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.

The Effectiveness of Different Concepts of Bracing in Adolescent Idiopathic Scoliosis (AIS): A Systematic Review and Meta-Analysis.

Brace treatment is the most common noninvasive treatment in adolescent idiopathic scoliosis (AIS); however it is currently not fully known whether there is a difference in effectiveness between brace types/concepts. All studies on brace treatment for AIS were searched for in PubMed and EMBASE up to January 2021. Articles that did not report on maturity of the study population were excluded. Critical appraisal was performed using the Methodological Index for Non-Randomized Studies tool (MINORS). Brace concepts were distinguished in prescribed wearing time and rigidity of the brace: full-time, part-time, and night-time, rigid braces and soft braces. In the meta-analysis, success was defined as ≤5° curve progression during follow-up. Of the 33 selected studies, 11 papers showed high risk of bias. The rigid full-time brace had on average a success rate of 73.2% (95% CI 61-86%), night-time of 78.7% (72-85%), soft braces of 62.4% (55-70%), observation only of 50% (44-56%). There was insufficient evidence on part-time wear for the meta-analysis. The majority of brace studies have significant risk of bias. No significant difference in outcome between the night-time or full-time concepts could be identified. Soft braces have a lower success rate compared to rigid braces. Bracing for scoliosis in Risser 0-2 and 0-3 stage of maturation appeared most effective.

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'.

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.

Blunt cerebrovascular injury: incidence and long-term follow-up.

PURPOSE: Blunt cerebrovascular injuries (BCVI), which can result in ischemic stroke, are identified in 1-2% of all blunt trauma patients. Computed tomography angiography (CTA) scanning has improved and is the diagnostic modality of choice in BCVI suspected patients. Data about long-term functional outcomes and the incidence of ischemic stroke after BCVI are limited. The aim of this study was to determine BCVI incidence in relation to imaging modality improvements and to determine long-term functional outcomes. METHODS: All consecutive trauma patients from 2007 to 2016 with BCVI were identified from the level 1 trauma center prospective trauma database. Three periods were identified where CTA diagnostic modalities for trauma patients were improved. Long-term functional outcomes using the EuroQol six-dimensional (EQ-6D™) were determined. RESULTS: Seventy-one BCVI patients were identified among the 12.122 (0.59%) blunt trauma patients. In the first period BCVI incidence among the overall study cohort, polytrauma, basilar skull fracture and cervical trauma subgroups was found to be 0.3%, 0.9%, 1.2%, 4.6%, respectively, which more than doubled towards the third period (0.8, 2.4, 1.9 and 8.5% respectively). Ischemic stroke as a result of BCVI was found in 20 patients (28%). In-hospital stroke rate was lower in patients receiving antiplatelet therapy (p < 0.01). Six in-hospital deaths were BCVI related. Long-term follow-up (follow-up rate of 83%) demonstrated lower functional outcomes compared to Dutch reference populations (p < 0.01). Ischemic stroke was identified as a major cause of functional impairment at long-term follow-up. CONCLUSIONS: Improved CTA diagnostic modalities have increased BCVI incidence. Furthermore, BCVI patients reported significant functional impairment at long-term follow-up. Antiplatelet therapy showed a significant effect on in-hospital stroke rate reduction.

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.

Changes in the Position of the Junctional Vertebrae After Posterior Spinal Fusion in Adolescent Idiopathic Scoliosis: Implication in Risk Assessment of Proximal Junctional Kyphosis Development.

BACKGROUND: The development of proximal junctional kyphosis (PJK) after posterior spinal fusion in adolescent idiopathic scoliosis is a major problem. Changes in the global sagittal parameters as they relate to PJK have been reported after surgery, however, the relationships between the changes in the upper-instrumented vertebra (UIV) during and after surgery as they relate to development of PJK have not been quantified. We hypothesize that the compensatory changes in the unfused segments of the spine over time are correlated with the surgically induced changes in the UIV position. METHODS: Sixty adolescent idiopathic scoliosis patients (with at least 1-year follow-up) who underwent posterior spinal surgery were included retrospectively. Global spinal parameters were calculated using 3-dimensional models of the spine, additional parameters [proximal junctional kyphosis angle (PJKA), cervical lordosis angle] were measured manually before surgery and at 3 postoperative follow-ups. The 3-dimensional position of the vertebral body centroids was calculated for T1, UIV, and lower-instrumented vertebra at all timepoints. The sagittal position of T1, UIV, and lower-instrumented vertebra were correlated to the cervical lordosis, PJKA, lumbar lordosis, and pelvic tilt. RESULTS: The position of T1 and UIV were significantly more anterior at first erect for patients who developed PJK. The posterior shift of UIV at the most recent follow-up as compared with the preoperative position was significant in both the PJK and non-PJK cohort. A larger anterior shift in UIV at first erect correlated with a larger T1 and UIV posterior shift at the most recent follow-up. At the most recent follow-up, a more posterior position of the UIV correlated with a larger angle of PJKA (P<0.05). CONCLUSION: Both a larger anterior shift of UIV between preoperative and first erect and a more posterior position of UIV at the most recent follow-up was correlated with a higher PJKA. A larger anterior shift in the position of the UIV after surgery was associated with a higher posterior shift of UIV at the last follow-up. The surgically induced changes in the UIV are an important parameter associated with the development of PJK. LEVEL OF EVIDENCE: Level IV.

CT-based study of vertebral and intravertebral rotation in right thoracic adolescent idiopathic scoliosis.

PURPOSE: To define the longitudinal rotation axis around which individual vertebrae rotate, and to establish the various extra- and intravertebral rotation patterns in thoracic adolescent idiopathic scoliosis (AIS) patients, for better understanding of the 3D development of the rotational deformity. METHODS: Seventy high-resolution CT scans from an existing database of thoracic AIS patients (Cobb angle: 46°-109°) were included to determine the vertebral axial rotation, rotation radius, intravertebral axial rotation, and local mechanical torsion for each spinal level, using previously validated image processing techniques. RESULTS: For all levels, the longitudinal rotation axis, from which the vertebrae rotate away from the midline, was localized posterior to the spine. The axis became closer to the spine at the apex: apex, r = 11.5 ± 5.1 cm versus two levels above (radius = 15.8 ± 8.5 cm; p < 0.001) and beneath (radius = 14.2 ± 8.2 cm; p < 0.001). The vertebral axial rotation, intravertebral axial rotation, and local mechanical torsion of the vertebral bodies were largest at the apex (21.9° ± 7.4°, 8.7° ± 13.5° and 3.0° ± 2.5°) and decreased toward the neutral, junctional zones (p < 0.001). CONCLUSION: In AIS, the vertebrae rotate away around an axis that is localized posterior to the spine. The distance between this axis and the spine is minimal at the apex and increases gradually to the neutral zones. The vertebral axial rotation is accompanied by smaller amounts of intravertebral rotation and local mechanical torsion, which increases toward the apical region. The altered morphology and alignment are important for a better understanding of the 3D pathoanatomical development of AIS and better therapeutic planning for bracing and surgical intervention. These slides can be retrieved under Electronic Supplementary Material.

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.

Scoliosis in association with the 22q11.2 deletion syndrome: an observational study.

OBJECTIVE: The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. It is characterised by wide phenotypic variability, including congenital heart disease (CHD), immunodeficiency and scoliosis. However, little is known regarding the prevalence and characteristics of scoliosis in patients with 22q11.2DS. The objective of this study is to assess the prevalence of scoliosis, its characteristics and the association with CHD in patients with 22q11.2DS. DESIGN: This prevalence study is based on physical examination and questionnaires of the world's largest 22q11.2DS longitudinal collected database (n=1393, Children's Hospital of Philadelphia) and was augmented with the scoliosis prevalence based on radiography in a smaller cohort (cross-sectional, University Medical Center Utrecht). PATIENTS: Patients with a laboratory-confirmed 22q11.2 deletion who visited the specialised outpatient clinics were considered for inclusion. MAIN OUTCOME MEASURES: (1) The prevalence of scoliosis, (2) its association with CHD, and (3) the similarity between 22q11.2DS curve patterns and adolescent idiopathic scoliosis (AIS) curve patterns. RESULTS: Within the Philadelphia cohort, the prevalence of scoliosis in patients older than 16 years (n=317) was 48% (n=152). A similar prevalence (49%) was shown for the younger Utrecht cohort (n=97). The occurrence of scoliosis was not associated with the presence of CHD. Sixty-three per cent of patients with scoliosis had a scoliotic curve pattern that resembled AIS. CONCLUSIONS: Clinicians should be aware that scoliosis is highly prevalent (48%-49%) in association with 22q11.2DS, irrespective of other clinical features (eg, the presence of CHD). Furthermore, 22q11.2DS may provide insights into the causes of AIS.

The Changing Position of the Center of Mass of the Thorax During Growth in Relation to Pre-existent Vertebral Rotation.

STUDY DESIGN: Cross-sectional. OBJECTIVE: The aim of this study was to analyze the thoracic center of mass (COM) position of children at different ages and evaluate its relation with the previously reported pre-existent rotational pattern of the normal spine. SUMMARY OF BACKGROUND DATA: The normal, nonscoliotic thoracic spine is known to have a rotational pattern that changes direction during growth, a transition from left-sided toward right-sided rotation with increasing age. This matches the changing curve convexity seen when idiopathic scoliosis develops at different ages. Furthermore, the direction of pre-existent rotation was shown to be related to organ orientation; in situs inversus the rotation is opposite to situs solitus. METHODS: Computed tomography (CT) scans of the thorax of infantile (0-4 years, n = 40), juvenile (4-10 years, n = 53), and adolescent (10-18 years, n = 62) children without spinal pathology were included from an existing database. The location of the COM inside the thorax was calculated based on Hounsfield-units, representing tissue mass. The COM offset was defined as the shortest distance to the midsagittal plane. RESULTS: At the infantile age, the COM was 2.5 ±â€Š2.1 mm on the right side, at juvenile age not significantly deviated, and at adolescent age 3.1 ±â€Š2.3 mm on the left side of the midsagittal plane. The mean COM offset correlated linearly with age (r = 0.77, P < 0.001). CONCLUSION: The COM shifts from slightly on the right side of the thorax at the infantile age, to neutral at juvenile age, to the left at adolescent age. This corresponds to the earlier demonstrated change in direction of pre-existent rotation in the normal spine with age, as well as with the well-known changing direction, from left to right, of thoracic curve convexity in scoliosis at different ages. LEVEL OF EVIDENCE: N/ A.

Club foot in association with the 22q11.2 deletion syndrome: An observational study.

The 22q11.2 Deletion Syndrome (22q11.2DS) occurs in ~1:3,000-6,000 individuals. Features less typically associated with 22q11.2DS, such as orthopedic manifestations, may be overlooked or may not lead to appropriate diagnostic testing. Club foot has a general population prevalence of ~1:1,000 and has been occasionally described in association with 22q11.2DS. Our hypothesis is that the prevalence of club foot is higher in patients with 22q11.2DS. We performed a retrospective review in two specialized 22q11.2DS centers to determine the prevalence of club foot. "True club foot" requires treatment (either conservative or surgical), therefore we only included those patients with proof of treatment. We investigated whether congenital heart disease (CHD) and/or cleft palate were associated with the presence of club foot within 22q11.2DS. The records of 1,466 patients were reviewed. Of these, 48 (3.3%) had confirmation of club foot (95% Confidence Interval: 2.4-4.3): 22 (46%) had a bilateral, 12 (25%) left, and 14 (29%) right club foot. Within our study, neither a CHD and/or a cleft palate were associated with a club foot. The prevalence of club foot in 22q11.2DS is 30 times higher than that observed in the general population. This suggests the diagnosis of club foot, especially in the face of other typically associated abnormalities of 22q11.2DS, should provoke consideration of 22q11.2DS as an underlying diagnosis, particularly in the neonatal setting.

What is new with 22q? An update from the 22q and You Center at the Children's Hospital of Philadelphia.

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome-specific, low copy repeat (LCR)-mediated copy-number losses of chromosome 22q11. The Children's Hospital of Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A-LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full-scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age.

Orthopaedic manifestations within the 22q11.2 Deletion syndrome: A systematic review.

The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome with an estimated prevalence of 1:4,000 live births. 22q11.2DS is known to have wide phenotypic variability, including orthopaedic manifestations. The purpose of this systematic review is to increase the awareness of orthopaedic manifestations associated with 22q11.2DS. This systematic review was performed according to the PRISMA Guidelines. Original epidemiological studies on the prevalence of orthopaedic manifestations within 22q11.2DS were systematically searched for in PubMed and EMBASE. The included articles were scored according to a risk-of-bias tool, a best-evidence synthesis was performed and the prevalence data was extracted. Sixty-nine published manuscripts described 58 orthopaedic manifestations in a total of 6,055 patients. The prevalence of at least one cervical or occipital anomaly is 90.5-100% (strong evidence). Fourteen studies (n = 2,264) revealed moderate evidence for a wide scoliosis prevalence of 0.6-60%. Two studies demonstrated that 5-6.4% of all 22q11.2DS patients required surgical scoliosis correction. Fifteen studies (n = 2,115) reported a 1.1-13.3% prevalence of clubfoot with moderate evidence. Other reported orthopaedic manifestations are patellar dislocation (10-20%), juvenile rheumatic arthritis (3.75%), impaired growth and skeletal anomalies like polydactyly (1.0-3.7%), syndactyly (11-11.8%), butterfly vertebrae (11.1%) and 13 ribs (2-19%). Orthopaedic findings are important manifestations of the 22q11.2DS, both in bringing patients to diagnostic attention and in requiring surveillance and appropriate intervention. Data on these manifestations are scattered and incomprehensive. Routinely screening for cervical anomalies, scoliosis, and upper and lower limb malformations is recommended in this vulnerable group of patients.