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Background: Variations in ZNF469 have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity., Materials and Methods: Detailed medical and family history, physical examination, and molecular analysis., Results: A 21-year-old female presented with bluish discoloration of sclera, diminution of vision following trivial trauma in childhood along with hearing loss and systemic features of arachnodactyly and joint laxity. Clinical diagnosis of brittle cornea syndrome was made which was molecularly proven using next-generation sequencing which identified compound heterozygosity in ZNF469 for pathogenic and likely pathogenic nonsense variants. One variant namely NM_001367624.2:c.5882dup was identified in the exon 3 which was novel and classified as likely pathogenic according to American College of Medical Genetics (ACMG) criteria for variant classification. Another variant NM_001367624.2:c.8992C>T in the exon 2 was classified as pathogenic for Brittle Cornea Syndrome 1., Conclusions: The report adds to the allelic heterogeneity in ZNF469 causative of Brittle Cornea Syndrome 1 and shall acquaint the physicians about this potentially vision threatening, underdiagnosed, rare syndrome.

Background: Benign Joint Hypermobility Syndrome (BJHS) is a most common hereditary connective tissue disorders in children and adolescents. This study aimed to investigate the prevalence and subtypes of headache in children with BJHS., Methods: This observational-analytical study was conducted in a case-control setting on school children aged 7 to 16 years in 2021-2023 in Isfahan, Iran. Students were examined for BJHS using Beighton criteria by a pediatric rheumatologist. Headache disorder was diagnosed according to the Child Headache-Attributed Restriction, Disability, and Social Handicap and Impaired Participation (HARDSHIP) questionnaires for child and adolescent and International Classification of Headache Disorders (ICHD-III)., Results: A total of 4,832 student (mean age 10.3 ± 3.1 years), 798 patients with BJHS and 912 healthy children were evaluated. The probability of headache in children aged 7-11 with hypermobility was 3.7 times lower than in children aged 12-16 with hypermobility (P = 0.001). The occurrence of headache in children with BJHS was more than the control group (P = 0.001), and the probability of headache in children with BJHS was 3.7 times higher than in healthy children (P = 0.001). Migraine was the most common headache type reported of total cases. The probability of migraine in children with BJHS was 4.5 times higher than healthy children ( P = 0.001)., Conclusion: This study showed a significant correlation between BJHS and headache (especially migraine) in children and adolescents., (© 2024. The Author(s).)

Background: There is frequent overlap between and the connective tissue diseases Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome (JHS/EDS) and disorders of the gut-brain interaction (DGBIs)., Aims: Because not all JHS/EDS patients develop DGBIs, we sought to determine whether secondary environmental triggers may lead to development of irritable bowel syndrome (IBS) and functional dyspepsia (FD) in patients with JHS/EDS., Methods: We sent electronic surveys to 253 patients from a JHS/EDS support group, with responses collected over one year. IBS and FD were diagnosed by the Rome IV criteria, with additional validated assessments of adverse childhood experiences (ACEs) and traumatic stressors according to DSM-V criteria. We compared clinical and psychological characteristics of JHS/EDS patients with and without DGBIs using univariable and multivariable analyses., Results: We enrolled 193 JHS/EDS patients, of whom 67.9% met Rome IV criteria for IBS. The IBS and JHS/EDS overlap group reported significantly more traumatic exposures (P < 0.001) and were more likely to have experienced greater than 3 ACEs (P < 0.001) than JHS/EDS patients without IBS. FD was found in 35.2% of patients and was associated with significantly more traumatic exposures (P < 0.001) and were more likely to have experienced greater than 3 ACEs (P < 0.001) than JHS/EDS patients without FD., Conclusions: We found that JHS/EDS patients with IBS and FD overlap reported significantly more traumatic exposures and ACEs compared to JHS/EDS patients without overlapping IBS or FD. JHS/EDS patients may have increased susceptibility to DGBIs, with traumatic life experiences and/or ACEs acting a secondary environmental trigger driving the subsequent development of DGBIs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Heavy menstrual bleeding has a high prevalence and is well documented in adult patients with hypermobile-type Ehlers-Danlos syndrome, but there is limited research surrounding work-up and treatment for the adolescent population. Excessive menstrual blood loss can significantly interfere with emotional and physical quality of life. A provider should acquire a comprehensive medical and menstrual history and focused physical examination, as well as baseline laboratory studies, to determine the presence of anemia or underlying bleeding disorder. Use of a pictorial blood assessment chart may be considered to help quantify the amount of bleeding. Treatment to reduce heavy menstrual flow and referral to specialty care should be initiated swiftly to improve quality of life for this population. [ Pediatr Ann . 2024;53(3):e104-e108.] .

Hereditary connective tissue diseases form a heterogeneous group of disorders that affect collagen and extracellular matrix components. The cornea and the skin are among the major forms of connective tissues, and syndromes affecting both organs are often due to mutations in single genes. Brittle cornea syndrome is one of the pathologies that illustrates this association well. Furthermore, sex hormones are known to play a role in the maintenance of the structure and the integrity of the connective tissue including the skin and cornea, and may be involved in pathogenesis of oculocutaneous diseases. Herein, a double consanguineous family of Moroccan origin with two affected siblings, with suspected brittle cornea syndrome, was recruited. Ophthalmic examinations and genetic testing were performed in all the nuclear family individuals. Clinical examinations showed that the two affected boys presented with thinning of the cornea, blue sclera, keratoconus, hyperelasticity of the skin, joint hypermobility, muscle weakness, hearing loss and dental abnormalities that are compatible with the diagnosis of BCS disease. They showed however additional clinical signs including micropenis, hypospadias and cryptorchidism, suggesting abnormalities in endocrine pathways. Using a duo exome sequencing analysis performed in the mother and the propositus, we identified the novel homozygous missense mutation c.461G > A (p.Arg154Gln) in the short-chain dehydrogenase/reductase family 42E member 1 (SDR42E1) gene. This novel mutation, which co-segregated with the disease in the family, was predicted to be pathogenic by bioinformatics tools. SDR42E1 stability analysis using DynaMut web-server showed that the p.Arg154Gln mutations has a destabilizing effect with a ΔΔG value of -1.039 kcal/mol. As this novel gene belongs to the large family of short-chain dehydrogenases/reductases (SDR) thought to be involved in steroid biosynthesis, endocrinological investigations subsequently revealed that the two patients also had low levels of cholesterol. Karyotyping revealed a normal 46,XY karyotype for the two boys, excluding other causes of disorders of sex development due to chromosomal rearrangements. In conclusion, our study reveals that mutation in the novel SDR42E1 gene alters the steroid hormone synthesis and associated with a new syndrome we named oculocutaneous genital syndrome. In addition, this study highlights the role of SDR42E1 in the regulation of cholesterol metabolism in the maintenance of connective tissue and sexual maturation in humans., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Functional dyspepsia (FD) is defined as the presence of gastroduodenal symptoms in the absence of organic disease that is likely to explain the symptoms. Joint hypermobility (JH) refers to the increased passive or active movement of a joint beyond its normal range and is characteristically present in patients with joint hypermobility syndrome (JHS), which is a hypermobile subtype of Ehlers-Danlos syndrome (EDS). Recent reports have highlighted the co-existence of FD with Ehlers-Danlos syndrome. Our aim was to study the prevalence of JHS in FD compared with healthy subjects and to study the impact of co-existing JHS on gastric motility, nutrient tolerance, and dyspeptic symptoms in FD., Methods: FD patients filled out a dyspepsia symptom severity score. Intragastric pressure (IGP) was measured with high-resolution manometry (HRM) during the intragastric infusion of nutrition drink (ND, 1.5 Kcal/ml, 60 ml/min) until maximal satiation in healthy subjects and FD. We compared IGP profiles and nutrient tolerance in HS and FD with or without JHS., Results: JHS was present in 54% of FD patients (n = 39, 41.2 ± 2.2 years old) and 7% of healthy subjects (n = 15, 27.3 ± 2.3 years old). IGP drop and nutrient tolerance were lower in non-JHS-FD compared with JHS-FD and HS (AUC JHS-FD: -17.9 ± 2.5 vs. non-JHS-FD: -13.0 ± 3.3 mmHg min, p = 0.2, HS:-19.6 ± 2.9 mmHg min; ND tolerance non-JHS-FD: 671.0 ± 96.0 vs. JHS-FD: 842.7 ± 105.7 Kcal, p = 0.25, HS: 980.0 ± 108.1 Kcal)., Conclusion: JHS often co-exists with FD. Non-JHS-FD was characterized by decreased accommodation and lower nutrient tolerance characterized compared with JHS-FD. Clinicaltrials.gov, reference number NCT04279990., (© 2021 John Wiley & Sons Ltd.)

Hypermobility spectrum disorders (HSDs) encompass an array of connective tissue disorders characterized by joint instability and chronic pain. Fatigue and other systemic symptoms that affect daily functioning may occur, as well. Accurate data on incidence and prevalence of HSDs is hampered by lack of awareness of these conditions and the wide heterogeneity of their clinical presentation. Identifying which type of HSD is present is important in guiding appropriate care. In particular, making the diagnosis of hypermobile Ehlers-Danlos syndrome (hEDS) is important, as individuals with hEDS may be at risk for more significant multisystem involvement. Diagnostic criteria for hEDS include measures of joint hypermobility, skin and other connective tissue findings, and lack of evidence of a different type of Ehlers-Danlos syndrome. Beyond accurate diagnosis, HSDs pose many challenges for primary care providers, as ongoing patient education, patient empowerment, and coordination of a multidisciplinary treatment team are integral to proper care. This article describes the incidence and prevalence, pathophysiology, diagnosis, and management of HSDs, including clinical cases exemplifying how joint hypermobility might present within a primary care setting., Competing Interests: Conflict of interest: None., (© Copyright 2021 by the American Board of Family Medicine.)

Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by corneal thinning and fragility, leading to corneal rupture, the main hallmark of this disorder. Non-ocular symptoms include not only hearing loss but also signs of connective tissue fragility, placing it in the Ehlers-Danlos syndrome (EDS) spectrum. It is caused by biallelic pathogenic variants in ZNF469 or PRDM5, which presumably encode transcription factors for extracellular matrix components. We report the clinical and molecular features of nine novel BCS families, four of which harbor variants in ZNF469 and five in PRDM5. We also performed a genotype- and phenotype-oriented literature overview of all (n = 85) reported patients with ZNF469 (n = 53) and PRDM5 (n = 32) variants. Musculoskeletal findings may be the main reason for referral and often raise suspicion of another heritable connective tissue disorder, such as kyphoscoliotic EDS, osteogenesis imperfecta, or Marfan syndrome, especially when a corneal rupture has not yet occurred. Our findings highlight the multisystemic nature of BCS and validate its inclusion in the EDS classification. Importantly, gene panels for heritable connective tissue disorders should include ZNF469 and PRDM5 to allow for timely diagnosis and appropriate preventive measures for this rare condition., (© 2021 Wiley Periodicals LLC.)

Objective: Malformations in the craniocervical junction (CCJ) are rare in the pediatric population but often need surgical treatment. We present a pediatric case series of patients treated with a 2-stage surgical approach with a halo vest and occipitocervical fusion and review complications and outcomes., Methods: A retrospective analysis of a single-center case series was performed. Pediatric patients affected by congenital craniocervical junction anomalies and treated with a 2-stage approach were included. A halo vest was implanted in the first surgery, and ambulatory progressive reduction was performed. When a favorable anatomic situation was observed, arthrodesis was performed. Safety analysis was undertaken by analyzing the incidence of complications in both procedures. Effectivity analysis was carried out analyzing radiologic and clinical outcome (Goel grade and modified Japanese Orthopaedic Association score). Student t test was used for statistical analysis., Results: Sixteen cases were included. Mean age of patients was 9.38 years. Safety analysis showed 2 halo loosenings, 1 pin infection, 2 wound infections, 1 cerebrospinal fluid leak, and 2 delayed broken rods. No major complications were observed. Radiologic analysis showed an improvement in the tip of the odontoid process to the McRae line distance (from -3.26 mm to -6.16 mm), atlantodental interval (from 3.05 mm to 1.88 mm), clival-canal angle (from 134.61° to 144.38°), and cervical kyphosis (from 6.39° to 1.54°). Clinical analysis also showed improvement in mean Goel grade (from 1.75 to 1.44) and modified Japanese Orthopaedic Association score (from 15.12 to 16.41)., Conclusions: The 2-stage approach was a suitable and effective treatment for craniocervical junction anomalies in pediatric patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Biomechanical impairments are not apparent during walking in people with Joint Hypermobility Syndrome (JHS). This research explored biomechanical alterations during a higher intensity task, vertical jumping., Materials and Methods: This cross-sectional study compared a JHS group (n = 29) to a healthy control group (n = 30). Joint kinematics and kinetics were recorded using a Qualisys motion capture system synchronized with a Kistler platform. Independent sample t-tests and standardised mean differences (SMD) were used for statistical analysis., Results: No significant statistical or clinical differences were found between groups in joint kinematics and jump height (p ≥ 0.01). Sagittal hip and knee peak power generation were statistically lower in the JHS group during the compression phase (p ≤ 0.01), but not clinically relevant (SMD < 0.5). Clinically relevant reductions were found in the JHS group knee and ankle peak moments during the compression phase, and hip and knee peak power generation during the push phase (SMD ≥ 0.5), although these were not statistically significant (p ≥ 0.01)., Conclusion: The JHS group achieved a similar jump height but with some biomechanical alterations. Further understanding of the joint biomechanical behavior could help to optimize management strategies for JHS, potentially focusing on neuromuscular control and strength/power training., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: The pathophysiology underlying functional dyspepsia (FD) is multifactorial and focuses on gastric sensorimotor dysfunction. Recent studies demonstrated that joint hypermobility syndrome (JHS) is strongly associated with unexplained dyspeptic symptoms in patients attending gastrointestinal clinics. We aimed to study the relationship between symptoms, gastric sensorimotor function, and JHS in FD patients., Methods: Tertiary care FD patients who underwent a gastric barostat study and a gastric emptying breath test with 13C-octanoic acid were recruited for assessment of JHS. The presence of JHS was evaluated by a 2-phase interview and clinical examination that included major and minor criteria of the Brighton classification., Results: A total of 62 FD patients (68% women, age 44 ± 1.8 years, and body mass index: 21.7 ± 0.7 kg/m) accepted to participate in the study. JHS was diagnosed in 55% of FD patients. Assessed symptom profiles during the visit did not differ between the groups. Delayed gastric emptying was not significantly more common in JHS group compared with non-JHS group (JHS group 32% vs non-JHS group 16%, P = 0.31). Prevalence of hypersensitivity to distention (JHS group 24% vs non-JHS group 29%, P = 0.76) and impaired gastric accommodation (JHS group 38% vs non-JHS group 42%, P = 0.79) was similar in patients with or without JHS. No correlations were found between the Beighton hypermobility score and gastric compliance (r = 0.09)., Discussion: A large subset of this study cohort of tertiary care FD patients has coexisting JHS. We did not identify any specific differences in gastric sensorimotor function between patients with and without JHS. Further prospective research will be required to elucidate the relationship between JHS, a multisystemic disorder with widespread manifestations, and FD symptoms.

Connective tissue diseases, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), exhibit a high degree of clinical and genetic heterogeneity. We report two sisters with blue sclerae, joint hypermobility and hearing loss. Whole-exome sequencing identified two compound heterozygous ZNF469 loss-of-function mutations due to a frameshift. Since these findings indicate the presence of brittle cornea syndrome (BCS), we performed ocular optical coherence tomography (OCT) and pachymetry, which revealed a moderate decrease in corneal thickness. While only one traumatic fracture was observed in each of the patients, a detailed skeletal assessment indicated no specific patterns of bone mass and microstructure reduction as well as normal bone turnover markers. Taken together, our findings point to a mild form of brittle cornea syndrome with a phenotype compatible with the extraskeletal features of OI but also with EDS.

Ehlers-Danlos Syndrome (EDS) is a hereditary disorder of the connective tissue, which has been classified into numerous subtypes over the years. EDS is generally characterized by hyperextensible skin, hypermobile joints, and tissue fragility. According to the 2017 International Classification of EDS, 13 subtypes of EDS have been recognized. The majority of genes involved in EDS are either collagen-encoding genes or genes encoding collagen-modifying enzymes. Orthopedic surgeons most commonly encounter patients with the hypermobile type EDS (hEDS), who present with signs and symptoms of hypermobility and/or instability in one or more joints. Patients with joint hypermobility syndrome (JHS) might also present with similar symptomatology. This article will focus on the surgical management of patients with knee or shoulder abnormalities related to hEDS/JHS., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported., (Copyright © 2020 by The Korean Orthopaedic Association.)

Anatomical variation is discovered frequently in humans, and much such variation in the musculoskeletal system has been reported. We present a rare case of unilateral congenital patellar tendon aplasia with concomitant apparent shortness of the bilateral halluces as a result of shortened first metatarsals as an anatomical variant.

Aims: Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder. The aim of this study was to review ZNF469 mutations associated with BCS type 1 to date and to describe an additional case of Czech/Polish background., Methods: Whole genome sequencing was undertaken to identify the molecular genetic cause of disease in the proband. Sequence variants in ZNF469 previously reported as BCS type 1-causing were searched in the literature, manually curated and aligned to the reference sequence NM&#95;001127464.2., Results: The proband has been reviewed since childhood with progressive myopia and hearing loss. Aged 13 years had been diagnosed with Stickler syndrome. Aged 16.5 years, he developed acute hydrops in the left eye managed by corneal transplantation. At the age of 26, he experienced right corneal rupture after blunt trauma, also managed by grafting. He had a number of secondary complications and despite regular follow-up and timely management, the right eye became totally blind and the left eye had light perception at the last follow-up visit, aged 42. He was found to be a compound heterozygote for two novel mutations c.1705C>T; p.(Gln569*) and c.1402&#95;1411del; p.(Pro468Alafs*31) in ZNF469. In total 22 disease-causing variants in ZNF469 have been identified, mainly in consanguineous families or endogamous populations. Only four probands, including the case described in the current study, harboured compound heterozygous mutations., Conclusion: BCS occurs very rarely in outbred populations which may cause diagnostic errors due to poor awareness of the disease. Investigation into the underlying molecular genetic cause in patients with connective tissue disorders may lead to a re-evaluation of their clinical diagnosis.

A 31-year-old woman with known Larsen syndrome presented with congenital chronic luxation of her right knee with increasing instability symptoms, which limited her daily activities. We refrained from a constrained knee arthroplasty due to her relatively young age and decided to perform a knee arthrodesis. Knee arthrodesis is a viable lifelong-lasting operative treatment alternative for specific instability-related knee disease. The knee arthrodesis was performed by double plating with an additional fixation of the patella. At 1-yearfollow-up, she was able to walk without limitations and did not experience any pain with complete consolidation of the arthrodesis. At 2-year follow-up, she performed all her daily activities without limitations. Both the Knee injury and Osteoarthritis Outcome Score (KOOS) and the International Knee Documentation Committee subjective knee form (IKDC) improved at 2-year follow-up (KOOS: 61.3; IKDC: 56.3) compared with 1-year follow-up (KOOS: 52; IKDC: 40.2)., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The coexistence of joint hypermobility syndrome (JHS) and spondyloarthropathy (SpA) presents a challenging clinical conundrum due to the contradictory clinical signs that may be present. Classic features such as restricted spinal movement or early morning back stiffness may not be present. Timely diagnosis and appropriate management of these patients are difficult as they tend to have lower scores on validated objective measures., Methods: We performed a medical records review study to identify patients with both JHS and SpA who had presented to the Leicester Spondyloarthropathy clinic. Patients were diagnosed with axial SpA if they met the Assessment of SpondyloArthritis international Society classification criteria. Their imaging was reviewed by a consultant musculoskeletal radiologist., Results: Four cases were identified from the patient database (female; average age, 37.5 years). All patients presented with lower back pain or sacroiliac joint pain but preserved spinal movement with a negative Schober's test. Two had a history of symptoms for more than 10 years. All had a Beighton score of greater than 6. Three of the patients were HLA positive, and 3 had a positive family history. All patients thus far have had their symptoms adequately controlled on nonsteroidal anti-inflammatory drugs and physiotherapy., Conclusions: The coexistence of JHS and SpA is rare but important to recognize. These patients are difficult to diagnose as they may present late because of preserved spinal movements. It is unclear whether the preserved flexibility masks the true extent of disease or whether clinically they represent a less severe disease phenotype.

Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are heritable connective tissue disorders associated with pain, activity limitations and participation restrictions. A key feature is reported to be reduced stiffness and increased extensibility and elasticity of connective tissues. Yet diagnosis relies on assessment of joint range of motion, which may be influenced by other factors, and semi-quantitative assessment of forearm skin extensibility. The objective of this systematic review was to determine if quantitative measures of tissue mechanics can discriminate between hEDS/HSD and healthy tissues. Literature was identified via online databases (AMED, CINAHL+, EMBASE, MEDLINE and SportDiscus) and snowballing. Studies were included if participants had a confirmed diagnosis of hEDS/HSD (or equivalent diagnosis) using internationally recognised criteria, a healthy control group was used as a comparator, and objective measures of tissue stiffness, extensibility or elasticity of muscle, tendon, connective tissue or skin were reported. Included studies were critically appraised, followed by group discussion, consensus and narrative synthesis. Two hundred three potentially relevant studies were identified. Application of the inclusion criteria resulted in four studies being included. A range of quantitative approaches to studying tissue mechanics were used, including diagnostic ultrasound. Overall, three of the four studies found that at least one measure of tissue mechanics distinguished between people with hEDS/HSD and healthy controls. The studies were generally conducted and reported to high standards. Quantitative measures of tissue mechanics have the potential to contribute towards more objective diagnosis of hEDS/HSD. Further validation, particularly within diagnostic scenarios, is required.

Introduction: A number of psychometric properties of the Bristol Impact of Hypermobility (BIoH) questionnaire have previously been demonstrated, including strong concurrent validity and test-retest reliability. This study aimed to identify whether it can discriminate between those with and without Joint Hypermobility Syndrome (JHS)., Methods: The wording of a small number of BIoH questionnaire items was adapted to create a generic version that asked about 'general health' rather than 'hypermobility'. The generic questionnaire was distributed online to university students and staff. A sampling frame was used to create age and sex-matched samples from the non-JHS respondents in the current study and a pre-existing JHS cohort. Questionnaire scores were then compared between samples., Results: 790 responses were received. 414 were excluded, mainly due to self-reported generalized joint hypermobility or a JHS diagnosis. The sampling frame was applied to the remaining non-JHS responders (n = 376) and the pre-existing JHS cohort (n = 448), resulting in 206 age and sex-matched participants in each sample. The median (IQR) BIoH scores (out of a maximum 360) were 81 (57.25) and 231.5 (74.25) in the non-JHS and JHS samples respectively (p < 0.001). There was a very strong correlation between BIoH score and the number of painful areas (r = 0.867, p < 0.001)., Conclusions: The BIoH questionnaire discriminates between those with and without JHS. The median difference (151.5 points) far exceeds the smallest detectable change of 42 points previously identified. The results provide further evidence of the psychometric properties of the BIoH questionnaire and its potential to support research and clinical practice., (© 2020 John Wiley & Sons, Ltd.)

Objectives: To describe the epidemiology of diagnosed hypermobility spectrum disorder (HSD) and Ehlers-Danlos syndromes (EDS) using linked electronic medical records. To examine whether these conditions remain rare and primarily affect the musculoskeletal system., Design: Nationwide linked electronic cohort and nested case-control study., Setting: Routinely collected data from primary care and hospital admissions in Wales, UK., Participants: People within the primary care or hospital data systems with a coded diagnosis of EDS or joint hypermobility syndrome (JHS) between 1 July 1990 and 30 June 2017., Main Outcome Measures: Combined prevalence of JHS and EDS in Wales. Additional diagnosis and prescription data in those diagnosed with EDS or JHS compared with matched controls., Results: We found 6021 individuals (men: 30%, women: 70%) with a diagnostic code of either EDS or JHS. This gives a diagnosed point prevalence of 194.2 per 100 000 in 2016/2017 or roughly 10 cases in a practice of 5000 patients. There was a pronounced gender difference of 8.5 years (95% CI: 7.70 to 9.22) in the mean age at diagnosis. EDS or JHS was not only associated with high odds for other musculoskeletal diagnoses and drug prescriptions but also with significantly higher odds of a diagnosis in other disease categories (eg, mental health, nervous and digestive systems) and higher odds of a prescription in most disease categories (eg, gastrointestinal and cardiovascular drugs) within the 12 months before and after the first recorded diagnosis., Conclusions: EDS and JHS (since March 2017 classified as EDS or HSD) have historically been considered rare diseases only affecting the musculoskeletal system and soft tissues. These data demonstrate that both these assertions should be reconsidered., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

We report the case of a 3-year-old boy presenting with bilateral keratoglobus and blue sclera in addition to hallux valgus, arachnodactyly, small joint hypermobility, mitral valve dysfunction and a history of generalized muscular hypotonia in early infancy. Molecular genetics provided evidence of two pathogenic mutations in the ZNF469 gene (compound heterozygosity) leading to the diagnosis of brittle cornea syndrome type 1. In addition to neuropediatric care, spectacles were prescribed to correct refractive error and for ocular protection. Owing to the thin cornea and sclera, eye injuries are the main cause for irreversible visual loss in this disease.

Purpose: Brittle cornea syndrome (BCS) is a rare recessive disorder affecting connective tissues, most prominently in the eye. Pathogenic mutations causing BCS have been identified in PRDM5 and ZNF469 genes. This study investigates the genetic cause of BCS in a large, consanguineous Pakistani family with 4 affected and 3 unaffected individuals., Methods: The coding region and exon-intron splice junctions of PRDM5 and ZNF469 genes were amplified by polymerase chain reaction, and bidirectional Sanger sequencing was performed to find the pathogenic change responsible for causing the disease in the family., Results: A novel homozygous duplication c.9831dupC (p.Arg3278GlnfsX197) in the ZNF469 gene was identified, which was found to be co-segregating with the disease in the family., Conclusions: This is the first report of a ZNF469 homozygous mutation causing a BCS phenotype in a consanguineous Pakistani family. Our data extend the mutation spectrum of ZNF469 variants implicated in BCS.

Introduction: Joint hypermobility syndrome (JHS) has been reported to have widespread impacts on people with the condition. However, our understanding of those impacts is still developing and we do not know if they can be captured effectively using patient-reported outcome measures. The aim of the present study was to explore written qualitative comments from previously administered questionnaires, to identify the impacts of JHS and any issues related to using patient-reported outcome measures to assess those impacts., Methods: Previous research administered a draft condition-specific questionnaire and Short Form-36 questionnaire to adult members of a patient organization in the UK, incorporating an open text box for further comments. Those comments were transcribed, anonymized and analysed using thematic analysis. A coding list, themes and subthemes were developed through double coding, parallel independent analysis and consensus., Results: A total of 393 of 614 eligible questionnaires (64%) contained qualitative comments and were analysed (mean respondent age 41 years, mean Bristol Impact of Hypermobility questionnaire score 228/360, 95% women). Three main themes were identified: (a) "Impacts of living with JHS"; (b) "Management strategies for JHS"; and (c) "Measurement and research into JHS". Participants highlighted a range of impacts of JHS, incorporating physical, social and psychological domains. Respondents described difficult journeys to diagnosis, and feeling unsupported and misunderstood by their peers and healthcare professionals. They detailed helpful strategies for managing their condition and provided useful comments on using questionnaires to assess JHS., Conclusions: The study yielded valuable findings that can be used to directly inform the assessment and management of JHS., (© 2019 John Wiley & Sons, Ltd.)

Background: Joint hypermobility syndrome (JHS) has been found to be associated with anxiety disorders in clinical and nonclinical populations, but to date no studies have evaluated this association in children. The main goal of this study is to evaluate JHS along with anxiety, somatic and behavioral measures in children to clarify if JHS is associated with any of these variables in this age range., Methods: A sample of 160 children (74 girls and 86 boys) ranging from 5 to 17 o were recruited from a Child-Adolescent Mental Health clinic to participate in the study. All children underwent a diagnostic interview using the Mini International Neuropsychiatric Interview for Children and Adolescents. Instruments used include the Child Behavior Checklist (CBCL), the Screening Questionnaire to detect Hypermobility (SQ-CH) and the Children Manifested Anxiety Scale (CMAS-R)., Results: The prevalence of JHS in this sample was 22%, and this was significantly higher in girls (31%) than in boys (14%) (χ2=6.83; P=.001). The JHS group scored significantly higher in the CMAS-R total anxiety (F=4.51; P=.035), CMAS-R Physiological anxiety (F=7.19; P=.008) and the CBCL somatic complaints (F=8.46; 0.004) and regression analyses showed that these 3 variables were predictors of JHS (χ2=36.77; P<.001; r2=0.22). The JHS group also scored higher in some behavioral measures., Conclusion: Children with JHS have higher frequency of anxiety disorders and higher intensity of physiological anxiety, somatic complaints, and therefore, JHS might be used as marker for this anxiety phenotype in youngsters., (Copyright © 2019 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Hypoplasia or congenital absence of the anterior cruciate ligament (ACL) is a rare disorder occurring in ∼1 in every 6000 births. Although some patients with hypoplasia or agenesis of the ACL may not complain of instability, others desire to participate in more demanding activities that require the stability of a competent ACL. There are limited reports of surgical treatment of this patient population. The purpose of this study was to report ACL reconstruction in a case series of patients with symptomatic congenital ACL deficiency., Methods: A retrospective medical record review of the surgical treatment of 14 knees (13 patients) with congenital absence of the ACL at a tertiary care institution from 1995 to 2012 was performed. Patients with a minimum of 1 year of clinical follow-up were eligible for inclusion., Results: The mean age at time of surgery was 12.6 (range, 3 to 22), including 6 patients <12 years of age. Mean follow-up was 2.9 years (range, 1 to 6.6). Nine of 13 patients (69%) had underlying congenital abnormalities/associated syndromes. Preoperative Lachman and pivot shift examination was International Knee Documentation Committee grade C or D in all but 1 knee. ACL reconstruction was performed with combined intra-articular/extra-articular physeal sparing reconstruction with iliotibial band (n=5), autograft hamstring (n=2) or bone-patellar tendon-bone (n=3), or allograft (n=4). Multiligament reconstruction of associated ligamentous deficiency was performed in 7 knees (50%). Postoperative Lachman and pivot shift testing was International Knee Documentation Committee (IKDC) grade A or B in all but 1 knee. One patient with congenital absence of multiple knee ligaments required revision ACL reconstruction surgery, with concurrent first-time posterior cruciate ligament reconstruction, due to persistent instability. None required revision surgery due to graft tear at a minimum of 1-year follow-up., Conclusions: Surgical stabilization of symptomatic congenital ACL insufficiency, with associated ligamentous reconstruction as required on a case-by-case basis, results in improved stability at early clinical follow-up, with low complication rates., Level of Evidence: Level IV-retrospective case series.

Objective: To investigate the prevalence and severity of subjective health complaints and describe illness perception in a population of Joint Hypermobility Syndrome or Ehlers-Danlos Syndrome-Hypermobile Type., Method: This study was a postal survey with a questionnaire battery on demographic data, subjective health complaints inventory, and illness perception. A total of 110 individuals diagnosed with Joint Hypermobility Syndrome or Ehlers-Danlos Syndrome-Hypermobile Type from two specialized hospitals in Norway were offered participation. Further, 140 gender- and age-matched healthy controls from statistics Norway representing the general population were sent the questionnaire for reference., Results: Overall response rate was 30.4% (n = 76), with 44.5% (n = 49) in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome-Hypermobile Type and 19.3% (n = 27) in controls. Subjective health complaints were significantly higher in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome-Hypermobile Type - than in the controls (32.06 vs. 11.08; p < 0.001). Further the brief illness perception questionnaire indicated that the adults with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome-Hypermobile Type had low understanding of their illness and symptoms (understanding, mean: 3.93, SD 2.88), and reported to have moderate personal and treatment control over their illness., Conclusion: Adults with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome-Hypermobile Type reported higher frequency and severity of subjective health complaints than the matched controls from the general adult population in Norway. Furthermore, Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome-Hypermobile Type reported low understanding of their illness and associated symptoms, and moderate belief that their illness can be kept under control through self-management or treatment. This may indicate one of the reasons why prognosis for these patients is poor. Implications for rehabilitation Awareness of the complexity of the subjective health complaints and inquiry into illness perception could contribute with valuable information about these patients' perceptions of their condition. Such information could in its turn be of value for clinicians as they work towards facilitating a more holistic treatment approach, for example patient education and cognitive behavioural therapy.

Background: The relation between chronic musculoskeletal pain and joint hypermobility in a small percentage of the pediatric population is well described. However, literature discussing the treatment of chronic pain associated with joint hypermobility in pediatrics is limited. The present study examines the impact of interdisciplinary treatment on chronic pain in pediatrics with joint hypermobility syndrome., Objective: To determine if pediatric patients with chronic pain related to joint hypermobility can be effectively treated with an intensive, interdisciplinary pain management program, as measured by changes in pain, psychosocial and physical functioning, as well as parental coping., Design: Retrospective cohort study., Setting: Urban academic tertiary intensive outpatient interdisciplinary pain management clinic., Participants: The study involved 30 patients who met the criteria for a diagnosis of joint hypermobility and chronic pain and completed an interdisciplinary pain management program., Intervention: All patients were treated in an intensive pediatric interdisciplinary pain management program for a duration of 6 to 8 weeks. The program provided physical therapy, occupational therapy, psychological counseling, and weekly pediatric rehabilitation medicine follow-up., Main Outcome Measures: Outcome measures included numeric rating scale pain scores, the Bath Adolescent Pain Questionnaire, and the Bath Adolescent Pain-Parent Impact Questionnaire. Changes from pre- to post-treatment were analyzed using paired-samples t tests., Results: Patients endorsed pre- to post-treatment improvements in pain, depression, general anxiety, pain-related anxiety, social functioning, and physical functioning (P < .05). The patients' parents showed significant improvements in depression, anxiety, catastrophic thinking, self-blame and helplessness, leisure functioning, and parental behavior (P < .05)., Conclusion: The present findings suggest that an intensive interdisciplinary rehabilitation pain management program yields short-term improvements in pain, emotional and physical function, and daily activity in a pediatric population diagnosed with joint hypermobility. Parents also experienced benefits from the program. A larger prospective study with longer-term follow-up is needed., Level of Evidence: III., (© 2018 American Academy of Physical Medicine and Rehabilitation.)

Background: In the relevant literature generalized hypermobility syndrome (GHS) has been shown to alter the kinetic and kinematic patterns of the human movement system. Although GHS affects the general body biomechanics of individuals, the body of knowledge in plantar pressure distribution in GHS is far from sufficient., Objective: The aim of this study was to determine whether individuals with joint hypermobility syndrome have abnormal plantar pressure distribution during normal gait compared to healthy individuals., Methods: A total of 37 participants (mean age: 22.16 ± 2.58 years) diagnosed with GHS and 37 aged-matched participants (mean age: 23.35 ± 2.85 years) without GHS were included in the study. Dynamic plantar pressure distribution was obtained as each participant walked in barefoot at a self-selected pace over EMED-m system (Novel GmbH, Munich, Germany). Correlations between hypermobility score (HS) (Beighton score) and plantar pressure variables, and between group differences in peak pressure (PP), pressure-time integral (PTI), average pressure (AP) and maximum force (MxF) were computed for 10 regions under the sole., Results: HS was significantly correlated with peak pressure under the mid-foot (MF) (r= 0.24, p= 0.043), 5th metatarsal head (MH5) (r= 0.33, p= 0.001), big toe (BT) (r= 0.44, p< 0.001), and second toe (ST) (r= 0.38, p= 0.001). A similar trend was observed for pressure-time integrals under hindfoot (HF) (r= 0.24, p= 0.04), MF (r= 0.30, p= 0.009), MH5 (r= 0.25, p= 0.033), BT (r= 0.37, p= 0.001) and ST (r= 0.34, p= 0.003). The only significant MxF detected was under the ST (r= 0.23, p= 0.048), and AP was determined to be significantly higher as HS increases indicated by APs under MH5 (r= 0.24, p= 0.042), BT (r= 0.32, p= 0.005) and ST (r= 0.40, p< 0.001). Peak pressure values under HF were significantly higher in the hypermobile group (p= 0.023), MH5 (p= 0.001), BT (p< 0.001) and ST (p= 0.003). AP and PTI were also found to be significantly higher in the hypermobile group under MH5 (p= 0.009), BT (p= 0.037), and ST (p= 0.003). MxF was higher only under MF5 (p= 0.029) and SF (p= 0.041) in the hypermobile group., Conclusion: The forefoot regions received a higher load in GHS during gait. This could be useful in clinical evaluation of the foot in GHS, preventing potential injuries of lower extremity, and also in processes related to decision making for foot orthotics and/or rehabilitation protocols.

Objective: Upper cervical fixation with C2 pedicle screw insertion may predispose patients to vertebral artery injury, in particular, patients with craniovertebral junction anomalies. The aim of this study was to describe an alternative technique with trans-C2 inferior articular process screw (C2IAPS) insertion for rigid C2 fixation, which can be used to anchor the C2 vertebra for upper cervical fixation., Methods: Records of 19 patients who underwent posterior atlantoaxial fixation using C2IAPS combined with C1 lateral mass screw were retrospectively reviewed. Efficacy was assessed by postoperative imaging and Japanese Orthopaedic Association scores., Results: There were 22 C2IAPSs successfully implanted (3 on both sides and 16 on 1 side). With the exception of 2 screws that had intruded into the outlet of the intervertebral foramen, all screws were safely implanted. Average Japanese Orthopaedic Association scores improved from 11.8 ± 1.9 preoperatively to 15.3 ± 1.3 postoperatively. Bony fusion rate was 100%., Conclusions: For patients who are not eligible for C2 pedicle screw fixation, C2IAPS fixation can be considered as an alternative technique for upper cervical fixation of C2., (Copyright © 2018. Published by Elsevier Inc.)

Joint hypermobility syndrome (JHS) (also termed hypermobility type Ehlers-Danlos syndrome, hEDS) is a heritable connective tissue disorder that is characterized by generalized joint hypermobility, chronic pain, fatigue, and minor skin changes. Initially, it was reported that there is a small subset of patients with JHS/hEDS who have haploinsufficiency of tenascin-X (TNX). However, the relationship between TNXB and JHS/hEDS has not been reported at all afterwards. EDS was reclassified into thirteen types in 2017, and the causative gene of JHS/hEDS remained to be identified. Therefore, in this study in order to determine whether JHS/hEDS can be diagnosed by the concentrations of serum form of TNX (sTNX), we measured the concentrations of sTNX in 17 JHS/hEDS patients. The sTNX concentrations in half of the JHS/hEDS patients were significantly lower than those in healthy individuals. No mutations, insertions or deletions were detected in the TNX exon sequence of the JHS/hEDS patients except for one in patient. That patient has a heterozygous mutation. A correlation between sTNX concentration and mutation of the TNXB genomic sequence was not found in the JHS/hEDS patients. These results indicate that the decrease in sTNX concentration could be used as a risk factor for JHS/hEDS.

Background: To report a patient who presented with bluish scleral discoloration, keratoconus, and progressive high myopia., Case Presentation: A 6-year-old Chinese female patient presented with a significant bluish discoloration of the sclera in both eyes and extreme corneal thinning with anterior corneal protrusion. General pediatric physical examination was normal for all systems and no genetic disorders known were observed., Conclusions: We aim to highlight the importance of diagnosis and treatment of patients suffering from Brittle cornea syndrome. Timely diagnosis and early provision of protective glasses seem to be the most important step in treating BCS. To our knowledge, this is the first case of BCS being reported in the Asia area.

Brittle cornea syndrome (BCS1 OMIM #229200, BCS2 #614170) is a rare autosomal recessive condition characterised by diffuse thinning and fragility of the cornea. Affected individuals are at risk of globe rupture and blindness after relatively minor eye trauma. We describe a 9-year-old girl with BCS1, already blind in one eye following trauma, who had a 14 mm diameter corneoscleral onlay graft to her contralateral eye to reduce gross irregular corneal astigmatism and potentially to reduce further risk from accidental injury. Although there was a significant initial improvement in the unaided visual acuity, there was subsequent visual loss from secondary glaucoma. In addition, despite the onlay graft, an acute corneal hydrops developed approximately 2 years following surgery, suggesting that in BCS1, corneal tissue degeneration or resorption continues despite external support. Finally, because secondary glaucoma is not a feature of BCS1, we speculate that the onlay graft may have reduced aqueous outflow by compression of the thinned sclera., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

The incidence of hip instability in children with Down syndrome is 1% to 7%. The natural history is often progressive, with the typical onset of hypermobility of the hip evolving to habitual dislocation, persistent subluxation, and fixed dislocation, and eventually leading to the loss of independent mobility. Treatment focuses on stabilizing the hip joint and depends on the patient's age and the severity of the disease. Typically, surgical intervention is recommended for the treatment of patients with habitual dislocation, subluxation, and complete dislocation of the hip. When indicated, surgical management must take into account associated anatomic abnormalities of the femur and acetabulum. Hip instability in Down syndrome may persist despite surgical intervention and remains a difficult condition to manage.

Joint hypermobility is a common, primarily benign finding in the general population. However, in a subset of individuals joint hypermobility causes a range of clinical problems mainly affecting the musculoskeletal system and, to a lesser extent, extra-articular disorders. Joint hypermobility often appears as a familial trait and is shared by several inherited connective tissue disorders, including the hypermobility subtype of Ehlers-Danlos syndrome (hEDS) and benign joint hypermobility syndrome (BJHS/JHS). Although joint hypermobility has primarily been thought of as a rheumatological disorder, increasing evidence shows significant associations between both hEDS and BJHS with specific extra-articular disorders. To date, the strongest associations of these 2 conditions are with anxiety disorders, orthostatic tachycardia, various functional gastrointestinal (GI) disorders and pelvic and bladder dysfunction. This review article focuses on GI disorders associated with both hEDS and BJHS. The aim of this review is to evaluate existing research and literature regarding associations between JHS (hEDS/BJHS) and GI disorders. Our goal is to raise awareness of BJHS/JHS and hEDS as an explanation for chronic unexplained symptoms and functional GI disorders as well as to review the current standard tests available for proper evaluation of GI symptoms in these patients., (Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Focal linear elastosis (FLE) is a benign skin findingcharacterized by hypertrophic linear plaques withabnormal elastic fibers on histology. We present aunique case in which focal linear elastosis occurredin the setting of joint hypermobility syndrome(JHS). Our patient, a 20-year-old man with a medicalhistory significant for symptoms consistent with JHS,had been followed by the rheumatology clinic formany months. He was referred to the dermatologydepartment for further evaluation of asymptomaticlongitudinal bands on his back that had been presentfor many years. He denied trauma but endorsed ahistory of 'stretch marks.' On examination there werenumerous horizontally oriented, firm, linear, yellowto flesh colored bands, all non-tender to palpation.Punch biopsies were performed of involved anduninvolved skin. Histopathology of normal skinrevealed no significant abnormalities whereasinvolved skin demonstrated broadened collagenbundles in the deep dermis. The elastic fiber stain,Verhoeff-Van Gieson, revealed a gross increase in thenumber of elastic fibers, fragmented fibers, fiberswith "paintbrush" or widened-ends, fibers of varyingthickness, and clumped fibers. This combination ofhistopathologic and clinical features was consistent with FLE.

The aim of this study was to investigate the effects of an 8-week lumbar spinal stabilization exercise program on pain, trunk muscle endurance, and postural stability in women with benign joint hypermobility syndrome (BJHS). Women with BJHS were randomly allocated into exercise (n = 20) and control (n = 18) groups. The lumbar spinal stabilization exercise program was carried out 3 days a week for 8 weeks. BJHS with Brighton criteria, musculoskeletal pain intensity with Visual Analog Scale, trunk muscle endurance with McGill's trunk muscle endurance tests, and postural stability as static and dynamic while eyes open and closed with Biodex Balance System SD were evaluated. Chi-square test, independent sample t test, Mann-Whitney U test, and Wilcoxon test were used for statistical analysis. It was shown that most of the patients with BJHS had low back (exercise group 40.0%; control group 22.2%) and knee pain (exercise group 15.0%; control group 22.2%). After the program, pain intensity, and static and dynamic stability scores (eyes closed) decreased, and trunk muscle endurance scores increased in the exercise group. There was no difference for all parameters in the control group. Pain intensity, trunk muscle endurance, and only dynamic stability (eyes open) improved in the exercise group in comparison to the control group. The lumbar spinal stabilization exercise program improved pain complaints, postural stability, and trunk muscle endurance of women with BJHS. The program can be used for general pain relief, trunk muscle weakness, and postural impairment in women with BJHS.

Objectives: Stage 1 - to identify the impact of joint hypermobility syndrome (JHS) on adults; Stage 2 - to develop a questionnaire to assess the impact of JHS; and Stage 3 - to undertake item reduction and establish the questionnaire's concurrent validity., Design: A mixed methods study employing qualitative focus groups and interviews (Stage 1); a working group of patients, clinicians and researchers, and 'think aloud' interviews (Stage 2); and quantitative analysis of questionnaire responses (Stage 3)., Setting: Stages 1 and 2 took place in one secondary care hospital in the UK. Members of a UK-wide patient organisation were recruited in Stage 3., Participants: In total, 15, four and 615 participants took part in Stages 1, 2 and 3, respectively. Inclusion criteria were: age ≥18 years; diagnosis of JHS; no other conditions affecting physical function; able to give informed consent; and able to understand and communicate in English., Interventions: None., Main Outcome Measures: The development of a questionnaire to assess the impact of JHS., Results: Stage 1 identified a wide range of impairments, activity limitations and participation restrictions In Stage 2, a draft questionnaire was developed and refined following 'think aloud' analysis, leaving 94 scored items. In Stage 3, items were removed on the basis of low severity and/or high correlation with other items. The final Bristol Impact of Hypermobility (BIoH) questionnaire had 55 scored items, and correlated well with the physical component score of the Short Form 36 health questionnaire (r=-0.725)., Conclusions: The BIoH questionnaire demonstrated good concurrent validity. Further psychometric properties need to be established., (Copyright © 2016 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two overlapping heritable disorders (JHS/EDS-HT) recognized by separated sets of diagnostic criteria and still lack a confirmatory test. This descriptive research was aimed at better characterizing the clinical phenotype of JHS/EDS-HT with focus on available diagnostic criteria, and in order to propose novel features and assessment strategies. One hundred and eighty-nine (163 females, 26 males; age: 2-73 years) patients from two Italian reference centers were investigated for Beighton score, range of motion in 21 additional joints, rate and sites of dislocations and sprains, recurrent soft-tissue injuries, tendon and muscle ruptures, body mass index, arm span/height ratio, wrist and thumb signs, and 12 additional orthopedic features. Rough rates were compared by age, sex, and handedness with a series of parametric and non-parametric tools. Multiple correspondence analysis was carried out for possible co-segregations of features. Beighton score and hypermobility at other joints were influenced by age at diagnosis. Rate and sites of joint instability complications did not vary according to age at diagnosis except for soft-tissue injuries. No major difference was registered by sex and dominant versus non-dominant body side. At multiple correspondence analysis, selected features tend to co-segregate in a dichotomous distribution. Dolichostenomelia and arachnodactyly segregated independently. This study pointed out a more protean musculoskeletal phenotype than previously considered according to available diagnostic criteria for JHS/EDS-HT. Our findings corroborated the need for a re-thinking of JHS/EDS-HT on clinical grounds in order to find better therapeutic and research strategies. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Introduction: An increased risk of preterm birth in women with joint hypermobility syndrome or Ehlers-Danlos syndrome is suspected., Material and Methods: In this nationwide cohort study from 1997 through 2011, women with either joint hypermobility syndrome or Ehlers-Danlos syndrome or both disorders were identified through the Swedish Patient Register, and linked to the Medical Birth Register. Thereby, 314 singleton births to women with joint hypermobility syndrome/Ehlers-Danlos syndrome before delivery were identified. These births were compared with 1 247 864 singleton births to women without a diagnosis of joint hypermobility syndrome/Ehlers-Danlos syndrome. We used logistic regression, adjusted for maternal age, smoking, parity, and year of birth, to calculate adjusted odds ratios for adverse pregnancy outcomes., Results: Maternal joint hypermobility syndrome/Ehlers-Danlos syndrome was not associated with any of our outcomes: preterm birth (adjusted odds ratio = 0.6, 95% confidence interval 0.3-1.2), preterm premature rupture of membranes (adjusted odds ratio = 0.8; 95% confidence interval 0.3-2.2), cesarean section (adjusted odds ratio = 0.9, 95% confidence interval 0.7-1.2), stillbirth (adjusted odds ratio = 1.1, 95% confidence interval 0.2-7.9), low Apgar score (adjusted odds ratio = 1.6, 95% confidence interval 0.7-3.6), small for gestational age (adjusted odds ratio = 0.9, 95% confidence interval 0.4-1.8) or large for gestational age (adjusted odds ratio = 1.2, 95% confidence interval 0.6-2.1). Examining only women with Ehlers-Danlos syndrome (n = 62), we found a higher risk of induction of labor (adjusted odds ratio = 2.6; 95% confidence interval 1.4-4.6) and amniotomy (adjusted odds ratio = 3.8; 95% confidence interval 2.0-7.1). No excess risks for adverse pregnancy outcome were seen in joint hypermobility syndrome., Conclusion: Women with joint hypermobility syndrome/Ehlers-Danlos syndrome do not seem to be at increased risk of adverse pregnancy outcome., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objectives: To explore differences in body structure and function in systemic lupus erythematosus (SLE) patients and controls, with particular reference to joint hypermobility, and to evaluate the usefulness of the Brighton criteria for diagnosing joint hypermobility syndrome (JHS) in SLE., Method: Female SLE patients were, according to age group, consecutively invited to participate in the study. Controls were healthy females matched for age. All individuals were examined by a physician according to the Brighton criteria, and by an occupational therapist and a physiotherapist to obtain the Beighton scores, overall joint mobility, and manifestations in body structure and function., Results: Sixteen (23%) SLE patients and 19 (27%) controls had a Beighton score ≥ 4 (non-significant, ns), and 39 (55%) individuals in the SLE group and 22 (31%) in the control group satisfied the Brighton criteria for JHS (p < 0.01). Many individuals in both groups exceeded the normative values for joint mobility in joints other than those included in the Beighton score. Stratifying for a Beighton score ≥ 4 vs. < 4, there were no significant differences in body structure or body function constituting JHS either in the SLE patients or in the controls., Conclusions: Although the presence of joint hypermobility in SLE patients was frequent, we could not verify that this caused excess manifestations in addition to the SLE symptoms.

Brittle cornea syndrome is a rare generalised connective tissue disorder with ocular features like keratoglobus or keratoconus, severe corneal thinning and a high risk of perforation. Various authors in different case reports and case series have brought out the fact that brittle cornea is a disorder with characteristic systemic manifestations such as deafness, joint hypermobility, hyperelasticity of skin, kyphoscoliosis and dental abnormalities alongwith ophthalmic features. We report a case of globe perforation following trivial trauma, in an individual with brittle cornea without any extraocular manifestations, posing a challenge in the diagnosis and dilemma in surgical repair of cornea, restoration of globe integrity and visual rehabilitation. The absence of systemic manifestations decreased the index of suspicion and led to a surprise in the theatre-a point this case emphasised., Competing Interests: Conflicts of Interest: None declared., (2016 BMJ Publishing Group Ltd.)

Background: Patients with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT) commonly suffer from pain. How this hereditary connective tissue disorder causes pain remains unclear although previous studies suggested it shares similar mechanisms with neuropathic pain and fibromyalgia., Methods: In this prospective study seeking information on the mechanisms underlying pain in patients with JHS/EDS-HT, we enrolled 27 consecutive patients with this connective tissue disorder. Patients underwent a detailed clinical examination, including the neuropathic pain questionnaire DN4 and the fibromyalgia rapid screening tool. As quantitative sensory testing methods, we included thermal-pain perceptive thresholds and the wind-up ratio and recorded a standard nerve conduction study to assess non-nociceptive fibres and laser-evoked potentials, assessing nociceptive fibres., Results: Clinical examination and diagnostic tests disclosed no somatosensory nervous system damage. Conversely, most patients suffered from widespread pain, the fibromyalgia rapid screening tool elicited positive findings, and quantitative sensory testing showed lowered cold and heat pain thresholds and an increased wind-up ratio., Conclusions: While the lack of somatosensory nervous system damage is incompatible with neuropathic pain as the mechanism underlying pain in JHS/EDS-HT, the lowered cold and heat pain thresholds and increased wind-up ratio imply that pain in JHS/EDS-HT might arise through central sensitization. Hence, this connective tissue disorder and fibromyalgia share similar pain mechanisms. WHAT DOES THIS STUDY ADD?: In patients with JHS/EDS-HT, the persistent nociceptive input due to joint abnormalities probably triggers central sensitization in the dorsal horn neurons and causes widespread pain., (© 2016 European Pain Federation - EFIC®)

Background: Brittle cornea syndrome (BCS) is a rare autosomal recessive connective tissue disease characterized by variable combinations of corneal thinning and fragility, corneal ruptures either spontaneously or after minor trauma, blue sclerae, keratoconus, keratoglobus, and high myopia. So far, mutations in 2 genes, PRDM5 and ZNF469, have been associated with BCS. The purpose of this study is to describe novel mutations in the PRDM5 gene in patients with BCS., Methods and Results: Using homozygosity mapping with single-nucleotide polymorphism markers followed by whole-exome sequencing, we identified a novel homozygous splice site variant (c.93+5G>A) in the PRDM5 gene in a consanguineous Pakistani family with 4 affected individuals. Reverse transcription-polymerase chain reaction analysis from lymphocyte-derived RNA failed to reveal any exon skipping because of this splice site variant. A homozygous variant (c.11T>G; p.Gln4Pro) in SEC24D also segregated with the disease in this particular family. One previously known mutation (c.974del; p.Cys325LeufsX2) was identified in a sporadic patient with BCS from Serbia., Conclusions: The current study revealed a novel mutation in the PRDM5 gene in a BCS family and recurrent mutation in a sporadic BCS patient. A variant in the SEC24D gene also segregated in the BCS family, although its role in the disease remains unclear.

Background: Joint hypermobility syndrome (JHS) is a heritable disorder associated with laxity and pain in multiple joints. Physiotherapy is the mainstay of treatment, but there is little research investigating its clinical effectiveness., Objectives: To develop a comprehensive physiotherapy intervention for adults with JHS; to pilot the intervention; and to conduct a pilot randomised controlled trial (RCT) to determine the feasibility of conducting a future definitive RCT., Design: Patients' and health professionals' perspectives on physiotherapy for JHS were explored in focus groups (stage 1). A working group of patient research partners, clinicians and researchers used this information to develop the physiotherapy intervention. This was piloted and refined on the basis of patients' and physiotherapists' feedback (stage 2). A parallel two-arm pilot RCT compared 'advice' with 'advice and physiotherapy' (stage 3). Random allocation was via an automated randomisation service, devised specifically for the study. Owing to the nature of the interventions, it was not possible to blind clinicians or patients to treatment allocation., Setting: Stage 1 - focus groups were conducted in four UK locations. Stages 2 and 3 - piloting of the intervention and the pilot RCT were conducted in two UK secondary care NHS trusts., Participants: Stage 1 - patient focus group participants (n = 25, three men) were aged > 18 years, had a JHS diagnosis and had received physiotherapy within the preceding 12 months. The health professional focus group participants (n = 16, three men; 14 physiotherapists, two podiatrists) had experience of managing JHS. Stage 2 - patient participants (n = 8) were aged > 18 years, had a JHS diagnosis and no other musculoskeletal conditions causing pain. Stage 3 - patient participants for the pilot RCT (n = 29) were as for stage 2 but the lower age limit was 16 years., Intervention: For the pilot RCT (stage 3) the advice intervention was a one-off session, supplemented by advice booklets. All participants could ask questions specific to their circumstances and receive tailored advice. Participants were randomly allocated to 'advice' (no further advice or physiotherapy) or 'advice and physiotherapy' (an additional six 30-minute sessions over 4 months). The physiotherapy intervention was supported by a patient handbook and was delivered on a one-to-one patient-therapist basis. It aimed to increase patients' physical activity through developing knowledge, understanding and skills to better manage their condition., Main Outcome Measures: Data from patient and health professional focus groups formed the main outcome from stage 1. Patient and physiotherapist interview data also formed a major component of stages 2 and 3. The primary outcome in stage 3 related to the feasibility of a future definitive RCT [number of referrals, recruitment and retention rates, and an estimate of the value of information (VOI) of a future RCT]. Secondary outcomes included clinical measures (physical function, pain, global status, self-reported joint count, quality of life, exercise self-efficacy and adverse events) and resource use (to estimate cost-effectiveness). Outcomes were recorded at baseline, 4 months and 7 months., Results: Stage 1 - JHS is complex and unpredictable. Physiotherapists should take a long-term holistic approach rather than treating acutely painful joints in isolation. Stage 2 - a user-informed physiotherapy intervention was developed and evaluated positively. Stage 3 - recruitment to the pilot RCT was challenging, primarily because of a perceived lack of equipoise between advice and physiotherapy. The qualitative evaluation provided very clear guidance to inform a future RCT, including enhancement of the advice intervention. Some patients reported that the advice intervention was useful and the physiotherapy intervention was again evaluated very positively. The rate of return of questionnaires was low in the advice group but reasonable in the physiotherapy group. The physiotherapy intervention showed evidence of promise in terms of primary and secondary clinical outcomes. The advice arm experienced more adverse events. The VOI analysis indicated the potential for high value from a future RCT. Such a trial should form the basis of future research efforts., Conclusion: A future definitive RCT of physiotherapy for JHS seems feasible, although the advice intervention should be made more robust to address perceived equipoise and subsequent attrition., Trial Registration: Current Controlled Trials ISRCTN29874209., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 47. See the NIHR Journals Library website for further project information.

Generalized joint hypermobility (GJH) and joint hypermobility syndrome (JHS) are gaining increased attention as potential sources of pain and injury. The aims of this study were to evaluate prevalence of GJH and JHS and to determine whether musculoskeletal injuries and symptoms commonly attributed to GJH and JHS were more common within a "healthy" college student population. The study involved a convenience sample of 267 college and graduate students, aged 17-26. GJH was assessed using the Beighton score with a cutoff of 5/9, while JHS was assessed using the Brighton criteria. Injury history and symptoms were assessed by recall. Prevalence of GJH was 26.2 % overall (females 36.7 %, males 13.7 %). Prevalence of JHS was 19.5 % overall (females 24.5 %, males 13.7 %). Injury rates were not significantly different for individuals who had GJH vs. those who did not have GJH. Individuals with JHS were significantly more likely to have had sprains, back pain, and stress fractures. Symptoms were no different between those with GJH and those who did not have GJH. However, individuals with JHS were significantly more likely to report clumsiness, easy bruising, and balance problems than those who did not have JHS. GJH and JHS were relatively common in this healthy college student population; GJH was not associated with increased incidence of injury or symptoms commonly attributed to JHS, but JHS was associated with increased incidence of some injuries and symptoms.

Background: Joint hypermobility syndrome (JHS) is one of the most common inherited connective tissue disorders. It causes significant pain and disability for all age groups, ranging from developmental delay among children to widespread chronic pain in adults. Experts in JHS assert that the condition is under-recognized and poorly managed., Purpose: The aim of this study was to assess US physical therapists' knowledge about JHS compared with other causes of widespread pain and activity limitations: fibromyalgia, juvenile rheumatoid arthritis and adult rheumatoid arthritis., Methods: Cross-sectional, Internet-based survey of randomly selected members of the American Physical Therapy Association and descriptive statistics were used to explore physical therapists' knowledge about JHS, fibromyalgia, juvenile rheumatoid arthritis and adult rheumatoid arthritis, and chi square was used to compare knowledge about the different conditions., Results: The response rate was 15.5% (496). Although 36% recognized the Beighton Scale for assessing joint hypermobility, only 26.8% of respondents were familiar with the Brighton Criteria for diagnosing JHS. Few respondents (11-19%) realized that JHS has extra-articular features such as anxiety disorder, fatigue, headache, delayed motor development, easy bruising and sleep disturbance. Physical therapists working in environments most likely to see patients with JHS underestimated the likely prevalence in their patient population., Conclusions: The results suggest that many physical therapists in the United States are not familiar with the diagnostic criteria, prevalence or common clinical presentation of JHS., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Joint hypermobility syndrome describes a disorder in which musculoskeletal pain occurs in a generalized joint hypermobility substrate. The clinical picture comprises variable manifestations which involve mainly but not exclusively the musculoskeletal system, and evolve over the person's lifetime., Case Presentation: Describing the case of a 20-year-old female with generalized arthro-myalgias, persistent fatigue and troublesome visceral pain, we illustrate how a frequently ignored clinical sign such as joint hypermobility can be the keystone to clarify different simultaneous symptoms. All of the patient's physical complaints had been investigated separately during her previous medical examinations, and several tests repeatedly gave negative results. The patient received different diagnoses that describe only part of her problems, such as irritable bowel syndrome for visceral pain, fibromyalgia for arthralgias or depression for fatigue. These approaches gave rise to pharmacological or physical treatments which did not improve her quality of life in any way and in some instances worsened the situation. Pronounced joint hypermobility which led the patient to flex her joints excessively, causing subluxations in several districts, was the only sign overlooked., Conclusion: Exploring the patient's articular features in her clinical context led us to diagnose joint hypermobility syndrome, a complex and often ignored condition. The case highlights the utility of a multidisciplinary approach and coordinated interventions to define and manage this clinical entity.