Updated clinical practice recommendations for managing adults with 22q11.2 deletion syndrome.

This review aimed to update the clinical practice guidelines for managing adults with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society recruited expert clinicians worldwide to revise the original clinical practice guidelines for adults in a stepwise process according to best practices: (1) a systematic literature search (1992-2021), (2) study selection and synthesis by clinical experts from 8 countries, covering 24 subspecialties, and (3) formulation of consensus recommendations based on the literature and further shaped by patient advocate survey results. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text review, with 2318 meeting inclusion criteria (clinical care relevance to 22q11.2DS) including 894 with potential relevance to adults. The evidence base remains limited. Thus multidisciplinary recommendations represent statements of current best practice for this evolving field, informed by the available literature. These recommendations provide guidance for the recognition, evaluation, surveillance, and management of the many emerging and chronic 22q11.2DS-associated multisystem morbidities relevant to adults. The recommendations also address key genetic counseling and psychosocial considerations for the increasing numbers of adults with this complex condition.

Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome.

This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.

The role of sagittal pelvic morphology in the development of adult degenerative scoliosis.

PURPOSE: Pelvic morphology dictates the alignment and biomechanics of the spine. Recent observations in different types of adolescent idiopathic scoliosis indicate that individual pelvic morphology is related to the spinal levels in which scoliosis develops: primary lumbar adolescent scoliosis is associated with a higher pelvic incidence (PI) than thoracic scoliosis and non-scoliotic controls. We hypothesize that adult degenerative scoliosis (ADS) of the lumbar spine follows the same mechanical principles and is associated with a high PI. METHODS: This study used an existing CT-scan database, 101 ADS patients were sex and age matched to 101 controls. The PI was measured by two observers with multi-planar reconstruction, perpendicular to the hip-axis according to a previously validated technique. RESULTS: The PI was 54.1° ± 10.8° in ADS patients and 47.7° ± 10.8° in non-scoliotic controls (p < 0.001). The median ADS curve apex was the disc L2-3 and median curve length was 4 vertebral levels. The mean supine Cobb angle was 21° ± 8° (ranged 10°-47°). There was no significant correlation between PI and the apex level (p = 0.883), the curve length (p = 0.418) or the Cobb angle (p = 0.518). CONCLUSIONS: ADS normally develops de novo in the lumbar spine of patients with a higher PI than controls, similar to primary lumbar adolescent idiopathic scoliosis. This suggests a shared mechanical basis of both deformities. Pelvic morphology dictates spinal sagittal alignment, which determines the segments of the spine that are prone to develop scoliosis.

Cross-validation of ultrasound imaging in adolescent idiopathic scoliosis.

PURPOSE: Adolescent idiopathic scoliosis (AIS) patients are exposed to 9-10 times more radiation and a fivefold increased lifetime cancer risk. Radiation-free imaging alternatives are needed. Ultrasound imaging of spinal curvature was shown to be accurate, however, systematically underestimating the Cobb angle. The purpose of this study is to create and cross-validate an equation that calculates the expected Cobb angle using ultrasound spinal measurements of AIS patients. METHODS: Seventy AIS patients with upright radiography and spinal ultrasound were split randomly in a 4:1 ratio to the equation creation (n = 54) or validation (n = 16) group. Ultrasound angles based on the spinous processes shadows were measured automatically by the ultrasound system (Scolioscan, Telefield, Hong Kong). For thoracic and lumbar curves separately, the equation: expected Cobb angle = regression coefficient × ultrasound angle, was created and subsequently cross-validated in the validation group. RESULTS: Linear regression analysis between ultrasound angles and radiographic Cobb angles (thoracic: R2 = 0.968, lumbar: R2 = 0.923, p < 0.001) in the creation group resulted in the equations: thoracic Cobb angle = 1.43 × ultrasound angle and lumbar Cobb angle = 1.23 × ultrasound angle. With these equations, expected Cobb angles in the validation group were calculated and showed an excellent correlation with the radiographic Cobb angles (thoracic: R2 = 0.959, lumbar: R2 = 0.936, p < 0.001). The mean absolute differences were 6.5°-7.3°. Bland-Altman plots showed good accuracy and no proportional bias. CONCLUSION: The equations from ultrasound measurements to Cobb angles were valid and accurate. This supports the implementation of ultrasound imaging, possibly leading to less frequent radiography and reducing ionizing radiation in AIS patients.

Genetic overlap between idiopathic scoliosis and schizophrenia in the general population.

INTRODUCTION: Adolescent idiopathic scoliosis (AIS) and schizophrenia (SCZ) are two distinct conditions with poorly understood aetiologies that both emerge in otherwise healthy young adolescents. One rare genetic condition associated with both phenotypic outcomes is the 22q11.2 deletion (22q11DS). This microdeletion, encompassing 47 genes, occurs in approximately 1 in 2,148 live births and confers a 20-fold higher risk for both AIS and schizophrenia compared to the general population. In the general population (non-22q11DS carriers), AIS and SCZ have also been reported to be related and genetic studies suggest the involvement of genetic variants implicated in the central nervous functioning. In this study, our objective was to further investigate genetic overlaps between these conditions in the general population. Specifically, we aimed to explore the role of genes within the 22q11.2 region, not only in terms of common variants but also their potential impact on gene networks and biopathways. METHODS: We used summary statistics from three genome-wide association studies (GWAS): two focused on AIS (n = 11,210), and one on schizophrenia (n = 36,989). To explore potential overlaps between the two conditions, we conducted a comparative analysis on the significance-based ranked single nucleotide polymorphisms (SNPs) that are associated with both AIS and SCZ. Next, we employed in silico analyses to assess gene-networks enrichment for the most significant SNPs and investigate the contribution of genes within the 22q11.2 region. Post-hoc analysis was conducted to explore the biological pathways correlated with SNPs significantly associated with both AIS and SCZ. RESULTS: The in silico analyses revealed a significant (adjusted-p < 0.05) genetic overlap between SCZ and both AIS cohorts. The top 3% of the most significant SNPs associated with both conditions exhibited a distinct enrichment cluster which is unlikely to be a result of chance (p < 3e-04). The gene-networks analyses showed a significant overlap of 26-41% with the ones involving genes in the 22q11DS region. However, there was no overlap between SNPs in this region and the most significant SNPs identified in the GWAS. CONCLUSION: This study revealed compelling evidence that beyond the shared association with 22q11DS as a rare genetic variant, AIS and SCZ exhibit common genetic risk variants and an overlap of important genes. The gene networks enriched by the most significant SNPs for both conditions also intersect with the ones involving genes in the 22q11DS region. However, SNPs within this region were not overrepresented among the most significant SNPs from GWAS for both conditions. Notably, gene networks linked to the risk for both conditions suggest an involvement of biopathways related to cellular signaling and neuronal development.

Early Sagittal Shape of the Spine Predicts Scoliosis Development in a Syndromic (22q11.2DS) Population: A Prospective Longitudinal Study.

BACKGROUND: Scoliosis is a deformation of the spine and trunk that, in its more severe forms, creates a life-long burden of disease and requires intensive treatment. For its most prevalent form, adolescent idiopathic scoliosis, no underlying condition can be defined, and the pathomechanism appears to be multifactorial; however, it has been suggested that the biomechanics of the spine play a role. For nonidiopathic scoliosis, underlying conditions can be recognized, but what drives the deformity remains unclear. In this study, we examined the early sagittal shape of the spine before the onset of scoliosis in a population with 22q11.2 deletion syndrome (22q11.2DS). This cohort was chosen since children with this syndrome have an approximately 50% chance of developing scoliosis that shares certain characteristics with idiopathic scoliosis, namely, age of onset, curve morphology, and rate of progression. METHODS: This prospective cohort study included patients with 22q11.2DS who were followed with the use of spinal radiographs during adolescent growth. All of the children, who initially had no scoliosis while still skeletally immature (Risser stages 0 and 1), were followed at 2-year intervals until they reached skeletal maturity (Risser stages 3 to 5). We assessed the segment of the spine that has previously been shown to be rotationally unstable, the posteriorly inclined segment, to determine if it was predictive of later scoliosis development. For quantification, the area of the "posteriorly inclined triangle" (PIT), a previously described parameter that integrates both the inclination and length of the at-risk segment, was measured. RESULTS: Of the 50 children who initially had no scoliosis (mean age at inclusion, 10.7 ± 1.7 years; mean follow-up, 4.8 ± 1.6 years), 24 (48%) developed scoliosis. Patients with an above-average PIT area (>60 cm2) at inclusion showed a relative risk of 2.55 for scoliosis development (95% confidence interval [CI]:1.22 to 5.34). PIT inclination was correlated with curve type: a taller and steeper hypotenuse predicted later thoracic scoliosis, while a shorter and less steep inclination predicted the development of (thoraco)lumbar scoliosis. CONCLUSIONS: This prospective study identified the pre-scoliotic sagittal shape of the spine as a risk factor for the later development of scoliosis in the population of children with 22q11.2DS. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Morphological Changes of the Intervertebral Disc During Growth.

STUDY DESIGN: Cross-sectional. OBJECTIVE: To describe morphological changes of the annulus fibrosus (AF) and nucleus pulposus (NP) in children during growth using magnetic resonance imaging (MRI). SUMMARY OF BACKGROUND DATA: Little is known of intervertebral disc (IVD) maturation as opposed to degeneration, such as changes in relative AF/NP proportions and orientation during growth. Studies suggest the IVD plays a role in the etiology of pediatric spinal deformities. Therefore, understanding the morphological development of the AF and NP during growth is key. METHODS: An existing database of children aged 0-18 that had magnetic resonance imaging (MRI) for indications unrelated to the spine were analyzed. The AF/NP were segmented semi-automatically from T1-L5. The parameters: mean IVD height, cross-sectional area, slenderness (height/width ratio), volume (ratio) and relative position of the centroid of the NP within the IVD in three directions (x,y,z) were extracted, and compared between age, sex and spinal level. RESULTS: IVD height increased modestly and predominantly in the low-thoracic and lumbar spine during the first 5-10 years of life. Cross-sectional area and thus volume increased steadily at all levels throughout growth. IVD slenderness decreased sharply the first years of life and remains relatively stable throughout the remainder of growth. IVDs were smaller and more slender in females, especially in the mid-thoracic spine at early adolescence. In the upper- and mid-thoracic spine the NP comprises 10-12% of total IVD volume during growth, this percentage increases in the low-thoracic and lumbar spine towards 20-25%. In the anterior-posterior direction, the position of the nucleus increasingly shifts with age, possibly in line with the developing sagittal profile of the spine. CONCLUSION: This study describes the development of thoracic and lumbar IVDs during growth and may be used as a reference for future studies on the IVD its role in the etiology of disc related disorders.

Convex-concave and anterior-posterior spinal length discrepancies in adolescent idiopathic scoliosis with major right thoracic curves versus matched controls.

PURPOSE: The apical deformation in adolescent idiopathic scoliosis (AIS) is a combination of rotation, coronal deviation and passive anterior lengthening of the spine. In AIS surgery, posterior-concave lengthening or anterior-convex shortening can be part of the corrective maneuver, as determined by the individual surgeon's technique. The magnitude of convex-concave and anterior-posterior length discrepancies, and how this needs to be modified to restore optimal spinal harmony, remains unknown. METHODS: CT-scans of 80 pre-operative AIS patients with right convex primary thoracic curves were sex- and age-matched to 80 healthy controls. The spinal length parameters of the main thoracic curves were compared to corresponding levels in controls. Vertebral body endplates and posterior elements were semi-automatically segmented to determine the length of the concave and convex side of the anterior column and along the posterior pedicle screw entry points while taking the 3D-orientation of each individual vertebra into account. RESULTS: The main thoracic curves showed anterior lengthening with a mean anterior-posterior length discrepancy of + 3 ± 6%, compared to a kyphosis of - 6 ± 3% in controls (p < 0.01). In AIS, the convex side was 20 ± 7% longer than concave (0 ± 1% in controls; p < 0.01). The anterior and posterior concavity were 7 and 22 mm shorter, respectively, while the anterior and posterior convexity were 21 and 8 mm longer compared to the controls. CONCLUSIONS: In thoracic AIS, the concave shortening is more excessive than the convex lengthening. To restore spinal harmony, the posterior concavity should be elongated while allowing for some shortening of the posterior convexity.

Comment on Grivas et al. Morphology, Development and Deformation of the Spine in Mild and Moderate Scoliosis: Are Changes in the Spine Primary or Secondary? J. Clin. Med. 2021, 10, 5901.

With great interest, we have read the article entitled "Morphology, Development and Deformation of the Spine in Mild and Moderate Scoliosis: Are Changes in the Spine Pri-mary or Secondary [...].

Ultrasound Shear Wave Elastography of the Intervertebral Disc and Idiopathic Scoliosis: A Systematic Review.

Ultrasound shear wave elastography is a radiation-free and low-cost technique for evaluating the mechanical properties of different tissues. This study systematically reviewed all relevant literature on shear wave elastography of the intervertebral disc. The purpose was twofold: first, to determine the validity of the elastography method, that is, the correlation between elastographically measured shear wave speed and disc mechanical properties, and inter-/intra-operator reliability; and second, to explore if disc elastography is potentially useful in identifying children at risk for idiopathic scoliosis. This systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. A comprehensive search was performed in PubMed and Embase, and study quality was assessed using the AXIS (Appraisal Tool for Cross-sectional Studies) critical appraisal instrument. Seven articles were included. Three animal ex vivo studies reported moderate-to-good correlations between shear wave speed and disc mechanical properties (r = 0.45-0.81). Three studies reported high intra-operator repeatability (intra-class correlation coefficient [ICC] 0.94-0.99) and inter-operator reproducibility (ICC 0.97-0.98). Four clinical studies measured shear wave speed in asymptomatic children. Two studies reported significantly higher shear wave speeds in scoliosis patients compared with healthy controls, measured in discs both inside and outside the scoliotic curve. In conclusion, shear wave elastography appears reliable in assessing intervertebral disc mechanical characteristics. Despite its promising capabilities to distinguish patients with asymptomatic from those with pathological discs, the exact correlation between disc mechanical properties and shear wave speed remains unclear.

Disc and Vertebral Body Morphology From Birth to Adulthood.

STUDY DESIGN: Cross-sectional. OBJECTIVE: The aim of this study was to describe the morphology of intervertebral discs and vertebral bodies during growth in asymptomatic children and adolescents. SUMMARY OF BACKGROUND DATA: Earlier studies demonstrated that spinal growth occurs predominantly in vertebral bodies. This axiom introduced a vertebral-body-focus for unravelling etiological questions and achieve growth-modulation in young spinal deformity patients. Recent studies show the importance of the intervertebral discs in the early phases and possible etiology of pediatric spinal deformities. There is presently a paucity of 3D morphometric data of spinal elements during growth. METHODS: A database of 298 patients aged 0 to 21 that have received a computed tomography scan for indications not related to the spine was analyzed. Custom made software was used to semi-automatically measure intervertebral disc and vertebral body morphology, corrected for orientation in all 3 planes. RESULTS: Vertebral body height increased from birth up to adulthood, from 4-to-14 mm in the cervical, 6 to 20 mm in the thoracic, and 9 to 28 mm in the lumbar spine. This increase was 0.70 mm/year in males, more pronounced than females with 0.62 mm/year (P = 0.001). Lumbar discs increased throughout growth from 4.4 to 9.0 mm, whereas thoracic discs only increased from 3.5 to 4.9 mm at age 4 and remained stable afterwards, similarly for cervical discs. The disc transverse surface area increased greatly and consistently throughout growth. Disc slenderness was stable in the lumbar spine during growth, but decreased in the thoracic and cervical spine. Overall, discs were more slender in females, especially around early adolescence. CONCLUSION: The spine grows predominantly in the vertebral bodies. Thoracic discs increase in height only during the first years, whereas the transverse surface area continues to increase throughout growth, thus discs slenderness decreases. Relatively, female discs remained slenderer around growth-spurt. These measurements may assist future studies on the role of disc morphology in the etiology and treatment of spinal deformity.Level of Evidence: 4.

Sagittal curvature of the spine as a predictor of the pediatric spinal deformity development.

BACKGROUND: The sagittal curvature of the spine is hypothesized to play an important role in induction of spinal deformities in adolescent idiopathic scoliosis. We previously showed an S shaped flexible rod, with the same curvature as the pediatric sagittal spinal curve, produces scoliotic-like deformities under physiologic loading. Yet, detailed characteristics of the pediatric sagittal spinal curves associated with higher risk of scoliosis are not well defined. METHODS: A total of 32 patients in a population with a high prevalence of idiopathic-like scoliosis, 22q11.2 deletion syndrome (22q), were included and followed up for at least two-years. We developed a reduced order finite element model (FEM) of the sagittal profile of these 32 patients where the spine was modeled as an S shaped elastic rod. We related the geometrical parameters of the sagittal curves and the deformed FEM of the corresponding S shaped rods to the risk of scoliosis development at two-year follow-up in this cohort. RESULTS: Variations in the sagittal curvature in the cohort of 22q patients resulted in five different deformity patterns shown by finite element analyses. Two sagittal plane deformity pattern groups had high rate of scoliosis development (86% and 100%) whereas the other 3 groups had less than 50% rate of scoliosis development (40%, 33%, and 0%). The pre-scoliotic position of the inflection point (where lordosis turns into kyphosis), the ratio of the spinal curvatures above and below the inflection point, and the length of the spinal curve above and below the inflection point were significantly different between the five deformity patterns groups, p < 0.05. CONCLUSION: Combination of geometrical parameters of the sagittal profile prior to onset of scoliosis can relate to the development of spinal deformity in pediatric population.

Ossification and Fusion of the Vertebral Ring Apophysis as an Important Part of Spinal Maturation.

In scoliosis, most of the deformity is in the disc and occurs during the period of rapid growth. The ring apophyses form the insertion of the disc into the vertebral body, they then ossify and fuse to the vertebrae during that same crucial period. Although this must have important implications for the mechanical properties of the spine, relatively little is known of how this process takes place. This study describes the maturation pattern of the ring apophyses in the thoracic and lumbar spine during normal growth. High-resolution CT scans of the spine for indications not related to this study were included. Ossification and fusion of each ring apophysis from T1 to the sacrum was classified on midsagittal and midcoronal images (4 points per ring) by two observers. The ring apophysis maturation (RAM) was compared between different ages, sexes, and spinal levels. The RAM strongly correlated with age (R = 0.892, p < 0.001). Maturation differed in different regions of the spine and between sexes. High thoracic and low lumbar levels fused earlier in both groups, but, around the peak of the growth spurt, in girls the mid-thoracic levels were less mature than in boys, which may have implications for the development of scoliosis.

What a stranded whale with scoliosis can teach us about human idiopathic scoliosis.

Scoliosis is a deformation of the spine that may have several known causes, but humans are the only mammal known to develop scoliosis without any obvious underlying cause. This is called 'idiopathic' scoliosis and is the most common type. Recent observations showed that human scoliosis, regardless of its cause, has a relatively uniform three-dimensional anatomy. We hypothesize that scoliosis is a universal compensatory mechanism of the spine, independent of cause and/or species. We had the opportunity to study the rare occurrence of scoliosis in a whale (Balaenoptera acutorostrata) that stranded in July 2019 in the Netherlands. A multidisciplinary team of biologists, pathologists, veterinarians, taxidermists, radiologists and orthopaedic surgeons conducted necropsy and imaging analysis. Blunt traumatic injury to two vertebrae caused an acute lateral deviation of the spine, which had initiated the development of compensatory curves in regions of the spine without anatomical abnormalities. Three-dimensional analysis of these compensatory curves showed strong resemblance with different types of human scoliosis, amongst which idiopathic. This suggests that any decompensation of spinal equilibrium can lead to a rather uniform response. The unique biomechanics of the upright human spine, with significantly decreased rotational stability, may explain why only in humans this mechanism can be induced relatively easily, without an obvious cause, and is therefore still called 'idiopathic'.

22q11.2 Deletion Syndrome as a Human Model for Idiopathic Scoliosis.

To better understand the etiology of idiopathic scoliosis, prospective research into the pre-scoliotic state is required, but this research is practically impossible to carry out in the general population. The use of 'models', such as idiopathic-like scoliosis established in genetically modified animals, may elucidate certain elements, but their translatability to the human situation is questionable. The 22q11.2 deletion syndrome (22q11.2DS), with a 20-fold increased risk of developing scoliosis, may be a valuable and more relevant alternative and serve as a human 'model' for idiopathic scoliosis. This multicenter study investigates the morphology, dynamic behavior, and presence of intraspinal anomalies in patients with 22q11.2DS and scoliosis compared to idiopathic scoliosis. Scoliosis patients with 22q11.2DS and spinal radiography (n = 185) or MRI (n = 38) were included (mean age 11.6 ± 4.2; median Cobb angle 16°) and compared to idiopathic scoliosis patients from recent literature. Radiographic analysis revealed that 98.4% of 22q11.2DS patients with scoliosis had a curve morphology following predefined criteria for idiopathic curves: eight or fewer vertebrae, an S-shape and no inclusion of the lowest lumbar vertebrae. Furthermore, curve progression was present in 54.2%, with a mean progression rate of 2.5°/year, similar to reports on idiopathic scoliosis with 49% and 2.2-9.6°/year. The prevalence of intraspinal anomalies on MRI was 10.5% in 22q11.2DS, which is also comparable to 11.4% reported for idiopathic scoliosis. This indicates that 22q11.2DS may be a good model for prospective studies to better understand the etiology of idiopathic scoliosis.

Anterior lengthening in scoliosis occurs only in the disc and is similar in different types of scoliosis.

BACKGROUND CONTEXT: Relative anterior spinal overgrowth was proposed as a generalized growth disturbance and a potential initiator of adolescent idiopathic scoliosis (AIS). However, anterior lengthening has also been observed in neuromuscular (NM) scoliosis and was shown to be restricted to the apical areas and located in the intervertebral discs, not in the bone. This suggests that relative anterior spinal overgrowth does not rightfully describe anterior lengthening in scoliosis, as it seems not a generalized active growth phenomenon, nor specific to AIS. PURPOSE: To determine if compensatory curves in congenital scoliosis exhibit a mechanism of anterior lengthening without changes in the vertebral body, similar to curves in AIS and NM scoliosis. STUDY DESIGN/SETTING: Cross-sectional. PATIENT SAMPLE: CT-scans were included of patients in whom a short segment congenital malformation had led to a long thoracic compensatory curve without bony abnormality. Based on data of other scoliosis types, the calculated required sample size was n=12 to detect equivalence of vertebral bodies as compared with nonscoliotic controls. Out of 143 congenital scoliosis patients, 18 fit the criteria and compared with 30 nonscoliotic controls, 30 AIS and 30 NM scoliosis patients. OUTCOME MEASURES: The anterior-posterior length discrepancy (AP%) of the total curve and for vertebral bodies and intervertebral discs separately. METHODS: Of each vertebral body and intervertebral disc in the compensatory curve, the anterior and posterior length was measured on CT-scans in the exact mid-sagittal plane, corrected for deformity in all three planes. The AP% was calculated for the total compensatory curve (Cobb-to-Cobb) and for the vertebral bodies and the intervertebral discs separately. Positive AP% indicated that the anterior side was longer than the posterior side. RESULTS: The total AP% of the compensatory curve in congenital scoliosis showed lordosis (+1.8%) that differed from the kyphosis in nonscoliotic controls (-3.0%; p<.001) and was comparable to the major curve in AIS (+1.2%) and NM scoliosis (+0.5%). This anterior lengthening was not located in the bone; the vertebral body AP% showed kyphosis (-3.2%), similar to nonscoliotic controls (-3.4%) as well as AIS (-2.5%) and NM scoliosis (-4.5%; p=1.000). However, the disc AP% showed lordosis (+24.3%), which sharply contrasts to the kyphotic discs of controls (-1.5%; p<.001), but was similar to AIS (+17.5%) and NM scoliosis (+20.5%). CONCLUSIONS: The current study on compensatory curves in congenital scoliosis confirms that anterior lengthening is part of the three-dimensional deformity in different types of scoliosis and is exclusively located in the intervertebral discs. The bony vertebral bodies maintain their kyphotic shape, which indicates that there is no active anterior bony overgrowth. Anterior lengthening appears to be a passive result of any scoliotic deformity, rather than being related to the specific cause of AIS.

The role of 22q11.2 deletion syndrome in the relationship between congenital heart disease and scoliosis.

BACKGROUND CONTEXT: For over four decades, clinicians and researchers have suggested a relationship between congenital heart disease (CHD) and scoliosis, attributed to either the disease itself or to the long-term effects of cardiac surgery on the immature thoracic cage. However, no study has yet accounted for 22q11.2 deletion syndrome (22q11.2DS), the second most common cause of CHD after Down syndrome. 22q11.2DS has a scoliosis risk of 50%, but within 22q11.2DS a previous report found no significant association between scoliosis and CHD. We, therefore, hypothesized that scoliosis within a CHD cohort would be related to an underlying 22q11.2 deletion. PURPOSE: To determine the prevalence of scoliosis in CHD patients with and without 22q11.2DS. STUDY DESIGN/SETTING: Cross-sectional. PATIENT SAMPLE: A well-characterized existing database of 315 adults with CHD (primarily tetralogy of Fallot), with (n=86) and without (n=229) 22q11.2DS, matched by sex and CHD severity, and excluding other known syndromic diagnoses. We compared the scoliosis prevalence of patients with 22q11.2DS and CHD patients to the prevalence of scoliosis in a cohort of adults with 22q11.2DS without CHD based on medical records. OUTCOME MEASURES: Presence of scoliosis (Cobb angle ≥10°). METHODS: We systematically determined the presence of scoliosis in all included patients using chest radiographs, blind to genetic diagnosis. Besides 22q11.2DS, we analyzed other suspected risk factors for scoliosis using a regression model: thoracotomy before the age of 12 years, severe CHD type and sex. RESULTS: The prevalence of scoliosis in adults with CHD and 22q11.2DS (n=46, 53.5%) was significantly greater than in those without 22q11.2DS (n=18, 7.9%, p<.0001). The presence of a 22q11.2 deletion (odds ratio [OR] 25.4, 95% confidence interval [95% CI] 11.2-57.4, p<.0001), a history of thoracotomy before the age of 12 years (OR 3.5, 95% CI 1.6-8.1, p=.0027) and most complex CHD class (OR 2.3, 95% CI 1.1-4.7, p=.0196), but not sex, were significant independent predictors of scoliosis. In the 22q11.2DS group, a right-sided aortic arch was associated with a left thoracic scoliotic curve (p=.036). CONCLUSIONS: The prevalence of scoliosis in those with CHD but without a 22q11.2 deletion approximates that of the general population. However, in the CHD population with a 22q11.2 deletion, the prevalence of scoliosis approximates that of others with 22q11.2DS. The pediatric surgical approach and severity of CHD were weaker independent contributors as compared to the 22q11.2 deletion. The results support the importance of a genetic diagnosis of 22q11.2DS to the risk of developing scoliosis in individuals with CHD. The 22q11.2 deletion may represent a common etiopathogenetic pathway for both CHD and scoliosis, possibly involving early laterality mechanisms.

A computed tomography-based spatial reference for pedicle screw placement in adolescent idiopathic scoliosis.

STUDY DESIGN: Cross-sectional. OBJECTIVES: To determine semiautomatically the 3D position of the pedicle axis in operative adolescent idiopathic scoliosis (AIS) patients relative to the operating table and the lamina, as orientation for pedicle screw placement for better understanding and reference of spine surgeons. Pedicle morphology is well described as the angle between the convex and concave pedicle. However, the pedicle angle as relative to the neutral anterior-posterior axis or to an easy-to-use intravertebral landmark, remained unknown. METHODS: The pedicles of the apex and two adjacent vertebrae cranial and caudal to the apex of 86 right-sided primary thoracic AIS curves were evaluated using semiautomatic 3D software on high-resolution CT scans, in the same prone position as during surgery. Pedicle vectors were obtained and calculated as transverse and sagittal angles, as relative to the neutral axis (corresponding with an axis perpendicular to the operating table) and to an axis perpendicular to the lamina. RESULTS: At the apex, the mean convex and concave transverse pedicle angles were 14.3º (95% confidence interval [95% CI]: 12.0-16.6) and 30.4º (95% CI: 28.1-32.8) to the right. The angles decreased toward the adjacent levels cranial and caudal to the apex (p < 0.001) and linearly increased with a higher Cobb angle (r ≥ 0.472; p < 0.001). The mean transverse pedicle-lamina angles, sagittal pedicle angles and the sagittal pedicle-lamina angles differed along the curve as well (p < 0.001). CONCLUSIONS: Pedicle angulation differs between convex and concave and depends on the position of the vertebra relative to the apex, as well as the curve severity. The transverse and sagittal pedicle angles, as relative to the operating table and laminae, could provide useful reference for better understanding of the distorted 3D morphology, and the angles, as given in this study, could serve as an approximate guideline for the expected direction of the pedicle screw. LEVEL OF EVIDENCE: Level IV.

Reliability and Validity of the Adapted Dutch Version of the Early-Onset Scoliosis-24-Item Questionnaire (EOSQ-24).

STUDY DESIGN: Translation and validation of the Early Onset Scoliosis-24 Questionnaire (EOSQ-24). OBJECTIVE: To cross-culturally adapt the English version of the EOSQ-24 to the Dutch language and to assess the questionnaire's reliability and validity. SUMMARY OF BACKGROUND DATA: Early-onset scoliosis (EOS) has a profound impact on health-related quality of life. The EOSQ-24 is health-related quality of life questionnaire filled in by parents of children with EOS. The EOSQ-24 was already translated into multiple languages and its application was confirmed in clinical studies. However, the EOSQ-24 is not yet translated and validated for the Dutch population. METHODS: The adaption of the EOSQ-24 for the Dutch population was done in three steps: 1) translation to the Dutch language, 2) cross-cultural adaptation, and 3) cross-cultural validation. To ensure that the Adapted Dutch EOSQ-24 is applicable for clinical use, the measurement properties were tested in four steps: 1) floor and ceiling effects, 2) validation, 3) reliability, and 4) discriminative ability. One hundred three parents completed the Adapted Dutch EOSQ-24, the Child Health Questionnaire (CHQ-28 PF), and the Scoliosis Research Society Questionnaire (SRS-22r). A second EOSQ-24 was completed for test-retest reproducibility. RESULTS: The EOSQ-24 was successfully translated, adapted, and validated for the Dutch language. Almost all response items showed a normal distribution. The EOSQ-24 showed excellent reliability (Cronbach α of 0.950). The EOSQ-24 was successfully validated against the CHQ-28-PF and the SRS-22r. Test-retest was excellent (ICC ≥ 0.8). Finally, The EOSQ-24 was found capable to discriminate patients with different curve severities (P = 0.003), diagnosis (P = 0.006), and ambulatory status (P < 0.001). CONCLUSION: The current Dutch EOSQ-24 proved to be a valid and reliable quality of life assessment tool for patients with EOS. Currently, long follow-up studies using the EOSQ-24, including the Dutch EOSQ-24, are lacking and are needed to fully validate the EOSQ-24 for use in a clinical setting. LEVEL OF EVIDENCE: 2.

The 22q11.2 deletion syndrome as a model for idiopathic scoliosis - A hypothesis.

Adolescent idiopathic scoliosis (AIS), defined as a lateral deviation of the spine of at least ten degrees, is a classic enigma in orthopaedics and affects 1-4% of the general population. Despite (over) a century of intensive research, the etiology is still largely unknown. One of the major problems in all existing AIS research is the fact that most patients come to medical attention after onset of the curve. Therefore, it is impossible to know whether current investigated parameters are causative, or an effect of the scoliosis. Moreover, up until now there is no known animal model that captures the core features of AIS. In order to identify causal pathways leading to AIS we propose another approach, which has been of great value in other medical disciplines: To use a subset of the population, with a higher risk for a certain disease as a "model" for the general population. Such a "model" may allow the identification of causative mechanisms that might be applicable to the general population. The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome and occurs in ∼1:3000-6000 children and 1:1000 pregnancies. Nearly half of the population of patients with 22q11.2DS develop a scoliosis that in most cases resembles AIS as far as age at onset and curve pattern. We postulate that within 22q11.2DS certain causal pathways leading to scoliosis can be identified and that these are applicable to the general population.