Clinical Characteristics of Adrenal Hemangioma.

Objective: Adrenal hemangioma (AH) is a rare, benign adrenal tumor often detected incidentally by imaging. This retrospective study aimed to investigate the clinical characteristics of AH, including clinical and diagnostic imaging features, to improve the recognition and understanding of AH. Methods: We retrospectively analyzed the medical records of patients diagnosed with AH at Peking Union Medical College Hospital between 2008 and 2022. Clinical manifestations, adrenal hormone levels, imaging findings, treatment approaches, and pathological results were collected and analyzed. Results: Of the 7140 adrenal tumor patients, 40 (0.56%) had AH confirmed postoperatively. The mean age at diagnosis was 53.9 years, with a female predominance. Most (70%) were asymptomatic and diagnosed incidentally. Misdiagnosis before surgery was common, most frequently as pheochromocytoma. Imaging characteristics, especially enhanced computed tomography, revealed distinct features based on tumor size. Surgery was the main treatment, with laparoscopic adrenalectomy preferred. Conclusion: This study elucidates the clinical characteristics of AH, including demographics, diagnostic challenges, and imaging features. AH often presents incidentally and is frequently misdiagnosed preoperatively. Recognizing distinct imaging characteristics and appropriate surgical management can enable accurate diagnosis and optimal treatment.

Updated prevalence of latent prostate cancer in Chinese population and comparison of biopsy results: An autopsy-based study.

Prostate cancer detected by autopsy is named latent prostate cancer. As the repertoire of clinical prostate cancer, latent cancer may better reflect the disease burden. Unlike clinical prostate specimens, which are obtained exclusively from biopsy-positive cases, prostate specimens obtained through autopsy provide information on biopsy-negative cases, helping calculate the true sensitivity of prostate biopsy. From 2014 to 2021, we collected autopsy specimens of the prostate from body donors in China and performed transperineal and transrectal biopsies on specimens before step-sectioning and pathological measurements. We found that the crude prevalence of latent prostate cancer in middle-aged and elderly men was 35.1% (81/231), which was higher than previous estimates for Chinese populations. The overall per-patient sensitivities of transperineal and transrectal biopsies were not significantly different (33.3% vs. 32.1%, p = 0.82), but the two approaches differed in preferential sampling area along the proximal-distal axis of the prostate. Transperineal biopsy had a higher sensitivity for detecting clinically significant lesions in the distal third (34.7% vs. 16.3%, p = 0.02) and distal half (30.6% vs. 18.1%, p = 0.04), while transrectal biopsy had a higher sensitivity for lesions in the proximal half (25.0% vs. 13.9%, p = 0.046). Both transperineal and transrectal methods of biopsy missed most small lesions (<0.1 mL) and 35.3% (6/17) of large lesions (>0.5 mL). In conclusion, the prevalence of latent prostate cancer in China has increased over the past 2 decades. Systematic transperineal and transrectal methods of biopsy had comparable sensitivities but had different preferential sampling areas. Both approaches miss one-third of large lesions.

A novel signature for predicting prognosis and immune landscape in cutaneous melanoma based on anoikis-related long non-coding RNAs.

Anoikis is a unique form of apoptosis associated with vascularization and distant metastasis in cancer. Eliminating anoikis resistance in tumor cells could be a promising target for improving the prognosis of terminal cancer patients. However, current studies have not elaborated on the prognosis effect of anoikis-related long non-coding RNAs (lncRNAs) in cutaneous melanoma. Pre-processed data, including RNA sequences and clinical information, were retrieved from TCGA and GTEx databases. After a series of statistical analyses, anoikis-related lncRNAs with prognostic significance were identified, and a unique risk signature was constructed. Risk scores were further analyzed in relation to the tumor microenvironment, tumor immune dysfunction and exclusion, immune checkpoint genes, and RNA methylation genes. The indicators were also used to predict the potentially sensitive anti-cancer drugs. An anoikis-related lncRNAs risk signature consisting of LINC01711, POLH-AS1, MIR205HG, and LINC02416 was successfully established in cutaneous melanoma. Overall survival and progression-free survival of patients were strongly linked with the risk score, independently of other clinical factors. The low-risk group exhibited a more beneficial immunological profile, was less affected by RNA methylation, and was more sensitive to the majority of anti-cancer drugs, all of which indicated a better prognostic outcome. The 4 hub lncRNAs may be fundamental to studying the mechanism of anoikis in cutaneous melanoma and provide personalized therapy for salvaging drug resistance.

Comprehensive prediction of immune microenvironment and hot and cold tumor differentiation in cutaneous melanoma based on necroptosis-related lncRNA.

As per research, causing cancer cells to necroptosis might be used as a therapy to combat cancer drug susceptibility. Long non-coding RNA (lncRNA) modulates the necroptosis process in Skin Cutaneous Melanoma (SKCM), even though the precise mechanism by which it does so has yet been unknown. RNA sequencing and clinical evidence of SKCM patients were accessed from The Cancer Genome Atlas database, and normal skin tissue sequencing data was available from the Genotype-Tissue Expression database. Person correlation analysis, differential screening, and univariate Cox regression were successively utilized to identify necroptosis-related hub lncRNAs. Following this, we adopt the least absolute shrinkage and selection operator regression analysis to construct a risk model. The model was evaluated on various clinical characteristics using many integrated approaches to ensure it generated accurate predictions. Through risk score comparisons and consistent cluster analysis, SKCM patients were sorted either high-risk or low-risk subgroups as well as distinct clusters. Finally, the effect of immune microenvironment, m7G methylation, and viable anti-cancer drugs in risk groups and potential clusters was evaluated in further detail. Included USP30-AS1, LINC01711, LINC00520, NRIR, BASP1-AS1, and LINC02178, the 6 necroptosis-related hub lncRNAs were utilized to construct a novel prediction model with excellent accuracy and sensitivity, which was not influenced by confounding clinical factors. Immune-related, necroptosis, and apoptosis pathways were enhanced in the model structure, as shown by Gene Set Enrichment Analysis findings. TME score, immune factors, immune checkpoint-related genes, m7G methylation-related genes, and anti-cancer drug sensitivity differed significantly between the high-risk and low-risk groups. Cluster 2 was identified as a hot tumor with a better immune response and therapeutic effect. Our study may provide potential biomarkers for predicting prognosis in SKCM and provide personalized clinical therapy for patients based on hot and cold tumor classification.

Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders.

Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-ß signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-ß signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-ß signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.

Identification of UAP1L1 as a critical factor for prostate cancer and underlying molecular mechanism in tumorigenicity.

BACKGROUND: Prostate cancer is the second most common cancer in men, and some new target genes are needed to predict the risk of prostate cancer progression and the treatment. METHODS: In this study, the effects of UAP1L1 (UAP1-like-1) on prostate cancer were investigated by detecting the proliferation, migration, invasion and apoptosis of prostate cancer cells in vitro using MTT, wound healing, Transwell and flow cytometry assay, and the tumor growth in vivo. The downstream genes and pathways of UAP1L1 were explored using Ingenuity Pathway Analysis (IPA), and screened by qRT-PCR and western blot. The effects of CDCA8 on prostate cancer cells were also verified in vitro, which was through detecting the change of proliferation, migration, invasion and apoptosis of prostate cancer cells after CDCA8 knockdown. RESULTS: The results indicated that UAP1L1 promoted the proliferation, migration and invasion of prostate cancer cells, which was inhibited by downregulating CDCA8. Furthermore, the promotion of CDCA8 knockdown on cell apoptosis was reduced when UAP1L1 was simultaneously overexpressed. CONCLUSIONS: In conclusion, the results in this study revealed that UAP1L1 promoted the progression of prostate cancer through the downstream gene CDCA8.

Development of a nomogram combining multiparametric magnetic resonance imaging and PSA-related parameters to enhance the detection of clinically significant cancer across different region.

OBJECTIVE: Prostate cancer (PCa) is the most prevalent cancer among males. This study attempted to develop a clinically significant prostate cancer (csPCa) risk nomogram including Prostate Imaging-Reporting and Data System (PI-RADS) score and other clinical indexes for initial prostate biopsy in light of the different prostate regions, and internal validation was further conducted. PATIENTS AND METHODS: A retrospective study was performed including 688 patients who underwent ultrasound-guided transperineal magnetic resonance imaging fusion prostate biopsy from December 2016 to July 2019. We constructed nomograms combining PI-RADS score and clinical variables (prostate-specific antigen [PSA], prostate volume (PV), age, free/total PSA, and PSA density) through univariate and multivariate logistic regression to identify patients eligible for biopsy. The performance of the predictive model was evaluated by bootstrap resampling. The area under the curve (AUC) of the receiver-operating characteristic (ROC) analysis was appointed to quantify the accuracy of the primary nomogram model for csPCa. Calibration curves were used to assess the agreement between the biopsy specimen and the predicted probability of the new nomogram. The χ2 test was also applied to evaluate the heterogeneity between fusion biopsy and systematic biopsy based on different PI-RADS scores and prostate regions. RESULTS: A total of 320 of 688 included patients were diagnosed with csPCa. csPCa was defined as Gleason score ≥7. The ROC and concordance-index both presented good performance. The nomogram reached an AUC of 0.867 for predicting csPCa at the peripheral zone; meanwhile, AUC for transitional and apex zones were 0.889 and 0.757, respectively. Statistical significance was detected between fusion biopsy and systematic biopsy for PI-RADS score >3 lesions and lesions at the peripheral and transitional zones. CONCLUSION: We produced a novel nomogram predicting csPCa in patients with suspected imaging according to different locations. Our results indicated that PI-RADS score combined with other clinical parameters showed a robust predictive capacity for csPCa before prostate biopsy. The new nomogram, which incorporates prebiopsy data including PSA, PV, age, and PI-RADS score, can be helpful for clinical decision-making to avoid unnecessary biopsy.

Multiple inferior vena cava aneurysms mimic a retroperitoneal tumor: a case report.

BACKGROUND: Inferior vena cava (IVC) aneurysms are extremely rare with variable clinical manifestations. Patients are usually asymptomatic or present with complications of thrombosis and rupture. To date, there have been only a few reports of the condition in the literature, and diagnosis of IVC aneurysms may be difficult. CASE PRESENTATION: A 33-year-old male patient presented to hospital because of a retroperitoneal mass found by computerized tomography during a health examination. He was asymptomatic, and post medical history and physical examination were unremarkable. Laboratory tests including tests for paraganglioma were all negative. Contrast-enhanced computed tomography scan revealed a stenosis of IVC in the suprarenal segment and two retroperitoneal mass on the right side of IVC. The larger one is about 3 cm in diameter and the smaller one is about 1 cm in diameter, which was considered as a retroperitoneal tumor with an enlarged lymph node. However, two IVC diverticular aneurysms were confirmed during the retroperitoneal laparoscopic exploration. The larger aneurysm was resected from the IVC successfully. Since the smaller aneurysm was about 1 cm in diameter without thrombosis, we did not resect it during surgery. The patient recovered well from surgery and discharged from our department successfully. CONCLUSIONS: This is the first report of multiple IVC aneurysms. Because of the extremely low prevalence of IVC diverticular aneurysm, it may be misdiagnosed as other disease. Due to the high rate of thrombosis, surgical treatment especially retroperitoneal laparoscopy is recommended for small diverticular aneurysms.

Hsa_circ_0085576 promotes clear cell renal cell carcinoma tumorigenesis and metastasis through the miR-498/YAP1 axis.

There is emerging evidence that circular RNAs (circRNAs) act as important regulators in various cancers. It is less clear, however, what role circRNA plays in the tumorigenesis and metastasis of clear cell renal cell carcinoma (ccRCC). In this study, using bioinformatics analysis and a series of experimental analysis, we characterized a novel circRNA, hsa_circ_0085576 was up-regulated in ccRCC tissues and cell lines. High hsa_circ_0085576 expression was significantly correlated with tumor size, clinical stage, and metastasis status and poorer survival. Knockdown of hsa_circ_0085576 notably inhibited cell proliferation, migration, invasion, whereas enhanced cell apoptosis of ccRCC cells, in vitro. In contrast, overexpression of hsa_circ_0085576 had the opposite effects. Moreover, hsa_circ_0085576 silencing significantly suppressed tumor growth and metastasis, whereas overexpression of hsa_circ_0085576 had the opposite effects, in vivo, Our results further showed that hsa_circ_0085576 acted as a competitive endogenous RNAs to interact with microRNA-498, to attenuate its repressive effect on target gene Yes-associated protein 1 (YAP1). Finally, functional studies revealed that inhibition of hsa_circ_0085576 suppressed cell growth and metastasis by regulating miR-498/YAP1 signaling, in ccRCC cells. Based on these findings, hsa_circ_0085576 may represent a valuable prognostic biomarker and a potential therapeutic target to curb the tumorigenesis and metastasis of ccRCC.

Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1.

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

Change in the cause of inpatient mortality after arthroplasty: a retrospective study.

BACKGROUND: Although arthroplasty has been proved to be a safe and effective procedure, data regarding inpatient mortality rates associated with arthroplasty in China is unclear. We aimed to investigate the inpatient mortality rate after arthroplasty and the determinants of mortality at our center to ensure improved perioperative management. METHODS: This retrospective study included all patients who underwent arthroplasty at our center. Clinical data of mortality patients were collected. The incidence and the causes of inpatient mortality after arthroplasty were analyzed. RESULTS: A total of 4176 total knee arthroplasties, 2164 total hip arthroplasties, and 1031 femoral head replacements were performed. A rapid growth in surgery volume was observed, and more than 50% of the surgeries were performed in the last 5 years. The overall inpatient mortality rate is 0.3%; however, the mortality rate even decreased in the last 5 years. The cause of death changed over time. Pneumonia has become the leading cause of death in the past 5 years instead of cardiovascular complications. CONCLUSIONS: Arthroplasty is a safe and effective procedure associated with a relatively low inpatient mortality in China. And inpatient mortality does not increase as the growing surgery volume due to improvement of perioperative management. However, patients presenting with risk factors and those undergoing non-elective procedures demonstrated a relatively high incidence of postoperative complications, particularly pneumonia.

Spinal and sacroiliac involvement in SAPHO syndrome: A single center study of a cohort of 354 patients.

OBJECTIVE: SAPHO syndrome is a highly heterogeneous disease with distinct treatment response. We report the largest cohort of SAPHO syndrome and explore its clinical classification with special interest in spinal and sacroiliac involvement. METHODS: A total of 354 patients with SAPHO syndrome were recruited in Peking Union Medical College Hospital. The demographic, clinical and imaging data were collected at baseline. Spinal and sacroiliac involvement was determined by the co-existence of related symptoms and imaging evidence of lesions in the spine or sacroiliac joints on either bone scintigraphy, CT or MRI. RESULTS: A total of 197 (55.6%) patients were identified to have spinal or sacroiliac involvement. Compared to those without spinal or sacroiliac lesions, these patients were significantly older at onset (38 ±â€¯12 vs 35 ±â€¯10 years old, p = 0.019) but had comparable duration of disease. Therapeutically, patients with spinal or sacroiliac involvement had been treated more aggressively with more frequently prescribed NSAIDs, glucocorticoids, DMARDs, TNF-α inhibitors, and bisphosphonates (all p ≤ 0.001). Nonetheless, greater disease activity was observed for these patients at baseline, supported by both inflammatory markers (ESR and hs-CRP) and visual analog scale (VAS) for pain (all p < 0.001). CONCLUSIONS: SAPHO patients with spinal or sacroiliac involvement are older at onset and have greater disease activity despite of more aggressive treatments compared to those without. Stratified management is in urgent need for this rare disease.

Efficacy of bisphosphonates in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a prospective open study.

OBJECTIVES: To evaluate the clinical efficacy of bisphosphonates treatment for spinal bone marrow oedema (BME) in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. METHODS: SAPHO syndrome patients presenting to Peking Union Medical College Hospital from 2015 to 2016 were recruited. Patients were administered pamidronate disodium 1 mg/kg/d intravenously, for 3 days, at baseline and 3 months later. The symptoms were evaluated using the Visual Analog Score (VAS) for pain, and other clinical measures including, spinal BME scores, ß-crosslaps, osteocalcin, and inflammatory factors, were collected. RESULTS: A total of 30 patients (20 women and 10 men) with a median age of 47.2 (interquartile range 8.8) years were recruited. In a short time, the patients showed a significant decrease in VAS (before vs. after; first treatment: 5.70±1.62 vs. 2.30±1.29 cm, second treatment: 4.03±1.88 vs. 2.17±1.23 cm) and ß-crosslaps (first treatment: 0.4441±0.1923 vs. 0.0859±0.0374 pg/ml, second treatment: 0.2891±0.1983 vs. 0.0962±0.0324 pg/ml) (all p<0.05). At 12-month follow-up, compared with the baseline, we noticed a significant drop in the VAS (5.70±1.62 vs. 2.43±1.25 cm), erythrocyte sedimentation rate (28.87±25.26 vs. 18.00±18.65 mm/h), high-sensitivity C-reactive protein level (11.76±10.19 vs. 5.84±5.88 mg/L), osteocalcin (2.30±1.27 vs. 1.65±0.80 ng/ml), and BME (30.50±24.09 vs. 22.13±27.79) (all p<0.05). No one had serious adverse events. CONCLUSIONS: Bisphosphonates can significantly and rapidly relieve symptoms in patients with SAPHO syndrome and have a long-term effect on inflammation and spinal BME. We suggest that bisphosphonates could be used as the first-line therapeutic drug for SAPHO syndrome, especially in patients with spinal BME.

TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model.

PURPOSE: To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model. METHODS: Patients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N = 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS). RESULTS: In cohort 1, TACS patients (N = 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 × 10‒8), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 × 10‒3); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 × 10‒7), while intraspinal anomalies were uncommon (P = 7.0 × 10‒7). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 × 10‒15). A Tbx6-/mh (mild-hypomorphic) mouse model supported that a gene dosage effect underlies the TACS phenotype. CONCLUSION: TACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of CS.

Three patterns of osteoarticular involvement in SAPHO syndrome: a cluster analysis based on whole body bone scintigraphy of 157 patients.

OBJECTIVES: To explore the patterns of osteoarticular involvement in SAPHO syndrome. METHODS: Baseline clinical characteristics and imaging data of 99mTc-MDP whole-body bone scintigraphy (WBBS) were collected from 157 out of 164 patients diagnosed with SAPHO syndrome. The twelve most frequently involved osteoarticular sites were analysed by hierarchical cluster analysis with the Ward minimum-variance method. RESULTS: Three distinctive patterns of osteoarticular involvement were identified: the spinal type (70 patients, 44.6%), with predominantly thoracic, lumbar or sacral vertebral lesions; the costal type (52 patients, 33.1%), with lesions of anterior ribs, particularly the first ribs; and the sternoclavicular type (35 patients, 22.3%), with predominantly sternal and bilateral sternoclavicular lesions, characterized by the typical bullhead sign. Notably, a total of 77 (49%) patients exhibited lesions of ribs on WBBS, of which 61.3% involved the first ribs. Interestingly, patients of spinal type were older at onset of cutaneous manifestations than those of sternoclavicular type (P = 0.036) and costal type (P = 0.035). The disease course was remarkably longer in sternoclavicular type than costal type (P = 0.001) and spinal type (P < 0.001). CONCLUSION: The osteoarticular involvement in SAPHO syndrome can be categorized as three distinct patterns with different corresponding clinical features. The costal involvement in SAPHO syndrome, which was under-recognized previously, may define a distinct sub-type of the disease.

Genetic polymorphisms of PAX1 are functionally associated with different PUMC types of adolescent idiopathic scoliosis in a northern Chinese Han population.

INTRODUCTION: PAX1 has been identified to be associated with adolescent idiopathic scoliosis (AIS). However, data are unavailable for northern Chinese populations, and it is important to determine the exact clinical phenotypes of the associated genetic polymorphisms. METHODS: Five PAX1 single nucleotide polymorphism (SNP) loci were genotyped in 480 northern Chinese Han AIS patients and 841 controls. A stratified genotype-phenotype correlation analysis was conducted based on positive SNP loci and the Peking Union Medical College (PUMC) classification system. Luciferase assays were performed to determine the regulation of PAX1 transcriptional activity. RESULTS: The A allele of rs17861031 and the G allele of rs6137473 were significantly associated with AIS [p = 0.05 and 3.12 × 10-3, odds ratio (OR) = 0.78 and 1.30, respectively]. Moreover, rs17861031 may regulate the PAX1 gene. The A allele of rs17861031 was identified as a risk allele for PUMC type I AIS (p = 0.03), and the G allele of rs6137473 was identified as a risk allele for PUMC type II AIS (p = 1.90 × 10-3). CONCLUSIONS: Both rs17861031 and rs6137473 were significantly associated with AIS and different PUMC classifications of AIS in a northern Chinese Han population.

Whole-Genome Methylation Analysis of Phenotype Discordant Monozygotic Twins Reveals Novel Epigenetic Perturbation Contributing to the Pathogenesis of Adolescent Idiopathic Scoliosis.

Background: Adolescent idiopathic scoliosis (AIS) is a complex disease affecting a large number of teenagers, especially in female. This study reveals novel epigenetic perturbation to the pathogenesis of AIS. Methods: A female monozygotic (MZ) twin pair discordant for AIS were examined for whole-exome sequencing and epigenome difference. Sets of differentially methylated regions (DMRs) were validated using MethylTarget™ method in 20 AIS female patients and 20 healthy female controls. Results: Few exome difference but several potential DMRs were found between the MZ twins. We identified 313 hypermethylated DMRs and 397 hypomethylated DMRs, respectively. Most of them were enriched in the MAPK and PI3K-Akt signaling pathway, which may contribute to the discordance of AIS. Several DMRs related to scoliosis genes were tested, and the NDN: TSS-DMR (chr15:23932133-23932304, hg19) was confirmed in additional samples. The methylation level of this DMR was significantly higher in the AIS group than in the control group (p = 0.04). Conclusions: We described the epigenome difference in an AIS female discordant MZ twin pair using Whole Genome Bisulfite Sequencing (WGBS). The NDN: TSS-DMR had higher methylation level in female AIS, which can help elucidate the potential etiology of AIS.

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.

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.

Multifocal Paraganglioma and Pheochromocytoma Due to Truncated SDHD Mutation.

OBJECTIVE: Pheochromocytoma and paraganglioma (PPGL) are rare autosomal dominant disorders derived from the neural crest chromaffin tissues of the autonomic nervous system. The succinate dehydrogenase complex subunit D (SDHD) gene has been implicated as one of the pathogenic genes. Although more than 100 SDHD mutations have been reported, the phenotype-genotype association remains unclear. METHODS: We reported a case of a patient who presented with multifocal PPGLs and with a rare SDHD mutation, and reviewed the phenotype-genotype association of SDHD. RESULTS: We identified a pathogenic variant of SDHD (c.170-1G>T, NM_003002.3), which caused the complete deletion of exon 3 in the transcript and resulted in a shorter and unstable SDHD mRNA. And truncated SDHD mutations were prone to cause multifocal PPGL, whereas missense SDHD mutations usually caused unifocal lesions. CONCLUSION: This is the first report linking the c.170-1G>T variant to multifocal tumors. We recommend whole-body imaging examinations and close, regular follow-up for these patients, given the risk of multifocal tumor development.