. A longitudinal study of anterior chest wall blood supply of girls with progressive right thoracic (RT) AIS, supports the view that RT AIS in females is associated with a disturbance in the autonomic nervous system regulating blood flow to the anterior chest wall [77, 78]. The thoraco-spinal concept is supported by recent peripheral nerve studies .
Lower spine AIS and hormesis
In lower spine AIS (thoracolumbar and lumbar curves), iliac height is greater on the curve concavity [101, 102]. In AIS girls with such curves, iliac height asymmetry and apical vertebral rotation, each correlate positively with BMI like the 'dose' of a hormetic effect . Given that BMI may be a surrogate measure for leptin , these findings are consistent with the phenomenon of hormesis ; that is a bimodal dose response, first stimulation and then an adverse response, usually inhibition, to drugs, toxins and a hormone such as leptin. In rats, infused leptin increases sympathoactivation in a dose-dependent manner suggesting that leptin may act hormetically on the normal rat hypothalamus . In AIS girls with lower spine scoliosis, the LHS concept postulates that the left-right iliac length asymmetries result from an adverse hormetic response to leptin in the hypothalamus , a suggestion considered plausible [Calabrese E, personal communication].
In the Rett syndrome, raised circulating leptin levels and overactivity of the sympathetic nervous system are pathophysiological features of this genetic neurodevelopmental disorder . In patients with Rett syndrome, the skin sympathetic responses were reported to show relatively lower amplitude on the foot ipsilateral to the convex side of the scoliosis . Skin sympathetic responses need studying in AIS girls with the recording electrodes placed on both sides of the trunk and at other sites .
Test of the hypothesis
A test of the autonomic component of the hypothesis testing skin sympathetic responses  in students with severe TAs is suggested.