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 6074 A > T nucleotide transition in the TNXB gene c...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 6074 A > T nucleotide transition in the TNXB gene causing an amino acid protein change at Asp2025 Val classified as likely pathogenic. We add this clinical report to the literature and classical human disease gene catalogs to identify this specific mutation as diseasecausing. 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 deficiency, but the variant identified 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 6074 A > T nucleotide transition in the TNXB gene may be classified as disease-causing for EDS due to tenascin-X deficiency.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, inflammation, or aging.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
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 6074 A > T nucleotide transition in the TNXB gene causing an amino acid protein change at Asp2025 Val classified as likely pathogenic. We add this clinical report to the literature and classical human disease gene catalogs to identify this specific mutation as diseasecausing. 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 deficiency, but the variant identified 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 6074 A > T nucleotide transition in the TNXB gene may be classified as disease-causing for EDS due to tenascin-X deficiency.
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, inflammation, or aging.
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.
