Development of a straight vertebrate body axis.

The vertebrate body plan is characterized by the presence of a segmented spine along its main axis. Here, we examine the current understanding of how the axial tissues that are formed during embryonic development give rise to the adult spine and summarize recent advances in the field, largely focused on recent studies in zebrafish, with comparisons to amniotes where appropriate. We discuss recent work illuminating the genetics and biological mechanisms mediating extension and straightening of the body axis during development, and highlight open questions. We specifically focus on the processes of notochord development and cerebrospinal fluid physiology, and how defects in those processes may lead to scoliosis.

Prenatal diagnosis of fetal multiple hemivertebrae: the importance of 3D ultrasound assessment.

We herein present a case of fetal multiple hemivertebrae detected at antenatal sonography. The use of the 3 D technology supported by a new contrast enhancement rendering algorithm (Crystal Vue) has allowed the accurate prenatal classification of the defect, confirmed at follow up, that would have been difficult to define by 2 D only.

High prevalence of same-sex twins in patients with cloacal exstrophy: Support for embryological association with monozygotic twinning.

PURPOSE: Previous studies have hypothesized that cloacal exstrophy may be caused by errors early in embryological development related to monozygotic twinning. This study reports the prevalence of twins in a large cohort of patients with cloacal exstrophy. METHODS: Patients with cloacal exstrophy treated 1974-2015 were reviewed for reports of multiple gestation or conjoined twinning. The genetic sex of the patient and their twin, and any mention of anomaly in the twin were recorded. Neither placental exam nor genetic testing results were available to definitively determine zygosity. RESULTS: Of 71 patients, 10 had a live born twin (14%), all of whom were of the same genetic sex as the affected patient. One additional patient's twin suffered intrauterine fetal demise, and another patient had a conjoined heteropagus twin. None of the twins were affected by exstrophy-epispadias complex. The rate of twin birth in this cohort was 4.4-7.7 higher than that reported by the Centers for Disease Control in the general population time period (P<0.001), with a striking preponderance of same-sex pairs. CONCLUSIONS: The highly significant prevalence of same-sex twin pairs within this cohort supports the hypothesis that the embryogenesis of cloacal exstrophy may be related to errors in monozygotic twinning. LEVEL OF EVIDENCE: 2b.

Disordered vertebral and rib morphology in pudgy mice. Structural relationships to human scoliosis.

Normal and abnormal vertebral development have been studied over the past 200 years at increasing levels of resolution as techniques for biological investigation have improved. Disordered development of the axial skeleton from the early embryonic period on leads to structurally malformed vertebrae and intervertebral discs and ribs causing the severe deformities of scoliosis, kyphosis, and kyphoscoliosis. Developmental malformation of the axial skeleton therefore has led to considerable biological and clinical interest. This work will detail our studies on the structural deformities of the vertebral column and adjacent ribs in the pudgy mouse [1] caused by mutations in the delta-like 3 (Dll3) gene of the Notch family [2]. While gene abnormalities in the pudgy mouse have been outlined, there has been no in-depth assessment of the histopathology of the pudgy vertebral and rib abnormalities that this study will provide. In addition, although congenital scoliosis has been recognized as a clinical problem since the mid-nineteenth century (1800s) [3] and accurately defined by radiography since the early twentieth century (1900s) [4-6], there have been few detailed histopathologic studies of human cases. We will also relate our histopathologic findings in the pudgy mouse to the histopathology of human vertebral and rib malformations in clinical cases of congenital scoliosis, one of which we defined in detail previously [7].

Possible Genetic Origin of Limb-Body Wall Complex.

Limb body wall complex (LBWC) is characterized by multiple severe congenital malformations including an abdominal and/or thoracic wall defect covered by amnion, a short or absent umbilical cord with the placenta almost attached to the anterior fetal wall, intestinal malrotation, scoliosis, and lower extremity anomalies. There is no consensus about the etiology of LBWC and many cases with abnormal facial cleft do not meet the requirements for the true complex. We describe a series of four patients with LBWC and other malformations in an attempt to explain their etiology. There are several reports of fetuses with LBWC and absent gallbladder and one of our patients also had polysplenia. Absent gallbladder and polysplenia are associated with laterality genes including HOX, bFGF, transforming growth factor beta/activins/BMP4, WNT 1-8, and SHH. We postulate that this severe malformation may be due to abnormal genes involved in laterality and caudal development.

Kinesin family member 6 (kif6) is necessary for spine development in zebrafish.

BACKGROUND: Idiopathic scoliosis is a form of spinal deformity that affects 2-3% of children and results in curvature of the spine without structural defects of the vertebral units. The pathogenesis of idiopathic scoliosis remains poorly understood, in part due to the lack of a relevant animal model. RESULTS: We performed a forward mutagenesis screen in zebrafish to identify new models for idiopathic scoliosis. We isolated a recessive zebrafish mutant, called skolios, which develops isolated spinal curvature that arises independent of vertebral malformations. Using meiotic mapping and whole genome sequencing, we identified a nonsense mutation in kinesin family member 6 (kif6(gw326) ) unique to skolios mutants. Three additional kif6 frameshift alleles (gw327, gw328, gw329) were generated with transcription activator-like effector nucleases (TALENs). Zebrafish homozygous or compound heterozygous for kif6 frameshift mutations developed a scoliosis phenotype indistinguishable from skolios mutants, confirming that skolios is caused by the loss of kif6. Although kif6 may play a role in cilia, no evidence for cilia dysfunction was seen in kif6(gw326) mutants. CONCLUSIONS: Overall, these findings demonstrate a novel role for kif6 in spinal development and identify a new candidate gene for human idiopathic scoliosis.

Fetal syringomyelia.

We explored the prevalence of syringomyelia in a series of 113 cases of fetal dysraphism and hindbrain crowding, of gestational age ranging from 17.5 to 34 weeks with the vast majority less than 26 weeks gestational age. We found syringomyelia in 13 cases of Chiari II malformations, 5 cases of Omphalocele/Exostrophy/Imperforate anus/Spinal abnormality (OEIS), 2 cases of Meckel Gruber syndrome and in a single pair of pyopagus conjoined twins. Secondary injury was not uncommon, with vernicomyelia in Chiari malformations, infarct like histology, or old hemorrhage in 8 cases of syringomyelia. Vernicomyelia did not occur in the absence of syrinx formation. The syringes extended from the sites of dysraphism, in ascending or descending patterns. The syringes were usually in a major proportion anatomically distinct from a dilated or denuded central canal and tended to be dorsal and paramedian or median. We suggest that fetal syringomyelia in Chiari II malformation and other dysraphic states is often established prior to midgestation, has contributions from the primary malformation as well as from secondary in utero injury and is anatomically and pathophysiologically distinct from post natal syringomyelia secondary to hindbrain crowding.

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.

Pathogenesis of idiopathic scoliosis: a review.

UNLABELLED: Idiopathic scoliosis is a three-dimensional deformation of the spine. As its name suggests, its pathogenesis remains poorly understood. Enhanced comprehension of its pathogenesis would be likely to improve current therapeutic results. While the hereditary and genetic origin of scoliosis appears unassailable and several chromosomes are known to be involved in transmission, the role assumed by each individual chromosome remains uncertain, and the mechanisms leading to the expression of scoliosis have yet to be determined. Even though a large number of pathogenetic hypotheses have been put forward and numerous studies carried out, none of these hypotheses have won unanimous approval, and the controversy remains persistent. OBJECTIVE: The objective of this paper is to identify the existing hypotheses and to group them within large-scale etiological categories. METHODS: We examined the Pubmed and Goggle databases using as keywords "idiopathic scoliosis" and "pathogenesis". The search was limited to articles in English and French. RESULTS: The vicious cycle hypothesis is markedly preponderant. However, no existing pathogenetic model adequately accounts for the formation of scolioses. CONCLUSION: We are proposing four main pathogenetic mechanisms: asymmetric bone growth dysregulation, susceptibility of bones to deformation, abnormal passive spinal system maintenance and disturbed active spinal system maintenance.

Scoliosis and segmentation defects of the vertebrae.

The vertebral column derives from somites, which are transient paired segments of mesoderm that surround the neural tube in the early embryo. Somites are formed by a genetic mechanism that is regulated by cyclical expression of genes in the Notch, Wnt, and fibroblast growth factor (FGF) signaling pathways. These oscillators together with signaling gradients within the presomitic mesoderm help to set somitic boundaries and rostral-caudal polarity that are essential for the precise patterning of the vertebral column. Disruption of this mechanism has been identified as the cause of severe segmentation defects of the vertebrae in humans. These segmentation defects are part of a spectrum of spinal disorders affecting the skeletal elements and musculature of the spine, resulting in curvatures such as scoliosis, kyphosis, and lordosis. While the etiology of most disorders with spinal curvatures is still unknown, genetic and developmental studies of somitogenesis and patterning of the axial skeleton and musculature are yielding insights into the causes of these diseases.

Spectrum of cloacal exstrophy.

Cloacal exstrophy, one of the most severe congenital anomalies compatible with life, occurs in up to 1 in 200,000 lives births. The condition affects nearly every major organ system with severe neurologic, skeletal, gastrointestinal, and genitourinary ramifications. With increased understanding of the anatomy and embryology combined with refinements in prenatal diagnosis and postnatal care, there is now near-universal survival of patients with cloacal exstrophy. Functional and cosmetic outcomes have improved with modifications in surgical technique. However, debate continues regarding the issue of gender identity, and long-term data are still accruing with respect to the best strategy for management. Despite the extensive malformations noted, many patients have gone on to live fruitful lives.

Building the spine: the vertebrate segmentation clock.

One of the most striking characteristics of many animal and plant species is their organization in a series of periodically repeated anatomical modules. In animals, this particular patterning strategy of the body axis is termed segmentation, and it is observed in both vertebrates and invertebrates. Vertebrate segmentation has been associated with a molecular oscillator-the segmentation clock-whose existence had been predicted on theoretical grounds in the clock and wave-front model. The segmentation clock is proposed to generate pulses of signaling used for the positioning of segmental boundaries. Whereas several models have proposed that simple negative autoregulatory circuits involving the transcription repressors of the hairy and enhancer of split family constitute the clock pacemaker, recent microarray studies in mouse have identified a large network of oscillating signaling genes belonging to the Notch, Wnt, and FGF (fibroblast growth factor) pathways. Thus, significant progress has been made, but the molecular nature of the clockwork underlying the oscillator remains poorly understood. Few examples of oscillators exist in developmental biology, and the segmentation clock provides a unique model of periodic regulation in patterning.

Spondylocostal dysostosis: thirteen new cases treated by conservative and surgical means.

STUDY DESIGN: Prospective assessment of a cohort of patients affected by spondylocostal dysostosis. OBJECTIVE: To report on the results of conservative and operative management of spondylocostal dysostosis and, based on this, to propose an assessment and treatment protocol for the condition. SUMMARY OF BACKGROUND DATA: Spondylocostal dysostosis and spondylothoracic dysostosis are subtypes of Jarcho-Levin syndrome, a hereditary condition manifested by vertebral body and related rib malformations. Mortality prevails in spondylothoracic dysostosis because of more severe respiratory compromise. METHODS: Details of prenatal and postnatal diagnosis, history, and management of 13 patients with spondylocostal dysostosis are presented. All patients were treated postnatally with repeated chest physiotherapy. Two patients refractory to conservative treatment underwent surgical intervention: the first had a chest wall reconstruction via a latissimus dorsi flap, the second a posterior spinal instrumented fusion for progressive scoliosis. RESULTS: Prenatal ultrasound in 4 of 13 cases showed full details of vertebral and rib anomalies. Thoracic and lumbar hemivertebrae were most common, leading to congenital scoliosis in 10 of 13 cases. A number of extraskeletal abnormalities were also identified. At an average follow-up of 4.5 years, the survival rate was 100% with a remarkable decrease of the rate of respiratory complications. Surgical treatment in selected cases led to satisfactory results. CONCLUSIONS: Prenatal diagnosis of spondylocostal dysostosis allows exclusion of spondylothoracic dysostosis and aids genetic counseling in quantifying the risk to siblings. Postnatally, prompt management of these patients with physiotherapy leads to prolonged survival. Surgical intervention may then be indicated to stabilize chest wall or spine deformities, with promising results.

Prenatal diagnosis of arthrogryposis multiplex congenita with increased nuchal translucency but without any underlying fetal neurogenic or myogenic pathology.

Arthrogryposis multiplex congenita is a general term for congenital multiple joint contractures, the aetiology of which is variable. Prenatal diagnosis is usually based on the detection of diminished fetal movements and joint contractures on ultrasound. There are also reports of early diagnosis of arthrogryposis in the first and early second trimester by detection of subcutaneous oedema. We report another case of arthrogryposis multiplex congenita with increased nuchal translucency and scoliosis diagnosed by ultrasonography at 15 weeks of gestation. The pregnancy was terminated at the request of the parents. Post-mortem examination revealed that it was not associated with fetal myopathy or neuropathy. Multiple joint contractures with increased nuchal translucency without any underlying fetal neurogenic and myogenic pathology may be a distinct form of arthrogryposis multiplex congenita.

[The etiology and pathogenesis of Sprengel's disease]. / Etiologiia i patogenez bolezni Shprengelia.

Basing on the analysis of clinico-radiological and functional signs, electromyographic and histological changes in the shoulder girdle (SG) upper extremities muscles, macro- and microscopic investigations of omovertebral formations in the patients with Sprengel disease, and the literature data there was formulated the scheme of etiology and pathogenesis of the inborn high position of shoulder blade. The leading role in the Sprengel disease etiology plays teratogenic exo- or endogenous harmful agent, affecting mesenchymal tissue in the moment of the vertebral column and SG inlay on the 4-5th week of embryogenesis. Underdevelopment and degeneration of the SG muscles, creation of fibrous, fibrous-cartilaginous and osteal tissues due to the embryogenesis disorder occurrence, are playing essential role in pathogenesis of anatomic-functional disorders, causing occurrence of the inborn high position of shoulder blade.

Congenital scoliosis of the cervical or cervicothoracic spine.

Congenital cervical or cervicothoracic scoliosis is an unusual but potentially severe disfiguring cause of spinal deformity in the growing child and adolescent. These forms of scoliosis are among the most infrequently encountered, and therefore, relatively little literature is available to guide the orthopedic surgeon. This article presents a brief overview of the etiology and epidemiology of these rare forms of scoliosis, defines the pathoanatomic variants, reviews the nonoperative treatment methods available, and discusses the role of early recognition and recommendation for spinal arthrodesis of those curves that clearly need surgical stabilization.

Pathogenesis of idiopathic scoliosis. The Nottingham concept.

There is no generally accepted scientific theory for the etiology of idiopathic scoliosis. Hence, current treatment is pragmatic and not based on knowledge of causation of the deformity. In Nottingham, we have evaluated data from studies of the hips, pelvis, spine, rib cage and trunk muscles in scoliotic (pre- and post operative) and control patients, cadavers and a mechanical model to formulate a new theory of etiology for idiopathic scoliosis (figs. 18 & 19 of ref. 15). Evidence is summarized for the view that idiopathic scoliosis results, in part, from a developmental abnormality in the central nervous system creating rib-vertebra angle asymmetry which leads to a cyclical failure of mechanisms of rotation control in the trunk; these involve rotation-inducing (pelvic) and rotation-defending (discal, ligamentous and costal) mechanisms acting mainly in gait. The mechanical breakdown of rotation occurs in association with a lateral spinal curvature and a lordotic segment to create the initial deformity of idiopathic scoliosis. Then, growth, both abnormal (secondary to vertebral hyper-pressures) and normal (linear spinal growth) with gravity adds to the initiating and continuing neuromuscular mechanisms to augment curve progression. This theory views the spine in the wider perspective of function in the trunk, evolution and development, all in relation to bipedalism. The goal of etiological research is ultimately to base a treatment on some knowledge of causation of the deformity.

Vascular causes of vertebral asymmetry and the laterality of scoliosis.

The aetiology of idiopathic scoliosis is multifactorial and complex, but the direction (laterality) of the curvature may depend on normal growth factors. It is postulated that vascular asymmetries are responsible for the left laterality of infantile thoracic scoliosis and the right laterality of adolescent thoracic scoliosis. Two hypotheses are presented. The left laterality of thoracic scoliosis in infancy may be due to the streaming of blood from the aortic arch to the right and streaming of blood from the ductus arteriosus to the left so that right vertebral arches receive better oxygenated blood, develop faster and grow larger. It is also suggested that, at a later stage, spontaneous resolution of infantile scoliosis and the right laterality of adolescent thoracic curvatures are due to the rotational force that is exerted on growing thoracic vertebrae by the asymmetrically situated descending thoracic aorta. It is emphasized that the normal growth factors that tend to a slight left thoracic scoliosis in infancy, and to a right thoracic scoliosis in adolescence, by themselves produce only a minimal scoliosis, and that progressive scoliosis involves additional unknown factors.