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 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.

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.

Spica cast application in the emergency room for select pediatric femur fractures.

OBJECTIVES: This study was designed to evaluate the efficacy and safety of immediate spica casting in the emergency room (ER) and evaluate the effect of discharge from the emergency room on short- term complications. DESIGN: Retrospective review of patients treated with immediate spica casting in the ER between June 1, 1993 and July 30, 2001. SETTING: Major, pediatric, orthopaedic trauma and referral center. PATIENTS: A total of 145 pediatric femur fractures in children, younger than age 7 years, treated with immediate spica casting in the ER were reviewed to determine radiographic outcome and short-term complication rates. INTERVENTION: All patients underwent immediate spica cast placement in the ER under conscious sedation. Patients meeting specific criteria were discharged immediately from the ER. MAIN OUTCOME MEASUREMENTS: Radiographic acceptability of alignment at fracture union (angulation, shortening), loss of reduction, number of return visits to the emergency room, and clinical outcome at final follow-up. RESULTS: Average follow-up was 20 +/- 16 weeks (range, 1-9 months). Forty-eight patients (33%) were discharged from the ER. No clinical complications were noted at last follow-up. All children younger than age 2 years, and 86.5% of children ages 2 to 5 years, met acceptable malalignment parameters on final radiographs. There were 16 ER visits (11%) for cast problems. Re-reduction in the operating room was needed in 11 patients (8.9%); 6.9% of patients had a cast problem noted during follow-up visits. Only 9% of patients developed a major complication. Initial shortening was the only independent risk factor found to be associated with loss of reduction. Admission status had no significant effect on the number of ER visits or development of a complication. CONCLUSIONS: If there are no associated factors requiring admission (ie, child abuse or polytrauma), spica casting in the ER for pediatric femur fractures followed by immediate discharge can be safely performed with a low complication rate in children younger than age 6 years, nearly eliminating the need for general anesthesia.