Introduction: Anxiety disorders have a lifetime prevalence of 34% with a similar level of heritability (31%) yet lack objective markers that could differentiate patients with underlying conditions. Up to 60%-70% of pa...Introduction: Anxiety disorders have a lifetime prevalence of 34% with a similar level of heritability (31%) yet lack objective markers that could differentiate patients with underlying conditions. Up to 60%-70% of patients with Ehlers-Danlos syndrome have anxiety that meets criteria of generalized anxiety disorder, their clinical-DNA findings worth examining as biomarkers for patients with generalized anxiety. Method: Of the 1899 patients diagnosed with Ehlers-Danlos syndrome, 1261 were systematically evaluated for 80 history and 40 physical findings and separated into 826 who reported anxiety and 435 who did not. The most consistently reported or management-directing 60 of these clinical findings were, along with variations in genes relevant to these disorders, examined for association with anxiety. Results: Among the 30 anxiety- associated findings judged most predictive of Ehlers-Danlos syndrome in patients with anxiety were expected ones of adrenergic stimulation (difficulty concentrating-87% frequency and 1.26 anxiety/no anxiety ratio;chronic fatigue-84%, 1.17;sleep issues 69%, 1.52 that are criteria for generalized anxiety disorder) or of cholinergic suppression (e.g., frequent nausea 64%, 1.26). Less associated but more discriminating for underlying disease were those reflective of neuromuscular impact (e.g., chronic daily headaches 76%, 1.12);hypermobility (e.g., awareness of flexibility 72%, 1.03), or skin changes (e.g., elasticity around jaw 71%, 1.06). Anxiety-associated DNA variants included 54 of 88 in collagen type I/V/VII/IX genes, 14 of 16 in sodium channel SCN9A/10A/ 11A genes, 59 of 85 in POLG/MT-DNA genes, and 21 of 28 in profilaggrin- FLG genes that respectively impacted tissue laxity, sensory neural, autonomic-mitochondrial, and autonomic-inflammatory functions. Conclusion: Analysis of pathogenetic mechanisms in Ehlers-Danlos syndrome selected some 50 clinical-DNA findings useful for its diagnosis in those with generalized anxiety disorders.展开更多
目的探讨Ehlers-Danlos综合征(EDS)消化系统受累患者的临床和遗传学特征。方法通过电子病案收集北京协和医院2003年1月至2023年9月有消化系统受累的EDS患者资料,于PubMed、Embase、Web of Science、the Cocharane Library数据库检索2000...目的探讨Ehlers-Danlos综合征(EDS)消化系统受累患者的临床和遗传学特征。方法通过电子病案收集北京协和医院2003年1月至2023年9月有消化系统受累的EDS患者资料,于PubMed、Embase、Web of Science、the Cocharane Library数据库检索2000年1月至2023年9月发表的有消化道受累的EDS病例,一并进行系统回顾和分析。结果本中心5例EDS消化系统受累患者,数据库检索出80篇文献涉及89例EDS消化系统受累患者,共94例纳入分析。患者诊断EDS的平均年龄为(29±14)岁。消化系统受累的表现依次为消化道穿孔(n=46,48.9%)、功能性胃肠道症状(n=33,35.1%)和消化系动脉病变(n=10,10.6%)。EDS消化系统受累患者中,最常见的临床亚型为血管型(vEDS)(n=50,53.2%),其次为关节过度活动型(hEDS)(n=20,21.3%),最常见的突变基因为COL3A1基因(n=30,31.9%)。vEDS患者中,消化系统受累表现分别为消化道穿孔(n=33,66.0%)、动脉病变(n=9,18.0%)和功能性胃肠道症状(n=7,14.0%)。hEDS患者中,消化系统受累表现分别为功能性胃肠道症状(n=18,90.0%)、内脏脱垂(n=3,15.0%)和肠扭转(n=1,5.0%)。结论EDS消化系统受累主要见于vEDS和hEDS两种亚型,vEDS以消化道穿孔、消化系动脉病变为主,而hEDS多表现为功能性胃肠道症状。展开更多
Findings in 1656 patients referred for evaluation of Ehlers-Danlos syndrome, 710 evaluated systematically using novel history and physical forms, defined a characteristic clinical pattern termed arthritis-adrenaline d...Findings in 1656 patients referred for evaluation of Ehlers-Danlos syndrome, 710 evaluated systematically using novel history and physical forms, defined a characteristic clinical pattern termed arthritis-adrenaline disorder, a genus that provides immediate therapy while delineation of particular tissue laxity/dysautonomia species is underway. Preliminary diagnoses, clinical findings, and laboratory results were entered into an MS Excel? database with IRB approval and correlations or statistical significance analyzed using Excel? functions. Frequencies of 80 findings by history and 40 on physical were similar among EDS groups, females paralleling males with more total history (35 versus 23) and physical (18 versus 15) findings. Finding frequencies in joint-skeletal (6.2 of 15) and dysautonomia (11 of 20) subcategories were substantial regardless of age, EDS diagnosis, or referral source, the latter was shown by 6.4 and 13 average findings for cardiology, 5.3 and 8.3 for orthopedic referrals. Early affliction evidenced by history findings averaging 19.5 in those under 12 increased dramatically to 25 for teens and 32 for adults with plateauing at older ages arguing against degenerative disease. Frequent neuromuscular symptoms in females emphasize surrounding muscle support and protection of joint-connective tissue as a key factor in decreased male severity. The congruent clinical profile suggests operation of an articulo-autonomic dysplasia cycle where lax vessels and lower body pooling elicit sympathetic response, autonomic imbalance in turn affecting small nerve fibers and enhancing connective tissue laxity. Recognition of this arthritis-adrenalin disorder can guide management strategies while underlying causes are pursued, among them, physical therapy, exercise, and vitamin D to build muscle/bone strength;lower gluten/dairy and antihistamine protocols for low bowel motility/mast-cell activation;hydration, salt, and exercise for postural orthostatic tachycardia syndrome.展开更多
A novel medical approach for qualifying DNA variants found by whole exome sequencing (WES) facilitates discovery of new gene-disease relationships and emphasizes that DNA change must be correlated with clinical findin...A novel medical approach for qualifying DNA variants found by whole exome sequencing (WES) facilitates discovery of new gene-disease relationships and emphasizes that DNA change must be correlated with clinical findings before having utility for diagnosis. Delineation of an arthritis-adrenaline disorder (AAD) process qualified variants in 23 genes as diagnostically useful in 727 patients having WES among 1656 with Ehlers-Danlos syndrome (EDS);these results distinguished them from 102 patients who had qualified gene variants among 728 with developmental disability. Excess maternal transmission of AAD by pedigree analysis plus 167 maternally versus 111 paternally transmitted DNA variants and 75 patients with only mitochondrial DNA variants suggest maternal influence on inheritance of AAD and its subsumed EDS types. Genes grouped by impact on different connective tissue elements showed variation in similar numbers of patients with hypermobile or classical EDS, benign joint hypermobility, or predominant dysautonomia: COL7A1, FLG acting on skin in 21 patients;SCN9A/10A/11A, POLG on nerve in 24;COL6A1/A2/A3, COL12 on muscle in 19;COL5A1/A2, FBN1, TGFB2/3, TGFBR1/2 on tissue matrix in 51;COL3A1, VWF on vessel in 18;COL1A1/A2, COL11A1/A2 acting on bone in 15 patients. Each gene group acts through a postulated articulo-autonomic dysplasia cycle to produce reciprocal tissue laxity and dysautonomia findings that transcend EDS types. This same tissue laxity-dysautonomia cycle acts to produce secondary complications in disorders ranging from distinctive connective tissue dysplasias to developmental disorders with hypotonia and acquired conditions with autonomic imbalance. Several altered genes were previously associated with neuromuscular disorders, foreshadowing a large myopathic EDS category that will incorporate many patients with hypermobility. The importance of muscle for joint constraint supports present exercise and future mesenchymal stem cell therapies, whether AAD is genetic or epigenetic from trauma, surgery, infla展开更多
We report a 28-year-old female who presented with severe joint pain, chronic muscle weakness, Raynaud’s phenomenon, and hypermobility. She was found to have a 6074A 〉 T nucleotide transition in the TNXB gene causing...We report a 28-year-old female who presented with severe joint pain, chronic muscle weakness, Raynaud’s phenomenon, and hypermobility. She was found to have a 6074A 〉 T nucleotide transition in the TNXB gene causing an amino acid protein change at Asp2025Val classifed as likely pathogenic. We add this clinical report to the literature and classical human disease gene catalogs to identify this specific mutation as disease-causing. This gene variant was reported previously in a different 36-year-old patient who shared our patient’s symptoms of joint hypermobility, skeletal and joint pain, skin elasticity and musculoskeletal problems, thereby causing a more severe presentation than seen in the hypermobility type of Ehlers-Danlos syndrome （EDS）. At the time of writing, a few mutations in the TNXB gene have been recognized as pathogenic causing EDS due to tenascin-X defciency, but the variant identifed in our patient has not been recognized as pathogenic in online genetic databases. Our case study in combination with peer-reviewed literature suggests that the 6074A 〉 T nucleotide transition in the TNXB gene may be classifed as disease-causing for EDS due to tenascin-X defciency.展开更多
BACKGROUND Spinal deformities in Ehlers-Danlos syndrome(EDS; type VI) are generally progressive and severe. Surgical treatment has been described for kyphoscoliosis in the thoracolumbar spine. However, there are few s...BACKGROUND Spinal deformities in Ehlers-Danlos syndrome(EDS; type VI) are generally progressive and severe. Surgical treatment has been described for kyphoscoliosis in the thoracolumbar spine. However, there are few studies describing the consequences of an anterior approach in cervical kyphosis. An anterior approach may not be able to fully decompress the spinal canal and restore the normal curvature of the cervical spine. Therefore, the anterior approach for cervical kyphosis in young children is hard. We describe the first case in an EDS girl with cervical kyphosis who received satisfactory anterior cervical corpectomy decompression and fusion.CASE SUMMARY The chief complaints of a 16-year-old girl with EDS were double upper limb weakness for 7 years and double lower limb walking instability for 2 years.Moreover, the imaging results revealed that the degree of kyphosis from cervical vertebra 2 to 4 accompanying with spinal cord compression was 30°. An anterior cervical corpectomy involving cervical vertebra 3 and a titanium mesh implant were performed with internal fixation. The results at 3 mo after surgery demonstrated that the anterior fusion was solid, and the kyphosis of the cervical spine was corrected. Additionally, the power of all four extremities was significantly improved.CONCLUSION The incidence rate of cervical kyphosis in EDS is rare. The surgical treatment for these patients, especially an anterior approach, is challenging. Therefore, to develop safer and more effective strategies to treat cervical kyphosis in EDS,there is still much work to do.展开更多
Background: There is an increasing recognition of patients with Ehlers Danlos Syndromes. The laxity of the ligaments and the weakness of the connective tissue has resulted in increasing number of patients requiring su...Background: There is an increasing recognition of patients with Ehlers Danlos Syndromes. The laxity of the ligaments and the weakness of the connective tissue has resulted in increasing number of patients requiring surgical intervention. Ehlers Danlos Syndromes are not about hypermobile joints only, they are associated with multiple co-existing conditions such as Chiari malformation, Tethered Cord Syndrome, spinal instability, abdominal pain, Dysautonomia and Mast Cell Activation Syndrome. The combined incidence of Ehlers Danlos Syndromes is 1 in 5000 people. Most experts believe that the actual incidence is much higher. Many of these cases are under-diagnosed. Nevertheless, patients with Ehlers Danlos Syndromes, diagnosed or undiagnosed often require surgical intervention. This review article has been written to shed light on the need for special consideration during anesthesia. Objectives: Our objective was to conduct a review of anesthetic considerations in patients with Ehlers Danlos Syndromes. Study Design: We used a narrative review design. Methods: This review was done using searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles from inception to 2019. Other data sources included hand searches of publications driven by manuscript authors. Search terms included concepts of “Ehlers Danlos Syndrome”, “EDS”, “pain”, “anesthesia”, “surgery” and combination of terms. Search method was not restricted to any one language. Results: Articles were screened by title, abstract, and full article review. They were then analyzed by specific clinical indications and appropriate data was presented based on critical analysis of those articles. Limitations: More studies about the effect of anesthetic techniques and Ehlers Danlos Syndromes are required. Conclusions: Patients with Ehlers Danlos Syndromes may present with an array of coexisting medical conditions such as Dysautonomia, Mast Cell Activation Syndrome, Chiari Malformation, Tethered展开更多
文摘Introduction: Anxiety disorders have a lifetime prevalence of 34% with a similar level of heritability (31%) yet lack objective markers that could differentiate patients with underlying conditions. Up to 60%-70% of patients with Ehlers-Danlos syndrome have anxiety that meets criteria of generalized anxiety disorder, their clinical-DNA findings worth examining as biomarkers for patients with generalized anxiety. Method: Of the 1899 patients diagnosed with Ehlers-Danlos syndrome, 1261 were systematically evaluated for 80 history and 40 physical findings and separated into 826 who reported anxiety and 435 who did not. The most consistently reported or management-directing 60 of these clinical findings were, along with variations in genes relevant to these disorders, examined for association with anxiety. Results: Among the 30 anxiety- associated findings judged most predictive of Ehlers-Danlos syndrome in patients with anxiety were expected ones of adrenergic stimulation (difficulty concentrating-87% frequency and 1.26 anxiety/no anxiety ratio;chronic fatigue-84%, 1.17;sleep issues 69%, 1.52 that are criteria for generalized anxiety disorder) or of cholinergic suppression (e.g., frequent nausea 64%, 1.26). Less associated but more discriminating for underlying disease were those reflective of neuromuscular impact (e.g., chronic daily headaches 76%, 1.12);hypermobility (e.g., awareness of flexibility 72%, 1.03), or skin changes (e.g., elasticity around jaw 71%, 1.06). Anxiety-associated DNA variants included 54 of 88 in collagen type I/V/VII/IX genes, 14 of 16 in sodium channel SCN9A/10A/ 11A genes, 59 of 85 in POLG/MT-DNA genes, and 21 of 28 in profilaggrin- FLG genes that respectively impacted tissue laxity, sensory neural, autonomic-mitochondrial, and autonomic-inflammatory functions. Conclusion: Analysis of pathogenetic mechanisms in Ehlers-Danlos syndrome selected some 50 clinical-DNA findings useful for its diagnosis in those with generalized anxiety disorders.
文摘目的探讨Ehlers-Danlos综合征(EDS)消化系统受累患者的临床和遗传学特征。方法通过电子病案收集北京协和医院2003年1月至2023年9月有消化系统受累的EDS患者资料,于PubMed、Embase、Web of Science、the Cocharane Library数据库检索2000年1月至2023年9月发表的有消化道受累的EDS病例,一并进行系统回顾和分析。结果本中心5例EDS消化系统受累患者,数据库检索出80篇文献涉及89例EDS消化系统受累患者,共94例纳入分析。患者诊断EDS的平均年龄为(29±14)岁。消化系统受累的表现依次为消化道穿孔(n=46,48.9%)、功能性胃肠道症状(n=33,35.1%)和消化系动脉病变(n=10,10.6%)。EDS消化系统受累患者中,最常见的临床亚型为血管型(vEDS)(n=50,53.2%),其次为关节过度活动型(hEDS)(n=20,21.3%),最常见的突变基因为COL3A1基因(n=30,31.9%)。vEDS患者中,消化系统受累表现分别为消化道穿孔(n=33,66.0%)、动脉病变(n=9,18.0%)和功能性胃肠道症状(n=7,14.0%)。hEDS患者中,消化系统受累表现分别为功能性胃肠道症状(n=18,90.0%)、内脏脱垂(n=3,15.0%)和肠扭转(n=1,5.0%)。结论EDS消化系统受累主要见于vEDS和hEDS两种亚型,vEDS以消化道穿孔、消化系动脉病变为主,而hEDS多表现为功能性胃肠道症状。
文摘Findings in 1656 patients referred for evaluation of Ehlers-Danlos syndrome, 710 evaluated systematically using novel history and physical forms, defined a characteristic clinical pattern termed arthritis-adrenaline disorder, a genus that provides immediate therapy while delineation of particular tissue laxity/dysautonomia species is underway. Preliminary diagnoses, clinical findings, and laboratory results were entered into an MS Excel? database with IRB approval and correlations or statistical significance analyzed using Excel? functions. Frequencies of 80 findings by history and 40 on physical were similar among EDS groups, females paralleling males with more total history (35 versus 23) and physical (18 versus 15) findings. Finding frequencies in joint-skeletal (6.2 of 15) and dysautonomia (11 of 20) subcategories were substantial regardless of age, EDS diagnosis, or referral source, the latter was shown by 6.4 and 13 average findings for cardiology, 5.3 and 8.3 for orthopedic referrals. Early affliction evidenced by history findings averaging 19.5 in those under 12 increased dramatically to 25 for teens and 32 for adults with plateauing at older ages arguing against degenerative disease. Frequent neuromuscular symptoms in females emphasize surrounding muscle support and protection of joint-connective tissue as a key factor in decreased male severity. The congruent clinical profile suggests operation of an articulo-autonomic dysplasia cycle where lax vessels and lower body pooling elicit sympathetic response, autonomic imbalance in turn affecting small nerve fibers and enhancing connective tissue laxity. Recognition of this arthritis-adrenalin disorder can guide management strategies while underlying causes are pursued, among them, physical therapy, exercise, and vitamin D to build muscle/bone strength;lower gluten/dairy and antihistamine protocols for low bowel motility/mast-cell activation;hydration, salt, and exercise for postural orthostatic tachycardia syndrome.
文摘A novel medical approach for qualifying DNA variants found by whole exome sequencing (WES) facilitates discovery of new gene-disease relationships and emphasizes that DNA change must be correlated with clinical findings before having utility for diagnosis. Delineation of an arthritis-adrenaline disorder (AAD) process qualified variants in 23 genes as diagnostically useful in 727 patients having WES among 1656 with Ehlers-Danlos syndrome (EDS);these results distinguished them from 102 patients who had qualified gene variants among 728 with developmental disability. Excess maternal transmission of AAD by pedigree analysis plus 167 maternally versus 111 paternally transmitted DNA variants and 75 patients with only mitochondrial DNA variants suggest maternal influence on inheritance of AAD and its subsumed EDS types. Genes grouped by impact on different connective tissue elements showed variation in similar numbers of patients with hypermobile or classical EDS, benign joint hypermobility, or predominant dysautonomia: COL7A1, FLG acting on skin in 21 patients;SCN9A/10A/11A, POLG on nerve in 24;COL6A1/A2/A3, COL12 on muscle in 19;COL5A1/A2, FBN1, TGFB2/3, TGFBR1/2 on tissue matrix in 51;COL3A1, VWF on vessel in 18;COL1A1/A2, COL11A1/A2 acting on bone in 15 patients. Each gene group acts through a postulated articulo-autonomic dysplasia cycle to produce reciprocal tissue laxity and dysautonomia findings that transcend EDS types. This same tissue laxity-dysautonomia cycle acts to produce secondary complications in disorders ranging from distinctive connective tissue dysplasias to developmental disorders with hypotonia and acquired conditions with autonomic imbalance. Several altered genes were previously associated with neuromuscular disorders, foreshadowing a large myopathic EDS category that will incorporate many patients with hypermobility. The importance of muscle for joint constraint supports present exercise and future mesenchymal stem cell therapies, whether AAD is genetic or epigenetic from trauma, surgery, infla
基金Supported by The National Institute of Child Health and Human Development(NICHD),No.HD02528
文摘We report a 28-year-old female who presented with severe joint pain, chronic muscle weakness, Raynaud’s phenomenon, and hypermobility. She was found to have a 6074A 〉 T nucleotide transition in the TNXB gene causing an amino acid protein change at Asp2025Val classifed as likely pathogenic. We add this clinical report to the literature and classical human disease gene catalogs to identify this specific mutation as disease-causing. This gene variant was reported previously in a different 36-year-old patient who shared our patient’s symptoms of joint hypermobility, skeletal and joint pain, skin elasticity and musculoskeletal problems, thereby causing a more severe presentation than seen in the hypermobility type of Ehlers-Danlos syndrome （EDS）. At the time of writing, a few mutations in the TNXB gene have been recognized as pathogenic causing EDS due to tenascin-X defciency, but the variant identifed in our patient has not been recognized as pathogenic in online genetic databases. Our case study in combination with peer-reviewed literature suggests that the 6074A 〉 T nucleotide transition in the TNXB gene may be classifed as disease-causing for EDS due to tenascin-X defciency.
文摘BACKGROUND Spinal deformities in Ehlers-Danlos syndrome(EDS; type VI) are generally progressive and severe. Surgical treatment has been described for kyphoscoliosis in the thoracolumbar spine. However, there are few studies describing the consequences of an anterior approach in cervical kyphosis. An anterior approach may not be able to fully decompress the spinal canal and restore the normal curvature of the cervical spine. Therefore, the anterior approach for cervical kyphosis in young children is hard. We describe the first case in an EDS girl with cervical kyphosis who received satisfactory anterior cervical corpectomy decompression and fusion.CASE SUMMARY The chief complaints of a 16-year-old girl with EDS were double upper limb weakness for 7 years and double lower limb walking instability for 2 years.Moreover, the imaging results revealed that the degree of kyphosis from cervical vertebra 2 to 4 accompanying with spinal cord compression was 30°. An anterior cervical corpectomy involving cervical vertebra 3 and a titanium mesh implant were performed with internal fixation. The results at 3 mo after surgery demonstrated that the anterior fusion was solid, and the kyphosis of the cervical spine was corrected. Additionally, the power of all four extremities was significantly improved.CONCLUSION The incidence rate of cervical kyphosis in EDS is rare. The surgical treatment for these patients, especially an anterior approach, is challenging. Therefore, to develop safer and more effective strategies to treat cervical kyphosis in EDS,there is still much work to do.
文摘Background: There is an increasing recognition of patients with Ehlers Danlos Syndromes. The laxity of the ligaments and the weakness of the connective tissue has resulted in increasing number of patients requiring surgical intervention. Ehlers Danlos Syndromes are not about hypermobile joints only, they are associated with multiple co-existing conditions such as Chiari malformation, Tethered Cord Syndrome, spinal instability, abdominal pain, Dysautonomia and Mast Cell Activation Syndrome. The combined incidence of Ehlers Danlos Syndromes is 1 in 5000 people. Most experts believe that the actual incidence is much higher. Many of these cases are under-diagnosed. Nevertheless, patients with Ehlers Danlos Syndromes, diagnosed or undiagnosed often require surgical intervention. This review article has been written to shed light on the need for special consideration during anesthesia. Objectives: Our objective was to conduct a review of anesthetic considerations in patients with Ehlers Danlos Syndromes. Study Design: We used a narrative review design. Methods: This review was done using searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles from inception to 2019. Other data sources included hand searches of publications driven by manuscript authors. Search terms included concepts of “Ehlers Danlos Syndrome”, “EDS”, “pain”, “anesthesia”, “surgery” and combination of terms. Search method was not restricted to any one language. Results: Articles were screened by title, abstract, and full article review. They were then analyzed by specific clinical indications and appropriate data was presented based on critical analysis of those articles. Limitations: More studies about the effect of anesthetic techniques and Ehlers Danlos Syndromes are required. Conclusions: Patients with Ehlers Danlos Syndromes may present with an array of coexisting medical conditions such as Dysautonomia, Mast Cell Activation Syndrome, Chiari Malformation, Tethered
