Yuzhi Zuo

Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients

OBJECTIVE The aim was to assess the clinical, laboratory and radiological features of SAPHO syndrome. METHODS We recruited all patients presenting to Peking Union Medical College Hospital from 2004 to 2015 diagnosed with SAPHO syndrome. The medical data, laboratory test results and imaging were collected for all patients. RESULTS One hundred and sixty-four patients (111 women and 53 men) were recruited to our cohort. The mean age of the patients was 40.71 years. Nine patients had osteoarticular symptoms without skin involvement. One hundred and forty-three and 25 patients had palmoplantar pustulosis and severe acne, respectively. Psoriasis vulgaris was accompanied by palmoplantar pustulosis or severe acne in 24 patients. One hundred and sixty-four patients suffered from pain in the anterior chest wall, followed by spine (12 in the cervical region, 36 in the thoracic region and 111 in the lumbosacral region) and peripheral joint (136 patients) involvement. None of the patients had IBD. The hs-CRP level was increased in 70.8% patients. Only 2.4% were HLA-B27 positive. CT scan indicated osteolysis, sclerosis and hyperostosis in the anterior chest wall and spine in SAPHO syndrome patients. The bull-horn sign was the typical characteristic of SAPHO syndrome seen in bone scintigraphy images. One hundred and thirty-one (79.9%), 85 (51.8%), 100 (61%) and 54 (32.9%) patients took NSAIDs, CSs, DMARDs and oral bisphosphonates, respectively. CONCLUSION SAPHO syndrome is predominant in middle-age women, characterized by dermatological and osteoarticular manifestations with unknown aetiology. CT scan and bone scintigraphy are useful for diagnosis. There is still no standard treatment to control the disease.

The genetic landscape and clinical implications of vertebral anomalies in VACTERL association

VACTERL association is a condition comprising multisystem congenital malformations, causing severe physical disability in affected individuals. It is typically defined by the concurrence of at least three of the following component features: vertebral anomalies (V), anal atresia (A), cardiac malformations (C), tracheo-oesophageal fistula (TE), renal dysplasia (R) and limb abnormalities (L). Vertebral anomaly is one of the most important and common defects that has been reported in approximately 60–95% of all VACTERL patients. Recent breakthroughs have suggested that genetic factors play an important role in VACTERL association, especially in those with vertebral phenotypes. In this review, we summarised the genetic studies of the VACTERL association, especially focusing on the genetic aetiology of patients with vertebral anomalies. Furthermore, genetic reports of other syndromes with vertebral phenotypes overlapping with VACTERL association are also included. We aim to provide a further understanding of the genetic aetiology and a better evidence for genetic diagnosis of the association and vertebral anomalies.

Genetic Polymorphism of lbx1 is Associated with Adolescent Idiopathic Scoliosis in Northern Chinese Han Population

Study Design. A case-control association study was performed to investigate the relationship between ladybird homeobox (LBX1) and adolescent idiopathic scoliosis (AIS) in northern Chinese Han population. Objective. To explore the prevalence and functional importance of LBX1 polymorphisms in patients with AIS within the northern Chinese Han population. Summary of Background Data. AIS is the most common subtype of idiopathic scoliosis. Genetic factors such as LBX1 polymorphisms have been recently proved to be associated with AIS in some populations. In this study we explored the prevalence and functional importance of the polymorphisms around LBX1 in patients with AIS within the northern Chinese Han population. Methods. Five tag single nucleotide polymorphisms (SNPs) around or in LBX1 were genotyped in 180 patients with AIS and 182 controls. And the luciferase assay was performed to explore the functional importance of the most significant SNPs. Results. We replicated that rs11190870, previously reported as the most significantly associated SNP, was enriched in our AIS cohort. In addition, we found that the T allele of rs1322331 was associated with a novel risk allele (odds ratio = 3.349, 95% confidence interval 1.742–6.436). In the following luciferase assay, the TT-type promoter showed significantly reduced transcription activity in vitro. Conclusion. Two SNPs around LBX1, rs11190870 and rs1322331 are associated with AIS in northern Chinese Han population. The T allele of rs1322331 is a novel risk allele. We hypothesize that rs1322331 might increase patients’ susceptibility to AIS by reducing LBX1-AS1 transcription and thus upregulating the function of LBX1. Level of Evidence: 3

Progress and perspective of TBX6 gene in congenital vertebral malformations.

Congenital vertebral malformation is a series of significant health problems affecting a large number of populations. It may present as an isolated condition or as a part of an underlying syndromes occurring with other malformations and/or clinical features. Disruption of the genesis of paraxial mesoderm, somites or axial bones can result in spinal deformity. In the course of somitogenesis, the segmentation clock and the wavefront are the leading factors during the entire process in which TBX6 gene plays an important role. TBX6 is a member of the T-box gene family, and its important pathogenicity in spinal deformity has been confirmed. Several TBX6 gene variants and novel pathogenic mechanisms have been recently revealed, and will likely have significant impact in understanding the genetic basis for CVM. In this review, we describe the role which TBX6 plays during human spine development including its interaction with other key elements during the process of somitogenesis. We then systematically review the association between TBX6 gene variants and CVM associated phenotypes, highlighting an important and emerging role for TBX6 and human malformations.

Whole-spine Computed Tomography Findings in SAPHO Syndrome

Objective. We evaluated the whole-spine computed tomography (CT) findings in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome to improve our understanding of this rare disease. Methods. Whole-spine CT images obtained in 69 patients with SAPHO were reviewed. For each individual, a total of 25 vertebrae were evaluated for the distribution of affected vertebrae, CT manifestations of vertebral lesions, symmetry and location of distribution of the lesions on vertebrae, involvement pattern, and narrowing of adjacent intervertebral disc space. Paravertebral ligamentous ossifications, apophyseal joint disorders, and costovertebral joint disorders were also evaluated. Results. All the 69 patients with SAPHO exhibited abnormalities on whole-spine CT. Sixty-four had vertebral lesions, 52 had paravertebral ossifications, and 47 had both. The vertebral lesions were observed in 441 vertebrae, with a predilection for thoracic spine. The lesions exhibited a mixture of cortical erosion, reactive osteosclerosis of surrounding cancellous bone, and syndesmophyte. They may be confined to the vertebral corner (65.1%) or be extensive, involving the endplate (34.9%). Corner lesions could start in any part of the epiphyseal ring. The lesions were asymmetrically distributed. The affected vertebrae were more consecutively involved in a “kissing” appearance (78.2%). Intervertebral disc spaces were usually normal or mildly narrowed. There were 320 foci of paravertebral ossifications observed, with a predilection for the supraspinous ligament. Paravertebral ossifications were delicate and segmental. Ossifications throughout annulus fibrosis and apophyseal joint were not observed. Conclusion. Our investigation of the distributional, morphological features and the involvement pattern of spinal lesions in patients with SAPHO demonstrated distinct CT characteristics.

Comparative analysis of serum proteome in congenital scoliosis patients with TBX6 haploinsufficiency - a first report pointing to lipid metabolism

Congenital scoliosis (CS) is a three‐dimensional deformity of the spine affecting quality of life. We have demonstrated TBX6 haploinsufficiency is the most important contributor to CS. However, the pathophysiology at the protein level remains unclear. Therefore, this study was to explore the differential proteome in serum of CS patients with TBX6 haploinsufficiency. Sera from nine CS patients with TBX6 haploinsufficiency and nine age‐ and gender‐matched healthy controls were collected and analysed by isobaric tagged relative and absolute quantification (iTRAQ) labelling coupled with mass spectrometry (MS). In total, 277 proteins were detected and 20 proteins were designated as differentially expressed proteins, which were submitted to subsequent bioinformatics analysis. Gene Ontology classification analysis showed the biological process was primarily related to ‘cellular process’, molecular function ‘structural molecule activity’ and cellular component ‘extracellular region’. IPA analysis revealed ‘LXR/RXR activation’ was the top pathway, which is a crucial pathway in lipid metabolism. Hierarchical clustering analysis generated two clusters. In summary, this study is the first proteomic research to delineate the total and differential serum proteins in TBX6 haploinsufficiency‐caused CS. The proteins discovered in this experiment may serve as potential biomarkers for CS, and lipid metabolism might play important roles in the pathogenesis of CS.

Recent advances in technique and clinical outcomes of minimally invasive spine surgery in adult scoliosis.

Objective: Conventional open spinal surgery of adult scoliosis can be performed from anterior, posterior, or combined approach. Minimally invasive spine surgery (MISS) was developed for the purpose of reducing the undesirable effects and complications. This review aimed to make a brief summary of recent studies of the approach and clinical outcomes of MISS in adult scoliosis. Data Sources: We conducted a systematic search from PubMed, Medline, EMBASE, and other literature databases to collect reports of surgical methods and clinical outcomes of MISS in treatment of adult scoliosis. Those reports were published up to March 2017 with the following key terms: “minimally invasive,” “spine,” “surgery,” and “scoliosis.” Study Selection: The inclusion criteria of the articles were as followings: diagnosed with adult degenerative scoliosis (DS) or adult idiopathic scoliosis; underwent MISS or open surgery; with follow-up data. The articles involving patients with congenital scoliosis or unknown type were excluded and those without any follow-up data were also excluded from the study. The initial search yielded 233 articles. After title and abstract extraction, 29 English articles were selected for full-text review. Of those, 20 studies with 831 patients diagnosed with adult DS or adult idiopathic scoliosis were reviewed. Seventeen were retrospective studies, and three were prospective studies. Results: The surgical technique reported in these articles was direct or extreme lateral interbody fusion, axial lumbar interbody fusion, and transforaminal lumbar interbody fusion. Among the clinical outcomes of these studies, the operated levels was 3–7, operative time was 2.3–8.5 h. Both the Cobb angle of coronal major curve and evaluation of Oswestry Disability Index and Visual Analog Scale decreased after surgery. There were 323 complications reported in the 831 (38.9%) patients, including 150 (18.1%) motor or sensory deficits, and 111 (13.4%) implant-related complications. Conclusions: MISS can provide good radiological and self-evaluation improvement in treatment of adult scoliosis. More prospective studies will be needed before it is widely used.

Phenotypic heterogeneity of intellectual disability in patients with congenital insensitivity to pain with anhidrosis: A case report and literature review:

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive heterogeneous disorder mainly caused by mutations in the neurotrophic tyrosine receptor kinase 1 gene (NTRK1) and characterized by insensitivity to noxious stimuli, anhidrosis, and intellectual disability. We herein report the first north Han Chinese patient with CIPA who exhibited classic phenotypic features and severe intellectual disability caused by a homozygous c.851-33T>A mutation of NTRK1, resulting in aberrant splicing and an open reading frame shift. We reviewed the literature and performed in silico analysis to determine the association between mutations and intellectual disability in patients with CIPA. We found that intellectual disability was correlated with the specific Ntrk1 protein domain that a mutation jeopardized. Mutations located peripheral to the Ntrk1 protein do not influence important functional domains and tend to cause milder symptoms without intellectual disability. Mutations that involve critical amino acids in the protein are prone to cause severe symptoms, including intellectual disability.

Genetic polymorphisms of GPR126 are functionally associated with PUMC classifications of adolescent idiopathic scoliosis in a Northern Han population

GPR126 has been identified to be associated with AIS (Adolescent Idiopathic Scoliosis) in different populations, but data on the northern Chinese population are unavailable. Additionally, it is important to know the exact clinical phenotypes associated with specific genetic polymorphisms. Fourteen SNP (single nucleotide polymorphism) loci in GPR126 were genotyped in 480 northern Chinese Han AIS patients and 841 controls. These patients were classified into three types based on the PUMC classification system. Luciferase assays were used to investigate their regulation of GPR126 transcription activity. Combined and stratified genotype–phenotype association analyses were conducted. The alleles rs225694, rs7774095 and rs2294773 were significantly associated with AIS (P = 0.021, 0.048 and 0.023, respectively). rs225694 and rs7774095 potentially have regulatory functions for the GRP126 gene. Correlation analysis revealed that allele A of rs225694 was a risk allele only for PUMC type II AIS (P = 0.036) and allele G of rs2294773 was a risk allele only for PUMC type I AIS (P = 0.018). In summary, rs225694, rs7774095 and rs2294773 are significantly associated with disease in northern Chinese Han AIS patients. The SNPs rs225694 and rs2294773 are associated with different AIS PUMC classifications.

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be ‘induced’ by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p < 1 × 10−6 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.