Congenital Vertebral Malformations Research Articles

Planar cell polarity zebrafish models of congenital scoliosis reveal novel underlying defects in notochord morphogenesis.

Congenital scoliosis (CS) is a type of vertebral malformation whose etiology remains elusive. The notochord is pivotal for vertebrae development but its role in CS is still understudied. Zebrafish knockout of ptk7a, a planar cell polarity (PCP) gene that is essential for convergence and extension (C&E) of the notochord, developed congenital scoliosis-like vertebral malformations (CVM). Maternal zygotic ptk7a mutants displayed severe C&E defects of the notochord. Excessive apoptosis occurred in the malformed notochord, causing a significantly reduced number of vacuolated cells, and compromising the mechanical properties of the notochord. The latter manifested as a less stiff extracellular matrix along with a significant reduction in the number of the caveolae and severely loosened intercellular junctions in the vacuolated region. These defects led to focal kinks, abnormal mineralization, and CVM exclusively at the anterior spine. Loss of function of another PCP gene, vangl2, also revealed excessive apoptosis in the notochord associated with CVM. This study suggests a new model for CS pathogenesis that is associated with defects in notochord C&E and highlights an essential role of PCP signaling in vertebrae development.

Prevalence of discospondylitis and association with congenital vertebral body malformations in English and French bulldogs.

Limited current information exists regarding discospondylitis within breeds commonly affected by congenital vertebral body malformations. Report the prevalence of discospondylitis in English and French bulldogs and investigate for possible associations of discospondylitis with congenital vertebral body malformations. 108 client-owned dogs. Retrospective multi-institutional study between June 2010 and 2020. Cases with a diagnosis of discospondylitis on computed tomography (CT) or magnetic resonance imaging (MRI) and complete medical records included. Signalment, discospondylitis location, presence of congenital vertebral body malformations, and the site of maximal kyphosis were recorded. The prevalence of discospondylitis was 3.4 (1.6-6.7, 95% confidence interval [CI]) times higher in French bulldogs (P < .001) and 4.3 (1.7-9.8, 95% CI) times higher in English bulldogs (<.001), compared with the overall hospital cohort. One or more vertebral malformations were present in 12 French bulldogs (92.3%), 6 English bulldogs (75.0%), and 1 "other" breed dog (1.1%). Discospondylitis was diagnosed adjacent to congenital vertebral body malformations in 12 (80%) intervertebral discs in French bulldogs and 5 (50%) intervertebral discs in English bulldogs. The median age at presentation was significantly younger in French bulldogs (1.1 years; range, 0.5-9.2 years) and English bulldogs (1.0 years; range, 0.4-7.0 years), compared with "other" breed dogs (7.3 years; range, 0.3-14.0 years; both P < .001). Congenital vertebral body malformations were frequently associated with discospondylitis in French and English bulldogs, with clinical signs commonly encountered at a significantly younger age.

Prevalence and classification of congenital thoracic vertebral body abnormalities in neurologically normal brachycephalic 'screw-tail' dog breeds in referral practice in Australia.

To evaluate the prevalence, type, site and breed predisposition of thoracic congenital vertebral malformations (CVM) in neurologically normal brachycephalic 'screw-tail' dog breeds. Retrospective case series. Neurologically normal French Bulldogs (n = 63), British Bulldogs (n = 42), Boston Terriers (n = 4) and Pugs (n = 86) presenting for brachycephalic obstructive airway syndrome treatment. Either a plain computer tomography scan of the thorax or lateral and dorso-ventral digital radiographs of the thoracic vertebral column of each dog were assessed for any vertebral malformations and classed according to the Modified McMaster vertebral abnormality classification scheme proposed by Guiterrez et al. RESULTS: The prevalence of dogs with one or more abnormal vertebrae was 96.82% in French Bulldogs, 90.47% in British Bulldogs, and 76.74% in Pugs. Pugs had significantly lower instances of CVMs than French Bulldogs. The four Boston Terriers all had vertebral malformations, but the results were not considered to be statistically significant due to their small sample size. In French Bulldogs and British Bulldogs, ventral hypoplasia (Type 3) occurred at greater rates than all other types, followed by ventral and median hypoplasia (Types 7) and symmetrical hypoplasia (Type 8). In Pugs, symmetrical hypoplasia (Type 8) was the most common and then ventral hypoplasia (Type 3). The most affected vertebrae were T6-T9 in Pugs and T5-T10 in French Bulldogs and British Bulldogs. The majority of neurologically normal brachycephalic 'screw-tail' dogs assessed in this paper possessed one or more congenital thoracic vertebral malformations. Dogs with vertebral malformations were found to be more likely to have more than one affected vertebra. Sex had no effect on the prevalence of CVM. A substantial number of neurologically normal brachycephalic 'screw-tail' dogs suffer from congenital vertebral malformations. Thus, the need for selective breeding programmes to eliminate this hereditary condition is crucial.

Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations

Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.

Histology and chronological magnetic resonance images of congenital spinal deformity: An experimental study in mice model

BackgroundThe natural history of the congenital spinal deformity and its clinical magnitude vary widely in human species. However, we previously reported that the spinal deformities of congenital scoliosis mice did not progress throughout our observational period according to soft X-ray and MRI data. In this study, congenital vertebral and intervertebral malformations in mice were assessed via magnetic resonance (MR) and histological images.MethodsCongenital spinal anomalies were chronologically assessed via soft X-ray and 7 T MR imaging. MR images were compared to the histological images to validate the findings around the malformations.ResultsSoft X-ray images showed the gross alignment of the spine and the contour of the malformed vertebrae, with the growth plate and cortical bone visible as higher density lines, but could not be used to distinguish the existence of intervertebral structures. In contrast, MR images could be used to distinguish each structure, including the cortical bone, growth plate, cartilaginous end plate, and nucleus pulposus, by combining the signal changes on T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI). The intervertebral structure adjacent to the malformed vertebrae also exhibited various abnormalities, such as growth plate and cartilaginous end plate irregularities, nucleus pulposus defects, and bone marrow formation. In the chronological observation, the thickness and shape of the malformed structures on T1WI did not change.ConclusionsSpinal malformations in mice were chronologically observed via 7 T MRI and histology. MR images could be used to distinguish the histological structures of normal and malformed mouse spines. Malformed vertebrae were accompanied by adjacent intervertebral structures that corresponded to the fully segmented structures observed in human congenital scoliosis, but the intervertebral conditions varied. This study suggested the importance of MRI and histological examinations of human congenital scoliosis patients with patterns other than nonsegmenting patterns, which may be used to predict the prognosis of patients with spinal deformities associated with malformed vertebrae.

Clinical outcomes of 20 brachycephalic dogs with thoracolumbar spinal deformities causing neurological signs treated with spinal stabilization using 3D-printed patient-specific drill guides.

To describe the clinical outcomes for pugs and French bulldogs with congenital vertebral malformations, undergoing thoracolumbar spinal stabilization surgery using 3D-printed patient-specific drill guides. To evaluate the accuracy of pedicle screw placement in this group of dogs. Retrospective descriptive study. Twenty dogs (12 pugs and eight French bulldogs). Medical records searched between August 2018 and March 2021 for pugs and French bulldogs diagnosed with congenital vertebral abnormalities via magnetic resonance imaging (MRI) scan and computed tomography (CT) scan causing T3-L3 myelopathy signs that underwent spinal stabilization surgery using 3D-printed patient-specific drill guides followed by a postoperative CT scan. The short-term outcome was based on the neurological grade (modified Frankel score-MFS) on the day after surgery, day of discharge, and at the follow-up examination at 4 to 6 weeks after surgery. The mid-term outcome was obtained via an online questionnaire (or direct examination in one case). Twenty dogs met the inclusion criteria (19/20 grade 2 MFS, 1/20 grade 4 MFS). No complications were reported in the immediate postoperative period and optimal pedicle screw placement was obtained in 169/201 of screws. Twenty-four hours after surgery 16/20 dogs displayed an unchanged neurological grade. Short-term outcomes revealed a static (17/20) or improved (2/20) neurological grade. Ten owners participated in the online questionnaire. All patients were reported to be ambulatory; however, 7/10 dogs displayed abnormal gait. Neurological signs had remained static (6/10) or improved (3/10) in comparison with the dogs' preoperative status at a median of 883.5 days from the surgery. Dogs in this study had a favorable short-term outcome and mid-term outcome evaluation revealed a static/improved neurological status. Thoracolumbar spinal stabilization surgery using 3D-printed patient-specific drill guides showed a favorable outcome in brachycephalic breeds affected by vertebral deformities.

Maternal risk factors for congenital vertebral formation and mixed defects: A population-based case-control study.

The etiology and risk factors of congenital vertebral anomalies are mainly unclear in isolated cases. Also, there are no reports on the risk factors for different subgroups of vertebral anomalies. Therefore, we assessed and identified potential maternal risk factors for these anomalies and hypothesized that diabetes, other chronic diseases, smoking, obesity, and medication in early pregnancy would increase the risk of congenital vertebral anomalies. All cases with congenital vertebral anomalies were identified in the Finnish Register of Congenital Malformations from 1997 to 2016 for this nationwide register-based case-control study. Five matched controls without vertebral malformations were randomly selected. Analyzed maternal risk factors included maternal age, body mass index, parity, smoking, history of miscarriages, chronic diseases, and prescription drug purchases in early pregnancy. The register search identified 256 cases with congenital vertebral malformations. After excluding 66 syndromic cases, 190 non-syndromic malformations (74 formation defects, 4 segmentation defects, and 112 mixed anomalies) were included in the study. Maternal smoking was a significant risk factor for formation defects (adjusted odds ratio 2.33, 95% confidence interval 1.21-4.47). Also, pregestational diabetes (adjusted odds ratio 8.53, 95% confidence interval 2.33-31.20) and rheumatoid arthritis (adjusted odds ratio 13.19, 95% confidence interval 1.31-132.95) were associated with mixed vertebral anomalies. Maternal pregestational diabetes and rheumatoid arthritis were associated with an increased risk of mixed vertebral anomalies. Maternal smoking increases the risk of formation defects and represents an avoidable risk factor for congenital scoliosis. III.

A mutation in TBXT causes congenital vertebral malformations in humans and mice

T-box transcription factor T (TBXT; T) is required for mesodermal formation and axial skeletal development. Although it has been extensively studied in various model organisms, human congenital vertebral malformations (CVMs) involving T are not well established. Here, we report a family with 15 CVM patients distributed across 4 generations. All affected individuals carry a heterozygous mutation, T c.596A>G (p.Q199R), which is not found in unaffected family members, indicating co-segregation of the genotype and phenotype. In vitro assays show that T p.Q199R increases the nucleocytoplasmic ratio and enhances its DNA-binding affinity, but reduces its transcriptional activity compared to the wild-type. To determine the pathogenicity of this mutation in vivo, we generated a Q199R knock-in mouse model that recapitulates the human CVM phenotype. Most heterozygous Q199R mice show subtle kinked or shortened tails, while homozygous mice exhibit tail filaments and severe vertebral deformities. Overall, we show that the Q199R mutation in T causes CVM in humans and mice, providing previously unreported evidence supporting the function of T in the genetic etiology of human CVM.

Congenital kyphoscoliosis associated with thoracic hemivertebrae in a 9‐month‐old Racking filly

SummaryThoracic hemivertebra is a rare congenital vertebral malformations in horses resulting in vertebral column deformity with or without neurological signs. A 9‐month‐old Racking filly was presented with a distinct lump over the back region. This lump was apparent at birth and had been increasing in size. Clinical examination revealed painless kyphoscoliosis over the thoracic vertebrae with mild hindlimb ataxia and gait abnormality. Plain radiographs of the vertebral column showed 13th–16th thoracic hemivertebrae. Myelography was performed under general anaesthesia. The ventral and dorsal aspects of the contrast medium column were narrowed at the level of the 13th–14th thoracic hemivertebrae. The contrast medium was not seen caudally, suggesting spinal cord compression. Little information about hemivertebra in horses exists, and a better understanding of hemivertebra aetiology is required.

Maternal Risk Factors for Congenital Vertebral Anomalies: A Population-Based Study.

The spectrum of congenital vertebral defects varies from benign lesions to severe, life-threatening conditions. The etiology and maternal risk factors remain mainly unclear in isolated cases. Hence, we aimed to assess and identify potential maternal risk factors for these anomalies. Based on previous studies, we hypothesized that maternal diabetes, smoking, advanced maternal age, obesity, chronic diseases, and medication used during the first trimester of pregnancy might increase the risk of congenital vertebral malformations. We performed a nationwide register-based case-control study. All cases with vertebral anomalies (including live births, stillbirths, and terminations for fetal anomaly) were identified in the Finnish Register of Congenital Malformations from 1997 to 2016. Five matched controls from the same geographic region were randomly selected for each case. Analyzed maternal risk factors included age, body mass index (BMI), parity, smoking, history of miscarriages, chronic diseases, and prescription drugs dispensed during the first trimester of pregnancy. In total, 256 cases with diagnosed congenital vertebral anomalies were identified. After excluding 66 malformations associated with known syndromes, 190 nonsyndromic malformation cases were included. These were compared with 950 matched controls. Maternal pregestational diabetes was a significant risk factor for congenital vertebral anomalies (adjusted odds ratio [OR], 7.30 [95% confidence interval (CI), 2.53 to 21.09). Also, rheumatoid arthritis (adjusted OR, 22.91 [95% CI, 2.67 to 196.40]), estrogens (adjusted OR, 5.30 [95% CI, 1.57 to 17.8]), and heparins (adjusted OR, 8.94 [95% CI, 1.38 to 57.9]) were associated with elevated risk. In a sensitivity analysis using imputation, maternal smoking was also significantly associated with an elevated risk (adjusted OR, 1.57 [95% CI, 1.05 to 2.34]). Maternal pregestational diabetes and rheumatoid arthritis increased the risk of congenital vertebral anomalies. Also, estrogens and heparins, both of which are frequently used in assisted reproductive technologies, were associated with an increased risk. Sensitivity analysis suggested an increased risk of vertebral anomalies with maternal smoking, warranting further studies. Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Congenital hypospadias and vertebral malformation in a Barbados Blackbelly neonate

A male purebred Barbados Blackbelly, twin to another male, was born with obvious external congenital abnormalities. Male twinwas normal. Abnormal lamb had a short torso and spinal column. At 1 week, the lamb was presented with dyspnea and lethargy,and euthanasia was elected. Lamb was submitted for full necropsy and for additional diagnostics. After postmortem, in additionto histopathology, radiographs and computed tomographs were obtained. Lamb had congenital vertebral and occipital malformations,meningitis, hypospadias, and renal malformation. To authors’ knowledge, hypospadias and vertebral malformation inthe Barbados Blackbelly breed has not been reported. Apparently, Barbados Blackbelly breed harbors closely related genetics, thusvigilant monitoring for genetic malformations is suggested.

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.

Identification of Copy Number Variants in a Southern Chinese Cohort of Patients with Congenital Scoliosis.

Congenital scoliosis (CS) is a lateral curvature of the spine resulting from congenital vertebral malformations (CVMs) and affects 0.5–1/1000 live births. The copy number variant (CNV) at chromosome 16p11.2 has been implicated in CVMs and recent studies identified a compound heterozygosity of 16p11.2 microdeletion and TBX6 variant/haplotype causing CS in multiple cohorts, which explains about 5–10% of the affected cases. Here, we studied the genetic etiology of CS by analyzing CNVs in a cohort of 67 patients with congenital hemivertebrae and 125 family controls. We employed both candidate gene and family-based approaches to filter CNVs called from whole exome sequencing data. This identified 12 CNVs in four scoliosis-associated genes (TBX6, NOTCH2, DSCAM, and SNTG1) as well as eight recessive and 64 novel rare CNVs in 15 additional genes. Some candidates, such as DHX40, NBPF20, RASA2, and MYSM1, have been found to be associated with syndromes with scoliosis or implicated in bone/spine development. In particular, the MYSM1 mutant mouse showed spinal deformities. Our findings suggest that, in addition to the 16p11.2 microdeletion, other CNVs are potentially important in predisposing to CS.

Transthoracic Vertebral Distraction and Stabilization in 10 Dogs with Congenital Thoracic Vertebral Malformations.

The aim of this study was to describe the surgical technique and outcomes of dogs with congenital thoracic vertebral body malformations (CTVBM) treated with unilateral vertebral distraction and stabilization with monocortical screws and polymethylmethacrylate (PMMA). Medical records of 10 client-owned dogs with CTVBM were retrospectively searched for signalment, history, neurological examination, neurological grade based on the modified Frankel scale (MFS), diagnostic method, CTVBM location, Cobb's angle, and vertebral canal angle (VCA), surgical procedure, complications and long-term follow-up. One dog suffered cardiac arrest 24 hours post-surgery and died. Median follow-up in nine dogs was 26.5 months (12-50 months). Cobb's angle improved from 33-83 to 10-46 degrees and the VCA ratio from 97-138 to 122-164 degrees. The MFS improved from 3 (n = 3)-4 (n = 7) to 4 (n = 2)-6 (n = 7). Seven dogs recovered full function. Nine dogs improved after surgery compared with preoperative status, recovering ambulation when lost or achieving normal neurological examination in seven cases. No complications were reported during the follow-up period (12-50 months). Unilateral transthoracic vertebral distraction and stabilization with monocortical screws and PMMA for treatment of compressive myelopathy due to CTVBM achieved long-term neurological improvement in 9 of 10 dogs.

The presence, morphology and clinical significance of vertebral body malformations in an Australian population of French Bulldogs and Pugs.

To describe the incidence, morphology and clinical significance of congenital vertebral malformations (CVM) in two breeds of brachycephalic dogs presenting to a referral veterinary hospital. Prospective cohort study series. Forty-nine French Bulldogs and Pugs were prospectively evaluated and placed in one of two groups based on whether or not they presented for neurological signs referable to spinal cord disease. A computed tomography (CT) of their entire spine was obtained and the presence and classification of CVM along with the degree of spinal kyphosis recorded for all dogs. Statistical analysis was performed to identify clinical associations between these factors (P < 0.05). CVM were prevalent across both breeds with the French Bulldog having more malformations than the Pug (Kruskal-Wallis nonparametric analysis of variance, P < 0.0001). Breed associated vertebral malformation subtypes included butterfly subtype in French Bulldogs (Chi-square, P=0.0002), and transitional subtype in Pugs (odds ratio, 22.7; P=0.000). A new subtype, dorsal wedge, was observed in 12 cases. The presence, number and subtype of vertebral malformation were not reliable for predicting the development of neurological signs across both breeds (Chi-square, P > 0.05). However, spinal kyphosis >35° calculated via Cobb angle was associated with Pugs that had neurological deficits (Chi-square, P=0.028). Congenital vertebral malformations largely appear to be incidental findings in this population of French Bulldogs but are of more significance in the Pug breed when spinal kyphosis is >35°. French Bulldogs that have spinal cord disease and CVM are more likely to have pathology distant to CVM with intervertebral disc herniation most common.

Epidemiological study of congenital malformations of the vertebral column in French bulldogs, English bulldogs and pugs

Congenital vertebral body malformations (CVBMs) have retrospectively been investigated in British and American canine populations. This study prospectively evaluates occurrence, localization, type and characteristic of CVBM along the entire vertebral column in a cohort of French Bulldogs, English Bulldogs and Pug dogs from Germany. Prospective clinical and radiological screenings for CVBM were performed in brachycephalic dogs presented for reasons unrelated to neurological problems. Neurological and orthopaedic examinations as well as radiographs in two orthogonal planes of the entire vertebral column including the tail were performed in all dogs. Cobb angle and vertebral step were determined. Associations between CVBM, tail malformation, neurological deficits and occurrence of concurrent orthopaedic diseases were investigated. A total of 707 VBMs were identified in the whole vertebral column of 169 of 265 brachycephalic dogs. The most common types of CVBMs were ventral wedge shape (48%), dorsal wedge shape (14%) and shortened vertebral body (14%). A new type of malformation was investigated: dorsal wedge shape vertebrae. There was significant association between severe tail malformations with CVBM. Neurological deficits were significantly associated with ventrolateral wedge shape, dorso lateral hemivertebrae, Cobb angle>30% and vertebral step ≥1.75mm. Orthopaedic conditions were not significantly associated with CVBM. Kyphotic Cobb angle and vertebral step are radiological findings associated with neurological deficits. We propose severe tail malformation as an easy and accurate selection factor for determining breeding dogs.

Axis spinous process malformations are commonly identified in a sample of English Bull Terriers without associated clinical signs.

Congenital cervical vertebral malformations (CCVM) have been infrequently reported in veterinary medicine, with limited examples of axis spinous process malformations. The objective of this retrospective cross-sectional study was to describe the radiological characteristics, prevalence, and clinical relevance of a characteristic axis vertebral malformation in a sample of English Bull Terriers (EBTs). Medical records and diagnostic imaging studies of the cervical vertebral column of EBTs presenting for any reason were reviewed and described. Based on evaluation of the images, EBTs were divided in two groups; axis spinous process malformation and normal cases. Referring veterinary surgeons were contacted for long-term follow-up information. A total of 27 cervical radiographs, 23 CT, and nine MRI studies from 53 EBTs were reviewed. An axis spinous process malformation, characterized by a linear defect of varying length along the base of the spinous process, was identified in 22 of 53 EBTs (41.5%). There was no significant difference in age, body weight, or sex (P<.05) between EBTs with and without the malformation. No traumatic causes or clinical signs were identified in EBTs with the malformation that could be directly attributed to it. To the authors' knowledge, this is the first report of a malformation of the axis spinous process in a sample of EBTs. The malformation was not associated with clinical signs and should not be misinterpreted as a traumatic vertebral fracture or other pathology.

Clinical characteristics of 1,055 Chinese patients with Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide multicentric study

To reveal the proportion of concomitant extragenital malformations in a large cohort of Chinese patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Retrospective study. Tertiary teaching hospitals in China. A total of 1,055 Chinese Han women with MRKH syndrome diagnosed and treated at 11 Chinese tertiary teaching hospitals from January 2015 to January 2020. Karyotype analysis, hormone profiling, pelvic ultrasonography, spinal roentgenograms, urologic ultrasonography, and Chinese female reproductive tract malformation registry platform (https://ecrf.linklab.com/). Patients' demographic and clinical characteristics, concurrent malformations, and family histories. Of the 1,055 Chinese Han patients with MRKH, 69.6% had type I MRKH syndrome and the remaining 30.4% had type II MRKH syndrome. Among the type II patients, 12.6% had müllerian duct aplasia, unilateral renal aplasia/ectopic kidney, and cervicothoracic somite dysplasia association. Skeletal malformations were the most common associated extragenital malformations in the study (22.0%, 232/1,055), of which idiopathic scoliosis and congenital vertebral malformations were the 2 main skeletal malformations (80.6% and 14.2%, respectively). Renal malformations were the second-highest associated extragenital malformations (9.7%, 102/1,055), with unilateral renal agenesis and ectopic kidney being the most common renal malformations (48.0% and 22.5%, respectively). Type II disease was less common among Chinese patients with MRKH syndrome compared with European patients. Skeletal malformations were more common extragenital malformations than renal malformations in our cohort.

Altered Circulating Cell-free Mitochondrial DNA of Patients with Congenital Scoliosis.

Case-control study. The aim of this study was to estimate the relationship between circulating cell-free DNA (ccf DNA) and clinical parameters of patients with congenital scoliosis (CS). CS is a complex spinal deformity characteristic of congenital vertebral malformations. Although numerous studies have centered on the etiology of CS, the cause of CS remains unclear. Previously, we reported that circulating cell-free DNA (ccf DNA) is altered in adolescent idiopathic scoliosis (AIS). However, the relationship between ccf DNA and the clinical parameters of patients with CS remains unclear. The plasma of peripheral blood from 35 patients with CS and 32 age-matched controls was collected for ccf DNA analysis. Quantitative PCR was used to detect ccf n-DNA and ccf mt-DNA levels, and correlation analyses between ccf n-DNA and ccf mt-DNA levels were conducted. Receiver-operating characteristic (ROC) curves were used to analyze the sensitivity and specificity of ccf n-DNA and ccf mt-DNA levels to different characteristics. The plasma ccf mt-DNA levels of both ND1 and CYTC were significantly decreased in patients with CS compared with levels in controls both in total and by sex, whereas the plasma ccf n-DNA levels showed no significant difference. There is no difference in both ccf mt-DNA and ccf n-DNA between S-SDV and M-SDV according to The International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) classification. The ROC curve analyses showed a reliable sensitivity and specificity of CS predicted by ccf mt-DNA levels in total but failed to distinguish different ICVAS types. Significantly decreased plasma ccf mt-DNA levels were observed in patients with CS compared with those in controls. Although this finding has limited significance for clinical practice, it indicates that ccf mt-DNA may predict the onset or development of CS. Further studies should focus on the role of ccf mt-DNA in embryo development and whether ccf mt-DNAs could be considered as a marker for prenatal screening in development disorder like CS.Level of Evidence: 4.

SCO-Spondin Defects and Neuroinflammation Are Conserved Mechanisms Driving Spinal Deformity across Genetic Models of Idiopathic Scoliosis

Adolescent idiopathic scoliosis (AIS) affects 3% to 4% of children between the ages of 11 and 18 [1, 2]. This disorder, characterized by abnormal three-dimensional spinal curvatures that typically develop during periods of rapid growth, occurs in the absence of congenital vertebral malformations or neuromuscular defects [1]. Genetic heterogeneity [3] and a historical lack of appropriate animal models [4] have confounded basic understanding of AIS biology; thus, treatment options remain limited [5, 6]. Recently, genetic studies using zebrafish have linked idiopathic-like scoliosis to irregularities in motile cilia-mediated cerebrospinal fluid flow [7-9]. However, because loss of cilia motility in human primary ciliary dyskinesia patients is not fully associated with scoliosis [10, 11], other pathogenic mechanisms remain to be determined. Here, we demonstrate that zebrafish scospondin (sspo) mutants develop late-onset idiopathic-like spinal curvatures in the absence of obvious cilia motility defects. Sspo is a large secreted glycoprotein functionally associated with the subcommissural organ and Reissner's fiber [12]-ancient and enigmatic organs of the brain ventricular system reported to govern cerebrospinal fluid homeostasis [13, 14], neurogenesis [12, 15-18], and embryonic morphogenesis [19]. We demonstrate that irregular deposition of Sspo within brain ventricles is associated with idiopathic-like scoliosis across diverse genetic models. Furthermore, Sspo defects are sufficient to induce oxidative stress and neuroinflammatory responses implicated in AIS pathogenesis [9]. Through screening for chemical suppressors of sspo mutant phenotypes, we also identify potent agents capable of blocking severe juvenile spine deformity. Our work thus defines a new preclinical model of AIS and provides tools to realize novel therapeutic strategies.