A mechanism for gene-environment interaction in the etiology of congenital scoliosis.

Congenital scoliosis, a lateral curvature of the spine caused by vertebral defects, occurs in approximately 1 in 1,000 live births. Here we demonstrate that haploinsufficiency of Notch signaling pathway genes in humans can cause this congenital abnormality. We also show that in a mouse model, the combination of this genetic risk factor with an environmental condition (short-term gestational hypoxia) significantly increases the penetrance and severity of vertebral defects. We demonstrate that hypoxia disrupts FGF signaling, leading to a temporary failure of embryonic somitogenesis. Our results potentially provide a mechanism for the genesis of a host of common sporadic congenital abnormalities through gene-environment interaction.

Musculoskeletal phenotypes in 3q29 deletion syndrome.

3q29 deletion syndrome (3q29del) is a rare genomic disorder caused by a 1.6 Mb deletion (hg19, chr3:195725000-197350000). 3q29del is associated with neurodevelopmental and psychiatric phenotypes, including an astonishing >40-fold increased risk for schizophrenia, but medical phenotypes are less well-described. We used the online 3q29 registry of 206 individuals (3q29deletion.org) to recruit 57 individuals with 3q29del (56.14% male) and requested information about musculoskeletal phenotypes with a custom questionnaire. 85.96% of participants with 3q29del reported at least one musculoskeletal phenotype. Congenital anomalies were most common (70.18%), with pes planus (40.35%), pectus excavatum (22.81%), and pectus carinatum (5.26%) significantly elevated relative to the pediatric general population. 49.12% of participants reported fatigue after 30 min or less of activity. Bone fractures (8.77%) were significantly elevated relative to the pediatric general population. Participants commonly report receiving medical care for musculoskeletal complaints (71.93%), indicating that these phenotypes impact quality of life for individuals with 3q29del. This is the most comprehensive description of musculoskeletal phenotypes in 3q29del to date, suggests ideas for clinical evaluation, and expands our understanding of the phenotypic spectrum of this syndrome.

Hematogenous Osteomyelitis in Infants and Children: Imaging of a Changing Disease.

In children, hematogenous osteomyelitis is an infection that primarily affects the most vascularized regions of the growing skeleton. The disease has increased in frequency, virulence, and degree of soft-tissue involvement. The change in clinical manifestations and management over the past 2 decades should be reflected in the current imaging approach to the disease. Imaging of infection must depict the location of a single focus or of multiple foci of involvement and the presence of drainable collections. This review provides an overview of the imaging implications directed by the changing epidemiology, the newer insights of anatomy and pathophysiology, the imaging characteristics with emphasis on specific locations and disease complications, and the differential diagnosis considerations. In addition, basic imaging guidelines for appropriate extent of area to image based on patient age are provided. © RSNA, 2017.

Rod fracture and lengthening intervals in traditional growing rods: is there a relationship?

PURPOSE: Is there any relationship between lengthening intervals and rod fracture in traditional growing rod (TGR) surgery? METHODS: A multicenter EOS database was queried for patients who had: (1) dual growing rods for EOS; (2) minimum 2-year follow-up; (3) a minimum of 2 lengthenings; and (4) revision surgery due to rod fracture. Of 138 patients who met the criteria: 56 patients experienced at least one-rod fracture (RF group) and 82 patients had no rod fractures (NRF group). In addition to each patient's lengthening intervals, demographics, construct details, and radiographic parameters were compared. RESULTS: RF and NRF patients had a mean pre-op age of 5.7 years (range 1.3-10.7) and 7.3 years (range 1.6-12.8), respectively (p < 0.001). There was no significant association between etiologies and rod fracture or between BMI and rod fracture (p = 0.979). There was no significant difference between lengthening intervals between the RF and NRF groups (p > 0.05). RF and NRF patients had statistically similar mean pre-op major curve size and max kyphosis (p = 0.279; p = 0.619, respectively). Stainless steel rods fractured more frequently compared with Titanium rods (SS 49.2 % vs. Ti 38 %; p = 0.004). Rod fracture occurred more in rods smaller than 4 mm (p = 0.011). CONCLUSIONS: Lengthening intervals were not statistically different in RF and NRF groups and there was no association between lengthening interval and rod fracture in TGR cases. It was shown that patients who had rod fracture were younger and were more likely to have SS rods with smaller than 4 mm diameter.

Surgical treatment of pelvic sarcoma in children: outcomes for twenty six patients.

PURPOSE: Pelvic sarcoma is uncommon in children and challenging to treat. This study examined different surgical approaches to treat pelvic sarcoma with the aim of assessing the oncologic, and functional outcomes. METHODS: We retrospectively examined the medical records of patients younger than 21 years of age who underwent surgery for pelvic sarcoma at our institution from 1992 to 2010. The functional status of the patients was examined after a minimum follow-up of two years. RESULTS: Twenty-six patients were included in the analysis. Nineteen (73%) patients were male and seven (27%) were female. Mean age at presentation was 12.0 ± 3.9 years. Nineteen patients had Ewing sarcoma (73%), five had osteosarcoma (19%), one had chondrosarcoma (4%) and one had rhabdomyosarcoma (4%). Iliac wing resection with no reconstruction was done in three patients. Reconstruction with free fibular graft A-frame was performed in four patients, saddle endoproshtesis in five patients, iliac autoclave in one patient, and internal hemipelvectomy in nine patients. Hindquarter amputation was performed in five patients. Median follow-up was 4.6 years (range, 2.6-16 years). Nineteen patients were alive (73%); of those, 13 were known to be without disease, three were with disease and three did not have known tumor status. Six patients were reported deceased, three had osteosarcoma and three had Ewing sarcoma. Function was assessed in 17 patients; 64% were asymptomatic and ambulatory and 36% were symptomatic and ambulatory. CONCLUSIONS: Salvage reconstruction for pelvic sarcoma can be performed through various procedures on the extent of necessary bony resection. Survival rate and functional outcomes were promising in the performed study.

Characterizing the differences between the 2D and 3D measurements of spine in adolescent idiopathic scoliosis.

PURPOSE: Although adolescent idiopathic scoliosis (AIS) is known to impact the 3D orientation of the spine and pelvis, the impact of the vertebral position relative to the X-ray scanner on the agreement between 2D and 3D measurements of a curve has not been evaluated. The purpose of this study was to investigate the agreement between 2D and 3D measurements of the scoliotic curve as a function of the 3D spinal parameters in AIS. METHODS: Three independent observers measured the thoracic and lumbar Cobb angles, Kyphosis, and lordosis on the posterior-anterior and lateral X-rays of AIS patients. The 3D reconstructions were created from bi-planar X-rays and the 3D spinal parameters were calculated in both radio and patient planes using SterEOS software. The degree of agreement between the 2D and 3D measurements was tested and its relationship with the curve axial rotation was determined. RESULTS: 2D and 3D measurements of the sagittal plane spinal parameters were significantly different (p < 0.05). The differences between the 2D and 3D measurements were related to the apical vertebrae rotation, the orientation of the plane of maximum curvature, pelvic axial rotation, and the curve magnitude. Differences between the radio plane and patient plane measurements were related to the pelvic axial rotation, Cobb angles, and apical vertebrae rotation, p < 0.05. CONCLUSION: Clinically and statistically significant differences were observed between the 2D and 3D measurements of the scoliotic spine. The differences between the 2D and 3D techniques were significant in sagittal plane and were related to the spinal curve and pelvic rotation in transverse plane.

Bi-planar spinal stereoradiography of adolescent idiopathic scoliosis: considerations in 3D alignment and functional balance.

PURPOSE: A prospective, cross-sectional study to determine the impact of arm position on the 3D spine and pelvic parameters and postural balance in adolescent idiopathic scoliosis. METHODS: A total number of 37 adolescent idiopathic scoliosis patients were enrolled prospectively. Three arm positions, (1) 45° shoulder flexion with knuckles on clavicles, (2) 90° shoulder and elbow flexion with forearms and palms on the front wall, and (3) arms hanging on either side, were instructed to the cohort. Bi-planar low dose X-ray images of the spine and pelvis were registered in a stereoradiography system in the first and second arm positions. A pressure mat recorded the position of the center of pressure in each arm position. Spinal and pelvic parameters were measured for the cohort. Statistical analysis was performed to determine the agreement between the spinal and pelvic parameters and standing balance in different arm positions. RESULTS: Thoracic kyphosis, sacral slope, sagittal vertical axis, T1 tilt, and spinal height were significantly different between the knuckles on clavicle and forearms on the wall positions p < 0.05. Significant differences were observed in the pressure distribution under the feet between the wall and freestanding positions. Bland-Altman plots determined disagreements between the first and second arm positions in clinical measurements and postural assessment of adolescent idiopathic scoliosis. CONCLUSION: The knuckles on clavicles position replicates the functional standing balance in AIS. Significant differences between the spinal and pelvic parameters suggest that the wall and clavicle arm positions should not be used interchangeably in AIS postural assessment. LEVEL OF EVIDENCE: Diagnostic level II.

Postural orthostatic tachycardia syndrome (POTS): association with Ehlers-Danlos syndrome and orthopaedic considerations.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is the most common of several types of dysautonomia, characterized by dysfunction of the autonomic nervous system manifesting with symptoms of orthostatic intolerance with or without associated orthostatic hypotension and excessive autonomic excitation. Given the numerous presenting musculoskeletal symptoms of POTS and its known associations with other clinical entities like Ehlers-Danlos syndrome, POTS constitutes an unusual treatment challenge of which the orthopaedic surgeon and other related healthcare providers should be aware. CASE DESCRIPTION: We describe two patients with a diagnosis of POTS and musculoskeletal manifestations. The first is a 13-year-old boy with a concurrent diagnosis of Ehlers-Danlos syndrome and worsening back pain. The patient had resolution of his musculoskeletal symptoms after treatment with a Boston Overlap LSO brace and physical therapy and resolution of his cardiovascular symptoms after pharmacologic treatment. The second patient is a 17-year-old girl with an L1 vertebral hemangioma and pain of sudden onset radiating to her lower extremities. Her symptoms were controlled with therapy and gabapentin. LITERATURE REVIEW: POTS is a poorly understood and controversial clinical entity with lack of awareness and knowledge regarding the syndrome by the majority of medical specialists. Its complex and wide range of clinical presentation has led to being commonly mistaken with malingering, depression and anxiety disorders. Review of the literature did not yield any previous studies addressing POTS and the special considerations for the orthopaedic surgeon caring for these patients; previous studies of large patient series focus on investigating the pathologic substrate of POTS and the efficacy of various treatment modalities on the cardiovascular dysregulation. CLINICAL RELEVANCE: These two cases show that understanding and knowledge of this syndrome and its comorbidities should guide any diagnostic approach or therapeutic intervention by the orthopaedic surgeon caring for patients with this syndrome. It is important that the surgeon is aware of the benefits of detailed patient education and physical conditioning, the increased perioperative complications, and the need for specialized anesthesia.

Antifibrinolytic Use and Blood Transfusions in Pediatric Scoliosis Surgeries Performed at US Children's Hospitals.

STUDY DESIGN: Retrospective cohort study using the Pediatric Health Information Systems database. OBJECTIVE: To determine the association between antifibrinolytic use and red cell transfusions in spinal fusion operations performed at 37 US Children's Hospitals. SUMMARY OF BACKGROUND DATA: Evidence from randomized clinical trials and systematic reviews suggests that antifibrinolytic therapy can significantly reduce blood loss in children undergoing scoliosis surgery; however, the effectiveness of these agents as used in surgeries performed at US children's has not been studied. MATERIALS AND METHODS: We included children aged 0-18 years with diagnoses indicating adolescent idiopathic scoliosis (AIS) or neuromuscular scoliosis (NMS) for whom a spinal fusion procedure was performed between January 1, 2006 and September 30, 2009. Patients with malignancy, trauma, coagulation disorders, or for whom a cell salvage device was employed were excluded. Multilevel logistic regression was used to determine associations between ε-aminocaproic acid (EACA), tranexamic acid (TXA), and aprotinin (APR) use and blood transfusions, controlling for patient and surgery characteristics. RESULTS: Cohorts consisted of 2722 AIS and 1547 NMS procedures. Antifibrinolytic use varied across hospitals (AIS 3.3%, interquartile range, 0%-42%; NMS 12 interquartile range, 0%-46%), and was significantly associated with NMS, posterior fusion, number of vertebrae fused. Overall, 15% of children received EACA, 7% TXA, and 2% APR. The median hospital-specific rate of red cell transfusions was 24% for AIS and 43% for NMS. In AIS operations, EACA use, but not TXA use, was associated with significantly lower odds of transfusion (odds ratio, 0.42; P<0.001 vs. odds ratio, 1.0; P=0.8). In NMS operations, neither EACA nor TXA use was associated with a decrease in odds of red cell transfusions. CONCLUSIONS: The effectiveness of antifibrinolytics as used outside of clinical trials is unclear and should continue to be explored. Future prospective research is needed to evaluate which administration protocols will most benefit patients, as well as to determine the comparative effectiveness of these drugs in the context of other blood conservation strategies.

Scoliosis in Children With Aicardi Syndrome.

BACKGROUND: Aicardi syndrome (ACS) is a rare neurodevelopmental disorder that was classically characterized by the triad of agenesis of corpus callosum, infantile spasms, and chorioretinal lacunae. As new cases emerge and new common phenotypic features are being described in subsequent reports, new modified diagnostic criteria have been proposed that now classify the observed costovertebral abnormalities as supporting diagnostic features. To our knowledge there are no previous studies focusing and describing the scoliosis observed in children with ACS. METHODS: We screened billing lists to identify patients seen in the Division of Orthopaedic Surgery at our institution with a diagnosis of ACS that were treated for scoliosis after 2001. A total of 5 patients were identified. Medical records and radiographs were retrospectively reviewed in all cases. In all of the patients the diagnosis of ACS had been confirmed through complete genetic evaluation and advanced imaging. RESULTS: The mean age when scoliosis was first noticed was 3.9±4.2 years (range, 0.5 to 10.5 y) with a mean Cobb angle of 22.5±6.7 degrees (range, 10 to 27 degrees). The mean age at the first orthopedic visit was 5.8±5.0 years (range, 1.5 to 13 y) with a progressed mean Cobb angle of 39.5±17.3 degrees (range, 15 to 57 degrees). Congenital vertebral anomalies were observed in 1 patient. Three patients were treated surgically; 1 of the 3 patients had a surgical complication with loss of intraoperative neuromonitoring signals. Two patients had not undergone surgery at the last visit with a mean Cobb angle of 75.5 degrees. The mean postoperative follow-up for the surgical group (cases 1 to 3) was 3±3.6 years (range, 0.6 to 7.2 y) and the mean total follow-up for both groups was 6.6±2.5 years (range, 2.6 to 8.6 y). CONCLUSIONS: Scoliosis in ACS can represent a clinically significant problem that is underdiagnosed and overshadowed by the other severe medical complications associated with the syndrome. Our data suggest that scoliosis in patients with ACS is rapidly progressive and bracing is ineffective; early screening, close observation, and low threshold for referral to an orthopedic surgeon are crucial. LEVEL OF EVIDENCE: Level IV-case series.

Pinless halo in the pediatric population: indications and complications.

BACKGROUND: The use of the conventional halo is accompanied by the possibility of serious complications, especially in the pediatric population. Complications could include penetration of pin into the skull, pin loosening, pin tract infection, cranial nerve palsies, and vest-related pressure sores. The noninvasive "pinless" halo was introduced in an attempt to mitigate these problems while retaining the effectiveness of the conventional halo. The purpose of this study is to determine the indications and complications related to pinless halo application. METHODS: We retrospectively reviewed 61 patients, whose treatment included the use of a pinless halo device, presenting to our institution between 2004 and 2012. RESULTS: There were 35 male and 26 female patients with an average age of 6.04 years. Indications of pinless halo application included postoperative immobilization for congenital muscular torticollis in 38 cases, conservative management of atlantoaxial rotatory subluxation in 11 cases, postoperative immobilization following cervical fusion in 10 cases, and immobilization for occipital condyle fracture in 2 cases. The average duration of the pinless halo application was 32.68 days. Thirteen patients had complications, among which major complications were seen in 2 patients, each of whom developed a pressure sore; one on the scalp and the other on the chest. Both the pressure sores responded to local treatment; however, 1 resulted in permanent alopecia. CONCLUSIONS: The use of the noninvasive pinless halo was found to be safe with few complications in our study. The complications were infrequent and patients were compliant to treatment, indicating that this modality is patient-friendly. Effectiveness of this treatment in comparison with invasive halos and other cervical orthoses was not determined and is a limitation of this study. LEVEL OF EVIDENCE: Level IV-Case series.

Melorheostosis: segmental osteopoikilosis or a separate entity?

PURPOSE: Melorheostosis is a progressive hyperostotic bone disease that commonly affects the appendicular skeleton. Melorheostosis has a significant degree of overlap with other hyperostosis conditions including osteopoikilosis and likely represent varying degrees of a clinical spectrum. METHODS: This is a report of 2 patients with melorheostosis who presented with different clinical presentations and involvement of different anatomic locations. RESULTS: One of the patients presented with foot size asymmetry along with intermittent foot pain and limping. This patient also had irregular nonblanching yellow plaque-like lesion on the forehead. The second patient presented with abnormal gait but no pain. Radiographs demonstrated endosteal hyperostosis, which were consistent with a mixed picture of melorheostosis and osteopoikilois. Genetic testing of the LEMD3 gene from a blood sample was negative in both cases. CONCLUSIONS: The diagnosis of melorheostosis can be made based on the clinical and radiographic features and can be challenging to differentiate from other hyperostosis conditions. LEVEL OF EVIDENCE: Level V.

Loss of ß-catenin induces multifocal periosteal chondroma-like masses in mice.

Osteochondromas and enchondromas are the most common tumors affecting the skeleton. Osteochondromas can occur as multiple lesions, such as those in patients with hereditary multiple exostoses. Unexpectedly, while studying the role of ß-catenin in cartilage development, we found that its conditional deletion induces ectopic chondroma-like cartilage formation in mice. Postnatal ablation of ß-catenin in cartilage induced lateral outgrowth of the growth plate within 2 weeks after ablation. The chondroma-like masses were present in the flanking periosteum by 5 weeks and persisted for more than 6 months after ß-catenin ablation. These long-lasting ectopic masses rarely contained apoptotic cells. In good correlation, transplants of ß-catenin-deficient chondrocytes into athymic mice persisted for a longer period of time and resisted replacement by bone compared to control wild-type chondrocytes. In contrast, a ß-catenin signaling stimulator increased cell death in control chondrocytes. Immunohistochemical analysis revealed that the amount of detectable ß-catenin in cartilage cells of osteochondromas obtained from hereditary multiple exostoses patients was much lower than that in hypertrophic chondrocytes in normal human growth plates. The findings in our study indicate that loss of ß-catenin expression in chondrocytes induces periosteal chondroma-like masses and may be linked to, and cause, the persistence of cartilage caps in osteochondromas.

Unicameral bone cysts: general characteristics and management controversies.

Unicameral bone cysts are benign bone lesions that are often asymptomatic and commonly develop in the proximal humerus and femur of skeletally immature patients. The etiology of these lesions remains unknown. Most patients present with a pathologic fracture, but these cysts can be discovered incidentally, as well. Radiographically, a unicameral bone cyst appears as a radiolucent lesion with cortical thinning and is centrally located within the metaphysis. Although diagnosis is frequently straightforward, management remains controversial. Because the results of various management methods are heterogeneous, no single method has emerged as the standard of care. New minimally invasive techniques involve cyst decompression with bone grafting and instrumentation. These techniques have yielded promising results, with low rates of complications and recurrence reported; however, prospective clinical trials are needed to compare these techniques with current evidence-based treatments.

Lipofibromatosis: an institutional and literature review of an uncommon entity.

We report six new cases of lipofibromatosis, an uncommon pediatric soft tissue neoplasm. This is the only series of patients to be described since the initial case series of 45 patients that characterized this entity in 2000. The purpose of this study was to characterize the presentation of lipofibromatosis to further define the clinical phenotype of this rare entity. Six patients were diagnosed with lipofibromatosis at our institution from 2000 to 2012. Patient age, sex, and ethnicity were recorded, along with tumor site and size, management, and recurrence data. Half of our patients were younger than 2 years old at presentation and the other half were school age. Boys and girls were affected with equal frequency. In five of six patients, lipofibromatosis presented in its "classic" form as a mass on the distal extremities. These tumors typically measured 1 to 2 cm in diameter, in contrast to case reports in the medical literature highlighting the occurrence of lipofibromatosis of greater size and at varied anatomic sites. The tumors in our series were managed using excision, with recurrence noted in 33%. Lipofibromatosis is an uncommon tumor typically found on the distal extremities of infants, although it can appear in various sizes and locations. It should be considered in the differential diagnosis of pediatric soft tissue neoplasms.

Bilateral C6 spondylolysis with spondylolisthesis in 3 adolescent siblings.

BACKGROUND: Cervical spondylolysis with spondylolisthesis is a rare condition in the pediatric population. The nature of this condition and clinical presentation are important to provide appropriate management. METHODS: This is a case report of 3 adolescent siblings who had C6 cervical spondylolysis with spondylolisthesis. RESULTS: Two cases were diagnosed insidiously with absence of neurological deficits and no instability on imaging and were treated conservatively. One case had a traumatic presentation associated with instability on imaging and was managed with cervical fusion and instrumentation. All 3 patients were doing well on a follow-up of >2 years. CONCLUSIONS: These cases suggest that cervical spondylolysis could be familial. The treatment was offered based on clinical presentation and presence of instability on radiographic studies. LEVEL OF EVIDENCE: Level IV.

Chest wall osteochondroma in children: a case series of surgical management.

BACKGROUND: Chest wall osteochondroma is a rare tumor in children. Even though the potential for malignant transformation or serious intrathoracic complications is low, it has led some centers to advocate surgical management of these bony tumors. We present our experience of the surgical management of costal osteochondromata. METHODS: Between January 1, 2006 and November 1, 2012 we saw 854 patients with solitary or multiple exostoses in our clinics. By reviewing our billing lists we found 7 children who had surgical management of chest wall osteochondromata. The indications for surgery were pain (3 patients), excision for confirmation of diagnosis (2 patients), recurrent pneumothorax (1 patient), and malignancy (1 patient). RESULTS: All patients made a good postoperative recovery with a median hospital stay of 1.8 days (range, 0 to 4 d). There was no recurrence of exostosis on follow-up (range, 8 mo to 2.6 y). One patient required surgery for excision of another chest wall osteochondroma at an adjacent location. No patient reported scar-related pain symptoms. No malignant transformation or intrathoracic complications occurred. We found ribs as the first site of presentation of multiple hereditary exostoses in 2 young patients. CONCLUSIONS: Surgical management of thoracic osteochondroma, with excision for painful, symptomatic, malignant lesions or lesions adjudged to be at risk of intrathoracic complications, yields good outcomes in terms of symptom control, establishing histologic diagnosis, and prevention of thoracic complications. LEVEL OF EVIDENCE: Level IV-case series.

Heparan sulfate in skeletal development, growth, and pathology: the case of hereditary multiple exostoses.

Heparan sulfate (HS) is an essential component of cell surface and matrix-associated proteoglycans. Due to their sulfation patterns, the HS chains interact with numerous signaling proteins and regulate their distribution and activity on target cells. Many of these proteins, including bone morphogenetic protein family members, are expressed in the growth plate of developing skeletal elements, and several skeletal phenotypes are caused by mutations in those proteins as well as in HS-synthesizing and modifying enzymes. The disease we discuss here is hereditary multiple exostoses (HME), a disorder caused by mutations in HS synthesizing enzymes EXT1 and EXT2, leading to HS deficiency. The exostoses are benign cartilaginous-bony outgrowths, form next to growth plates, can cause growth retardation and deformities, chronic pain and impaired motion, and progress to malignancy in 2-5% of patients. We describe recent advancements on HME pathogenesis and exostosis formation deriving from studies that have determined distribution, activities and roles of signaling proteins in wild-type and HS-deficient cells and tissues. Aberrant distribution of signaling factors combined with aberrant responsiveness of target cells to those same factors appear to be a major culprit in exostosis formation. Insights from these studies suggest plausible and cogent ideas about how HME could be treated in the future.

Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes.

Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ∼327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P < 8 × 10(-8) for rs1400180). We genotyped additional chromosome 3p26.3 SNPs and tested replication in two follow-up case-control cohorts, obtaining strongest results when all three cohorts were combined (rs10510181 odds ratio = 1.49, 95% confidence interval = 1.29-1.73, P = 2.58 × 10(-8)), but these were not confirmed in a separate GWAS. CHL1 is of interest, as it encodes an axon guidance protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease.

Chondroblastoma and chondromyxoid fibroma.

Chondroblastoma and chondromyxoid fibroma are benign but locally aggressive bone tumors. Chondroblastoma, a destructive lesion with a thin radiodense border, is usually seen in the epiphysis of long bones. Chondromyxoid fibroma presents as a bigger, lucent, loculated lesion with a sharp sclerotic margin in the metaphysis of long bones. Although uncommon, these tumors can be challenging to manage. They share similarities in pathology that could be related to their histogenic similarity. Very rarely, chondroblastoma may lead to lung metastases; however, the mechanism is not well understood.