Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations.

Genetic perturbations in nicotinamide adenine dinucleotide de novo (NAD) synthesis pathway predispose individuals to congenital birth defects. The NADSYN1 encodes the final enzyme in the de novo NAD synthesis pathway and, therefore, plays an important role in NAD metabolism and organ embryogenesis. Biallelic mutations in the NADSYN1 gene have been reported to be causative of congenital organ defects known as VCRL syndrome (Vertebral-Cardiac-Renal-Limb syndrome). Here, we analyzed the genetic variants in NADSYN1 in an exome-sequenced cohort consisting of patients with congenital vertebral malformations (CVMs). A total number of eight variants in NADSYN1, including two truncating variants and six missense variants, were identified in nine unrelated patients. All enrolled patients presented multiple organ defects, with the involvement of either the heart, kidney, limbs, or liver, as well as intraspinal deformities. An in vitro assay using COS-7 cells demonstrated either significantly reduced protein levels or disrupted enzymatic activity of the identified variants. Our findings demonstrated that functional variants in NADSYN1 were involved in the complex genetic etiology of CVMs and provided further evidence for the causative NADSYN1 variants in congenital NAD Deficiency Disorder.

Radiographic evaluation of congenital vertebral anomalies in Korean raccoon dogs (Nyctereutes procyonoides koreensis).

BACKGROUND: The normal vertebral anatomy of Korean raccoon dogs and their variants require research attention as a prerequisite for identifying pathologies and anomalies. OBJECTIVES: This retrospective study aimed at describing the vertebral formula and congenital vertebral anomalies in Korean raccoon dogs (Nyctereutes procyonoides koreensis). METHODS: Radiographs of 82 raccoon dogs (42 males, 40 females) acquired from May 2013 to June 2020 in the Gangwon Wildlife Medical Rescue Center were reviewed to evaluate the cervical, thoracic, and lumbar vertebrae of the spine. RESULTS: Normal morphology of all vertebrae was observed in 50 of the 82 raccoon dogs, and the vertebral formula was cervical 7, thoracic 13, and lumbar 7. Congenital vertebral anomalies were found in 32 raccoon dogs: transitional vertebrae (TV) in 31 and block vertebrae in 2. Two raccoon dogs had 2 types of vertebral anomalies: one had TV and block vertebra, and the other had 2 types of TV. Twenty-nine raccoon dogs had thoracolumbar TV (TTV) and 3 had lumbosacral TV. TTV was morphologically classified into 4 different types: unilateral extra-rib in 5 raccoon dogs, bilateral extra-ribs in 14, bilateral elongated transverse processes in 4, and an asymmetric mixed formation of extra-rib with elongated transverse process in 6. CONCLUSIONS: This study showed that TTV is common in Korean raccoon dogs, and that the vertebral formula is relatively diverse. The bilateral extra-ribs type TTV is the most common variant, which is almost similar to normal rib to be confused the radiographic evaluation.

Pictorial review: imaging of the spinal manifestations of achondroplasia.

Achondroplasia is the commonest hereditary skeletal dysplasia exhibiting dwarfism with characteristic rhizomelic (proximal) shortening of the limbs. It is predominantly linked with an autosomal dominant inheritance, but sporadic mutations can occur which are associated with advanced maternal age. Approximately 1 in every 25 000-30 000 live births are affected, and the overall life expectancy is marginally reduced by ~10 years. Mutations in the fibroblast growth factor receptor causes a decrease in endochondral ossification, which results in stunted growth of cartilaginous bones. A resultant narrowed foramen magnum and a short clivus are seen which predisposes to craniocervical spinal canal stenosis. Apnoeic events arising from the compression of the vertebral arteries at the level of the craniocervical junction lead to fatality in the young, with a death rate as high as 7.5%. Decrease in the caudal inter-pedicular distance is characteristic and a contributory factor for cervical, thoracic and lumbar spinal canal stenosis, most pronounced in the lumbar spine with patients often requiring surgical intervention to ease symptoms. Thoracolumbar kyphoscoliosis and sacral manifestations such as small sacro-sciatic notches and a horizontal pelvis are seen. The aim of this pictorial review is to demonstrate the imaging findings of the spinal and pelvic manifestations of achondroplasia.

Fetal body MRI and its application to fetal and neonatal treatment: an illustrative review.

This Review depicts the evolving role of MRI in the diagnosis and prognostication of anomalies of the fetal body, here including head and neck, thorax, abdomen and spine. A review of the current literature on the latest developments in antenatal imaging for diagnosis and prognostication of congenital anomalies is coupled with illustrative cases in true radiological planes with viewable three-dimensional video models that show the potential of post-acquisition reconstruction protocols. We discuss the benefits and limitations of fetal MRI, from anomaly detection, to classification and prognostication, and defines the role of imaging in the decision to proceed to fetal intervention, across the breadth of included conditions. We also consider the current capabilities of ultrasound and explore how MRI and ultrasound can complement each other in the future of fetal imaging.

Twin pregnancy complicated with congenital Hemivertebra: report of two cases and literature review.

BACKGROUND: Hemivertebra deformity, involving one or multiple vertebral bodies, is one of the important causes of congenital scoliosis. Congenital fetal hemivertebrae could be diagnosed by ultrasonography and confirmed by fetal magnetic resonance imaging during pregnancy. However, reports of hemivertebrae in twins during the perinatal period are very rare. CASE PRESENTATION: We report two cases of congenital fetal hemivertebrae, each affecting one fetus in a dichorionic diamniotic (DCDA) twin pregnancy. We have also conducted a literature review of its prenatal screening, diagnosis, management, and outcomes. These two cases of congenital fetal hemivertebrae in one fetus of a DCDA twin were both initially found by ultrasonography and confirmed by fetal magnetic resonance imaging (MRI). One couple chose selective termination of the hemivertebrae fetus after they were extensively counseled by the multidisciplinary team regarding the treatment and prognosis of the hemivertebrae twin, and a healthy baby weighing 2320 g was delivered at the 37+ 1 gestational week. The other couple decided to continue the twin pregnancy and gave birth to two living newborns weighing 2580 g and 2060 g at 37+ 1 gestational weeks. These three babies were all in good health during follow-up. CONCLUSIONS: Based on our center's experience, comprehensive ultrasonography is necessary for early prenatal diagnosis of this condition. In addition, fetal MRI will confirm the diagnosis of hemivertebrae and provide parents with helpful information for their decision about the fate of the affected fetus.

Perosomus elumbis in a stillborn rhesus macaque (Macaca mulatta): A case report.

Perosomus Elumbis (PE) is a rare congenital disorder characterized by absence of caudal spine (lumbar, sacral, and coccygeal vertebrae). Here, we present the first reported case of PE in a rhesus macaque (Macaca mulatta) and relate our findings to those described in other species.

Multimodal Intraoperative Spinal Cord Monitoring during Spinal Deformity Surgery: Efficacy, Diagnostic Characteristics, and Algorithm Development.

OBJECTIVE: This study aims to present the diagnostic characteristics of multimodal intraoperative monitoring (IOM) in spinal deformity surgery and to define and categorise the neuromonitoring events, as well as propose an algorithm of action. MATERIALS AND METHODS: We reviewed 1,155 consecutive patients (807 female, 348 male) who underwent deformity correction using standardised perioperative care, cortical/cervical somatosensory evoked potentials (SSEPs), and upper/lower limb transcranial electrical motor evoked potential (MEPs) by a single surgeon. The mean age at surgery was 13.8 years (range 10-23.3). We categorised IOM events as true, transient true, and false positive or negative. Diagnostic performance criteria were calculated. RESULTS: The most common diagnosis was adolescent idiopathic scoliosis in 717 (62%) patients. We identified 3 true positive monitoring events occurring in 2 patients (0.17%), 8 transient true positive (0.69%), and 8 transient false positive events (0.69%). There were no false negative events and no patient had postoperative neurological complications. The multimodal IOM technique had a sensitivity of 100%, specificity of 99.3%, positive predictive value of 55.6%, and negative predictive value of 100%. Sensitivity was 100% for MEPs and multimodal monitoring compared to 20% for cortical or cervical SSEPs. The frequency of true or transient true positive events was higher (p = 0.07) in Scheuermann's kyphosis (3/91 patients, 3.3%) compared to adolescent idiopathic scoliosis (6/717 patients, 0.84%). CONCLUSION: Multimodal IOM is highly sensitive and specific for spinal cord injury. This technique is reliable for the assessment of the condition of the spinal cord during major deformity surgery. We propose an algorithm of intraoperative action to allow close cooperation between the surgical, anaesthetic, and neurophysiology teams and to prevent neurological deficits.

A Recurrent Rare SOX9 Variant (M469V) is Associated with Congenital Vertebral Malformations.

OBJECTIVE: The genetic variations contributed to a substantial proportion of congenital vertebral malformations (CVM). SOX9 gene, a member of the SOX gene family, has been implicated in CVM. To study the SOX9 mutation in CVM patients is of great significance to explain the pathogenesis of scoliosis (the clinical manifestation of CVM) and to explore the pathogenesis of SOX9-related skeletal deformities. METHODS: A total of 50 singleton patients with CVM were included in this study. Exome Sequencing (ES) was performed on all the patients. The recurrent candidate variant of SOX9 gene was validated by Sanger sequencing. Luciferase assay was performed to investigate the functional changes of this variant. RESULTS: A recurrent rare heterozygous missense variant in SOX9 gene (NM_000346.3: c.1405A>G, p.M469V) which had not been reported previously was identified in three CVM patients who had the clinical findings of congenital scoliosis without deformities in other systems. This variant was absent from our in-house database and it was predicted to be deleterious (CADD = 24.5). The luciferase assay demonstrated that transactivation capacity of the mutated SOX9 protein was significantly lower than that of the wild-type for the two luciferase reporters (p = 0.0202, p = 0.0082, respectively). CONCLUSION: This SOX9 mutation (p.M469V) may contribute to CVM without other systematic deformity, which provides important implications and better understanding of phenotypic variability in SOX9-related skeletal deformities.

Congenital malformations of the lumbosacral vertebral column are common in neurologically normal French Bulldogs, English Bulldogs, and Pugs, with breed-specific differences.

Congenital vertebral malformations are common findings on diagnostic imaging of the vertebral column in "screw-tailed" brachycephalic dogs. The aims of this study were to evaluate the prevalence and anatomical characteristics of lumbosacral congenital vertebral malformations in French Bulldogs, English Bulldogs, and Pugs presenting for problems unrelated to spinal disease, as well as possible associations with the degree of tail malformation, lumbosacral intervertebral disc herniation, or spondylosis deformans. In this retrospective cross-sectional study, CT scans of vertebrae L6 to S3 and of the coccygeal vertebrae were reviewed for type of congenital vertebral malformations (hemivertebrae, block vertebrae, lumbosacral transitional vertebrae, and spina bifida), lumbosacral intervertebral disc herniation, lumbosacral spondylosis deformans, and degree of tail malformation. In 76 (51.0%) of the 149 included dogs (53 French Bulldogs, 37 English Bulldogs, and 59 Pugs) at least one type of congenital vertebral malformations was found, with lumbosacral transitional vertebrae being the most common (34.2%). There was a significantly higher prevalence of lumbosacral transitional vertebrae (54.2%) and lower prevalence of hemivertebrae (1.7%) in Pugs compared to English (13.5% and 24.3%, respectively) and French Bulldogs (26.4% and 32.0%, respectively). Tail malformation was significantly more severe in dogs with evidence of hemivertebrae. Congenital vertebral malformations are a common finding in the lumbosacral vertebral column of French Bulldogs, English Bulldogs, and Pugs. These anatomical variances need to be considered when interpreting diagnostic studies and when planning for neurosurgical and neurodiagnostic procedures. Furthermore, this study suggests a possible association between the degree of tail malformation and lumbosacral hemivertebrae.

[Congenital spine deformities during growth : Modern concepts of treatment]. / Kongenitale Wirbelsäulendeformitäten im Wachstumsalter : Moderne Behandlungsstrategien.

BACKGROUND: Congenital malformations of the spine can produce scoliosis, kyphosis, lordoscoliosis or kyphoscoliosis. Deformities may progress slowly or fast or may even be stable without progression. Knowledge of the natural history of such deformities is of utmost importance. Besides deformities of the spine and the thorax, a number of associated anomalies have to be taken into account, like thoracic, intraspinal, cardiac and urogenital abnormalities. Special examinations, including MRI of the entire spinal canal need to be ordered prior to beginning of treatment. TREATMENT: Conservative treatment, including physical therapy and bracing, will not control progression of the curve. Serial casting may be offered for some types of congenital malformations in early childhood. An isolated hemivertebra is best resected by a posterior approach only at age 5 to 6. Growth guiding anterior or posterior procedures like growing rods are currently indicated for very few cases. However, the VEPTR procedure is well indicated for complex congenital deformities with or without thoracic malformations, preserving the growth potential of the spine and the thorax. KYPHOTIC DEFORMITIES: Kyphotic deformities can not be treated with growth preserving surgery, so that early correction with short fusion is usually indicated. The most severe deformities may have to be treated with complex osteotomies, including VCR (vertebral column resection).

The Managment of cervical spine abnormalities in children with spondyloepiphyseal dysplasia congenita: Observational study.

Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant disorder, characterized by disproportionate dwarfism with short spine, short neck associated with variable degrees of coxa vara. Cervical cord compression is the most hazardous skeletal deformity in patients with SEDC which requires special attention and management.Ten patients with the clinical and the radiographic phenotypes of spondyloepiphyseal dysplasia congenita have been recognized and the genotype was compatible with single base substitutions, deletions or duplication of part of the COL2A1 gene (6 patients out of ten have been sequenced). Cervical spine radiographs showed apparent atlantoaxial instability in correlation with odontoid hypoplasia or os-odontoideum.Instability of 8 mm or more and or the presence of symptoms of myelopathy were the main indications for surgery. Posterior cervical fusion from the occiput or C1-3, decompression of C1-2 and application of autorib transfer followed by halo vest immobilization have been applied accordingly.Orthopedic management of children with spondyloepiphyseal dysplasia congenita (SEDC) should begin with the cervical spine to avoid serious neurological deficits and or mortality.

Spine deformities and trauma in Avicenna's Canon of Medicine.

AIM OF THE STUDY: The purpose of this historic review is to summarize the life and work of Avicenna (980-1037) and his contribution to the diagnosis and treatment of spinal deformities and trauma. METHOD: We conducted an extensive search in libraries as well as online in Pubmed and Google Scholar. RESULTS: Avicenna in his work Canon of Medicine combines the knowledge of ancient Greek and Roman physicians and surgeons and he combines them with the extensive of Arabic medicine and pharmacology. CONCLUSION: Avicenna made an impact with his medical writings in which he summarized the works of ancient Greek and Roman physicians like Hippocrates and Galen with the influence of medieval authors and the knowledge of the Arabic medicine and pharmacology. His descriptions and comments in his work Canon of Medicine summarize and comment the work of his predecessors and it remained a work of reference until at least the sixteenth century.

Segmentation failure of the posterior elements at the cervical spine and cervicothoracic junction: report of three cases.

PURPOSE: Vertebral segmentation and fusion failures are quite common and often occur as incidental findings. These anatomical variants may be associated with deformity and lead to pain and other neurological signs. They are less frequent in the cervical spine. We report three cases of rare posterior arch segmentation failure at the cervical spine and cervicothoracic junction, with an interesting pattern of laminar arrangement. METHODS: The clinical and radiological findings of three patients with unusual anatomical variants of the posterior elements of the subaxial cervical spine and cervicothoracic junction are reported. RESULTS: We found various association of scoliosis, partial butterfly vertebra, absent pedicle, transverse process and lateral mass anomalies. Interestingly, we report two different and unusual laminar morphologies. CONCLUSION: Congenital morphological disorders may occur at the lower cervical spine and cervicothoracic junction, and they can involve the vertebral body as well as the posterior arch. We reported three cases of uncommon malformations, with a unique Y- and S-shaped laminar pattern.

Cervical hemivertebra resection and torticollis correction: report on two cases and literature review.

PURPOSE: Hemivertebra of the cervical spine is a rare but complex spinal malformation. To our knowledge, only one publication describes excision of an upper-middle cervical (between C2 and C4) hemivertebra. We present our experience with two cases of C3 hemivertebra resection and torticollis correction via a combined anterior-posterior-anterior surgical approach and short segment fixation. METHODS: Two 12-year-old patients with torticollis due to congenital C3 hemivertebra underwent surgery consisting of combined anterior vertebral body osteotomy, posterior element resection with segment instrumentation and deformity correction, and iliac bone graft reconstruction and fixation via an anterior approach. During the osteotomies, the transverse process accompanied with the vertebral artery was disconnected and freed away from the spinal column. Then the deformity was corrected without touching the vertebral artery, which made the procedure safe and comfortable. The details of this technique are presented. Pre- and postoperative radiographic features, as well as clinical outcomes were evaluated. RESULTS: The treatment process was uneventful. The patients had satisfactory clinical outcomes at a mean of 1.5 years follow-up. Head tilt and chin rotation were corrected completely. Radiographs showed favorable deformity correction, well-balanced coronal and sagittal alignment, and solid bony fusion. CONCLUSION: Combined anterior-posterior-anterior hemivertebra resection with short segment instrumentation is a reasonable option for the treatment of congenital cervical hemivertebra, which provided satisfactory deformity correction and good clinical outcomes. LEVEL OF EVIDENCE: 4.

Vertebral abnormality without spine-curvature deformity on prenatal ultrasonography: sonographic findings and postnatal radiographic correlations.

PURPOSE: To evaluate prenatal US features and postnatal radiographic findings of fetuses with a sonographically detected vertebral abnormality (VA) without spine-curvature deformity (SCD). METHODS: Twenty-six fetuses showing a VA without SCD on prenatal US at our ultrasound center for a 5-year period were retrospectively identified and evaluated for sonographic data and coexisting anomalies. Medical records and postnatal radiographs of all 16 live births were reviewed. RESULTS: Coexisting major anomalies were suspected prenatally in 8/26 fetuses (30.8%). Sonographic abnormalities were noted in the vertebral body in 27/31 (87.1%) and in the posterior element in 4/31 (12.9%). US features were absent (n = 2) or small vertebral body echo (n = 21), two separate vertebral body echoes (n = 4), or smaller or lobulated posterior arch echoes (n = 4). Among 16 live-born neonates, postnatal radiographs revealed a vertebral abnormality in 20 (95.2%) of 21 prenatally detected VA without SCD. The abnormalities were vertebral body hypoplasia (18/19) with an incomplete sagittal cleft, asymmetric/unilateral hypoplasia, or hypoplasia with a complete sagittal cleft; or abnormalities in the spinous process (2/2). CONCLUSIONS: Most fetuses with prenatally detected VA without SCD had hypoplastic vertebrae on postnatal radiographs. Prenatal recognition of VA without SCD can lead to an early postnatal diagnosis of a vertebral abnormality and guidance for follow-up.

The prevalence of congenital C1 arch anomalies.

PURPOSE: To determine the prevalence, radiographic features and reporting rate of, and the association between the congenital anterior and posterior C1 arch anomalies. METHODS: The computed tomography (CT) images of the cervical spines of all patients over 18 years who had CT examinations in our hospital during the study period were reviewed to evaluate for congenital anomalies of the anterior and posterior C1 arches. Radiology reports of the corresponding CT examinations were reviewed to determine the reporting rate of these defects. RESULTS: Of 3273 subjects, 185 (5.65%) had congenital atlas anomalies: 169 isolated posterior (5.16%), 15 combined anterior and posterior (bipartite, 0.46%), and one isolated anterior (0.031%) arch defects. Females had a higher prevalence than males (7.46 versus 4.72%, P = 0.0013). Eighty-three cases (44.9%) of C1 arch anomalies were not reported. The Currarino type A, B, C and E posterior arch defects accounted for 81.6, 8.1, 1.1, and 0.5% of all arch anomalies while type D was not observed. Fifteen patients (0.46%) had combined anterior and posterior arch anomalies (bipartite atlas) versus only one with an isolated anterior C1 defect, indicating a significant association between the anterior and posterior arch defects (P < 0.0001). CONCLUSIONS: Although some types of congenital C1 arch anomalies are rare, type A defects are relatively common radiological findings that are unreported approximately 45% of the time. Based on the significant association between the anterior and posterior arch defects, we propose possible mechanisms for the formation of the bipartite atlas.

Retrotransverse foramen of the atlas: prevalence and bony variations.

PURPOSE: To analyze the prevalence of the retrotransverse foramen (RTF) and its bony variations. METHODS: One hundred ten atlases of living adult subjects, 161 twentieth century dry adult cervical atlases and four dry adult cervical atlases from medieval skeletons were studied to detect the RTF and its abnormal bony variations. The 110 living adult subjects underwent a computed tomography study to detect the RTF. RESULTS: In the in vivo sample (n = 110; 100%), the RTF was found in four (3.6%) atlases. It was bilateral in all cases, but three (2.7%) patients showed complete RTF and the other patient presented a complete RTF in the left transverse process and an unclosed RTF in the right transverse process. In addition, the RTF was observed in combination with an unclosed transverse foramen in two cases (1.8%). In the twentieth century skeletal sample (n = 206; 100%) the RTF was found in 15 (7.3%) C1 vertebrae. It was bilateral in three (1.5%) vertebrae and unilateral in another 12 (5.8%) vertebrae. In the medieval skeletal sample (n = 4; 100%) one cadaveric atlas (25%) presented a bilateral RTF with special bony characteristics which presented an unexpected spicula in the left RTF. CONCLUSIONS: The RTF is a nonmetric variant of the atlas vertebra that can present non-degenerative and non-traumatic spiculae or it can be unclosed. In addition, it can be associated with the presence of unclosed transverse foramina.

Sonographic spinal imaging of normal anatomy, pathology and magnetic growing rods in children.

The wide availability of ultrasound, along with its lack of ionizing radiation burden and need for sedation for most exams, often make sonography the first line in the imaging evaluation of children. The developing osseous anatomy of the spine in young infants provides a distinct window allowing for a detailed depiction of the spinal canal and its contents, which is not present in older children or adults. Here we review the clinical indications, sonographic technique, normal anatomy and pathology for imaging the lumbosacral spine in neonates and young infants. Additionally, we review the procedure for ultrasound assessment of the lengthening of magnetically controlled growing spinal rods, which allows orthopedists and radiologists to evaluate the effectiveness of distraction procedures of this hardware without the use of ionizing radiation.