Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.

Dysregulated transforming growth factor TGF-ß signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-ß-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-ß signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-ß signaling during development and reinforces the existing link between TGF-ß signaling and connective tissue defects.

Comparison of range of motion during the cervical flexion rotation versus the side-bending rotation test in individuals with and without hyperlaxity.

Objective: The flexion rotation test (FRT) is used to determine C1-2 involvement in individuals with neck pain and headaches. Some individuals present with generalized joint hyperlaxity (GJH) which could influence the results of this test, which relies on a soft tissue locking mechanism. The purpose of this study was to examine the side-bend rotation test (SBRT), which utilizes osseous locking, compared to the FRT. Methods: Thirty-eight healthy individuals (25 female, 26.03 years) were assessed for GJH via the Beighton Hypermobility Index (BHI). A blinded examiner performed the FRT and SBRT bilaterally, measuring ROM using a digital goniometer device. Results: Statistically significant differences in ROM were present for the FRT based on negative (0-3) and positive (4-9) BHI score: (Right 46.4±3.6, 49.6±4.8, p=.031), (Left 45.5±3.5, 49.0±5.2, p=.023); no differences were observed for the SBRT (Right 37.6±4.3, 38.9±3.4), (Left 37.7±4.2, 37.6±3.4).  When further stratifying the groups, a one-way ANOVA and post-hoc testing revealed significant differences of FRT range of motion between the BHI 7-9 group(52.4 ± 4.4 -53.9 ± 3.4) compared to BHI 0-3 (45.4 ± 3.6-46.2 ± 3.5) and 4-6 groups (46.0 ± 3.7-46.4 ± 2.2), p < .001; there were no significant differences between the 0-3 and 4-6 groups. There were no between group differences for the SBRT, BHI 0-3 (37.5 ± 4.4-37.7 ± 4.3), BHI 7-9 (39.9 ± 3.7-39.2 ± 3.5). Discussion: Individuals with GJH demonstrated significant differences in ROM for the FRT, but not the SBRT. The SBRT may be a useful alternative to the FRT for individuals with hyperlaxity. However, further research needs to be conducted to assess the diagnostic ability of this test in individuals with cervical pathology.

Diagnosis of Ehlers-Danlos syndrome after a first shoulder dislocation.

BACKGROUND: Shoulder dislocation is often the first symptom of Ehlers-Danlos syndrome (EDS). Whether it occurs in early-onset EDS is unknown. In most cases, surgical failure leads to the diagnosis. We aimed to determine whether clinical symptoms can signal the presence of EDS at a first dislocation. MATERIALS AND METHODS: In this retrospective study, we analyzed clinical and radiologic data for 27 patients with EDS and shoulder instability and a control population of 40 consecutive non-EDS patients undergoing surgery for an unstable shoulder. Data were collected on gender, age, single or bilateral disease, general hyperlaxity, shoulder hyperlaxity, number of dislocations or subluxations, nontraumatic onset, and pain specificity. Nerve and vascular injuries, joint disorders, and family history were recorded, and radiologic data were reported. RESULTS: Age <14 years, female sex, bilateral disorder, and general hyperlaxity were significantly more frequent in patients with EDS and a first dislocation than in those without EDS. Painless dislocation with pain after dislocation and concomitant nerve injury were more frequent in affected patients, as were hemostasis disorders and a family history of joint hyperlaxity. Bone lesions were not seen on radiographs. Only the hyperlaxity sign (external rotation >85°) did not differ between the groups. CONCLUSION: After a first dislocation in a young girl with global hyperlaxity but not necessarily shoulder hyperlaxity, painless atraumatic dislocation with pain after reduction can suggest EDS.

Adult-onset respiratory insufficiency, scoliosis, and distal joint hyperlaxity in patients with multiminicore disease due to novel Megf10 mutations.

INTRODUCTION: Multiminicore disease is a congenital myopathy characterized pathologically by the presence of multiple minicore structures in the sarcoplasm. Mutations in the selenoprotein N1-encoding gene (SEPN1) and ryanodine receptor 1-encoding gene (RYR1) are responsible for half of the reported cases. Mutations in multiple epidermal growth factor-like domains 10-encoding gene (MEGF10) have been identified only recently in a few patients with antenatal to infantile-onset myopathy, with and without minicore pathology. METHODS: We report 2 sisters with adult-onset respiratory insufficiency followed by development of limb weakness. Both had scoliosis, distal joint hyperlaxity, and high-arched feet. RESULTS: A biopsy of the right triceps muscle in 1 sister showed multiple minicore structures. She had electromyographic changes of myopathy with fibrillation potentials and myotonic discharges. Next generation sequencing identified novel compound heterozygous missense variants in MEGF10 c.230G>A (p.Arg77Gln) and c.1833T>G (p.Cys611Trp) in both sisters. CONCLUSIONS: MEGF10 mutations can cause myopathy with adult-onset respiratory insufficiency. Muscle Nerve, 2016 Muscle Nerve 53: 984-988, 2016.

Acetabular dysplasia may be related to global joint hyperlaxity.

PURPOSE: Some patients with shoulder laxity complain of coxalgia without a history of trauma. We hypothesised that patients who have recurrent shoulder instability accompanied with generalised joint hyperlaxity tend to have acetabular dysplasia. METHODS: Pelvic radiographs of 26 young patients with hyperlaxity who had shoulder instability complaints without any history of hip joint trauma were evaluated by measuring their centre-edge angle (CEA) and acetabular angle (AA). In addition, Beighton generalised joint laxity tests were performed. All of the patients had shoulder pain and instability accompanied with hyperlaxity. We performed magnetic resonance imaging examination to show SLAP-Bankart lesions and pelvis anteroposterior X-rays to detect acetabular dysplasia. RESULTS: The average age of the study group was 26 ± 8.03 years (13-39). Six patients were female and 20 were male. When CEA (<22.6 degrees) was used as a criterion for acetabular dysplasia, the dysplasia rate of our patient group was 3.84 % for the right hip, 3.84 % for the left hip and 3.84 % overall. When AA (>42.2 degrees) was used as the dysplasia criterion, the dysplasia rate of patient group was 30.76 % for the right hip, 57.69 % for the left hip and 57.69 % overall. CONCLUSIONS: CEA values were significantly lower (p = 0.009) and AA values were significantly higher (p < 0.001) in our study group than the previously-reported average values of the Turkish population. We think that acetabular dysplasia is more frequent in patients with hyperlaxity; further studies are needed to test this idea.

A Comprehensive Case Study of a Hyperlaxity Dilemma: An Injury-Prone Young Athlete.

A prevalent condition that is frequently linked to joint trauma is joint hyper-laxity. The knee joint is one of the most complex and injury-prone joints in sports. The most commonly injured is the anterior cruciate ligament (ACL). The case presented below is of a 24-year-old athlete with a past history of many sports-related injuries who is now presented with a complete tear of the ACL with hyper-laxity as a risk factor. The patient has a Beighton score of six out of nine without any other symptoms, which is suggestive of benign hyper-laxity of the joints and not hyper-laxity syndrome. Here, we emphasize that medical professionals must know the fundamental connection between hyper-laxity and musculoskeletal injuries and their proper management and rehabilitation for future prevention.

The association between keratoconus and systemic manifestations of connective tissue hyperlaxity.

PURPOSE: To evaluate the correlation between keratoconus and systemic manifestations of tissue hyperlaxity in the general population. METHODS: In this population based cross-sectional study 940,763 medical records of Israeli adolescents and young adults in military service were reviewed. Demographic and medical data were extracted. The prevalence of ligament injuries, habitual orthopedic deformities and umbilical/inguinal hernia was evaluated in cases with and without keratoconus. The association was tested using uni- and multivariant analyses. RESULTS: Overall 938,411 adolescents and adults were included. Mean age was 17.55 ± 1.50 years, and 40.70% were female. Keratoconus was documented in 1,529 cases, with a prevalence of 0.16%. Compared to the general population, patients with keratoconus were significantly more likely to be diagnosed with genu varum/valgus (OR = 2.75, CI 1.48-5.13, p = 0.0015), pes planus (OR = 1.97, 95% CI: 1.62-2.38, p < 0.0001), scoliosis (OR = 1.88, 95% CI: 1.45-2.43, p < 0.0001) and umbilical/inguinal hernias (OR = 2.18, 95% CI: 1.47-3.24, p = 0.0001). On multivariate analysis the results remained significant (p < 0.05 for all). Joint injuries (ankle sprains, shoulder dislocation and injury to knee ligaments and menisci) were not significantly related to keratoconus (p > 0.05 for all). CONCLUSIONS: In this large cohort of adolescents and young adults, an association was found between keratoconus and connective tissue hyperlaxity manifestations involving the knees, feet, spine and abdomen. These findings suggest that keratoconus might be a manifestation of a generalized connective tissue disorder, rather than just a local ocular phenomenon.

Joint Hypermobility as a Potential Indicator of Marfan Syndrome and Ehlers-Danlos Syndrome.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder associated with the mutation of the FBN1 gene. Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders with similar clinical features to MFS that often requires genetic testing to confirm a diagnosis of an EDS subtype. MFS is diagnosed using the Ghent Nosology criteria, which screens for cardiovascular, musculoskeletal, integumentary, ocular, and pulmonary abnormalities. Though genetic testing has recently been increasingly emphasized in diagnosing MFS, it is not currently a mandatory component of the Ghent Nosology. We present the case of a nine-year-old male who presented with joint hypermobility of the shoulders, knees, and thumbs, and a family history of joint hypermobility in his 15-year-old brother. Genetic testing ruled out MFS, and the patient subsequently underwent testing for EDS, which further ruled out classical and hypermobile EDS. This case highlights the importance of supplementing the Ghent Nosology criteria with genetic testing in diagnosing MFS because it can aid in generating a differential diagnosis and optimizing diagnostic accuracy.

Association Between Keratoconus and Shoulder Dislocation: A Cross-Sectional Study.

Introduction Few studies have highlighted the correlation between shoulder dislocation and keratoconus (KC). This study aimed to examine the association between KC and shoulder dislocation using patients with KC and matched controls. Methods This cross-sectional study was conducted at Jordan University Hospital. We included patients diagnosed with KC from Jordan University Hospital's Ophthalmology Department between 2015 and 2018. We also included age- and sex-matched controls recruited randomly from fitness centers and shopping malls. All participants had complete ophthalmic and orthopedic assessments. KC was diagnosed by clinical examination followed by Pentacam (Scheimpflug Images, Oculyzer, WaveLight, Alcon, USA) confirmation. Results A total of 238 patients, with a mean age of 29.53 (±11.20) years, were included in this study. They were 144 (60.5%) men and 94 (39.5%) women. Moreover, 120 (50.4%) had KC while 118 (49.6%) did not have KC. Only 11 (4.6%) patients had previous shoulder dislocation. We did not find a significant difference in the frequency of shoulder dislocation between patients with and without KC (p = 0.512). Conclusion This study provides further evidence on the lack of association between shoulder dislocation and KC, an association that was presumed due to shared collagen characteristics.

Chronic Low Back Pain Occurring in Association With Hypermobility Spectrum Disorder and Ehlers-Danlos Syndrome.

BACKGROUND: This review paper outlines recent advances in diagnostic criteria for hypermobility spectrum disorder (HSD) and its association with Ehlers-Danlos syndrome (EDS), as well as current literature on the association between joint hypermobility syndrome and lumbar back pain. We outline the optimal multidisciplinary management of lumbar back pain in the context of joint hypermobility syndrome, as well as the indications and possible side effects of surgical management of patients with these conditions.Several studies have suggested a link between chronic low back pain and hypermobility. HSD has been described as an excessive range of motion in a joint, when accounting for patient demographics. The nomenclature surrounding symptomatic joint hypermobility has varied historically, and various groups, including most notably the international EDS consortium, have introduced new classification schemes to acknowledge the systemic effects of joint hypermobility, which were previously poorly understood. METHODS: Narrative literature review. RESULTS: Not applicable. CONCLUSIONS: Lower back pain experienced in patients on the HSD-EDS spectrum is multifactorial in origin and should not be considered solely in anatomical terms. Caution has been advised in the surgical management of patients on the HSD-hEDS spectrum, particularly where the subtype is unclear. The vascular type of EDS has a particular propensity for severe bleeding complications. Rates of perioperative complications after lumbar spinal surgery in the hypermobile EDS population have been reported to be up to 50%. When hypermobility and chronic lumbar back pain coexist, we advocate management in a multidisciplinary setting involving physiotherapists, pain physicians, surgeons, and psychologists.

The Brain-Lung-Thyroid syndrome (BLTS): A novel deletion in chromosome 14q13.2-q21.1 expands the phenotype to humoral immunodeficiency.

Genetic defects of NKX2-1 are classically associated with hypothyroidism, benign chorea and neonatal respiratory distress. The purpose of this study was to identify the genetic pathogenesis of the "NKX2-1 triad" in a 10 year-old female presenting additional features barely described in the disorder. In the neonatal period, she presented with generalized hypotonia and respiratory distress, with later episodes of frequent wheezing. At 3 month-age developmental dysplasia of the hip was diagnosed and at 10 months, primary hypothyroidism was detected and treated. Subsequently, delayed achievement of developmental milestones and then subtle choreic movements of extremities were identified at 2 years of age. Furthermore, delayed teeth eruption and agenesis of some dental pieces, short stature and joint hyperlaxity were also noticed. At 10 years, a poor immune response to polysaccharide antigens and hypogammaglobulinemia, including all IgG subclasses were detected. Surprisingly, no mutations were identified in the complete coding region of NKX2-1 by PCR and Sanger sequencing. MLPA showed a de novo loss of gene dosage in all 3 probes located in NKX2-1 exons. A CGH-array identified a deletion of 3.32 Mb in chromosome 14q13.2-q21.1 containing 20 genes, including NKX2-1, PAX9 and two candidate genes (NFKB1A and PPP2R3C) involved in immune response. The Brain-Lung-Thyroid syndrome (OMIM#610978; ORPHA:209905) associated with other clinical phenotypes should suggest monoallelic deletions of chromosome 14 causing haploinsufficiency of NKX2-1, and other contiguous genes like PAX9 (hypodontia) or other dosage-sensitive genes in the chromosomal vicinity that emerge as candidates for hypogammaglobulinemia, mainly NFKBIA.

Síndrome de Ehlers Danlos tipo III en un adolescente masculino / Ehlers-Danlos Syndrome Type III in a Male Adolescent

Introducción: El síndrome de Ehlers Danlos tipo III o síndrome de hiperlaxitud articular benigna, consiste en una alteración genética del colágeno tipo III/I con un patrón de herencia autosómico dominante, caracterizado por la presencia de articulaciones con una amplitud de movilidad incrementada y síntomas musculoesqueléticos y extraesqueléticos. Objetivo: Valorar la importancia de la aplicación del método clínico para el diagnóstico del Síndrome de Ehlers Danlos tipo III. Caso clínico: Se presenta el caso de un adolescente masculino de 15 años de edad con diagnóstico clínico reciente del Síndrome de Ehlers Danlos tipo III. Conclusiones: Para lograr un diagnóstico certero del síndrome de Ehlers Danlos tipo III es imprescindible aplicar con ciencia y conciencia el método clínico(AU)

Introduction: Ehlers-Danlos syndrome type III or benign joint hyperlaxity syndrome consists in a genetic alteration of collagen type III/I with a dominant autosomal inheritance pattern, characterized by the presence of joints with increased range of motion, as well as musculoskeletal and extraskeletal symptoms. Objective: To assess the importance of applying the clinical method for the diagnosis of Ehlers-Danlos syndrome type III. Clinical case: The case is presented of a 15-year-old male adolescent with a recent clinical diagnosis of Ehlers-Danlos syndrome type III. Conclusions: In order to achieve an accurate diagnosis of Ehlers-Danlos syndrome type III, it is essential to apply the clinical method scientifically and conscientiously(AU)

Distrofia muscular congênita de Ullrich moderadamente progressiva / Moderately progressive Ullrich congenital muscular dystrophy

OBJETIVOS: Descrever características clínicas e genéticas da distrofia muscular congênita de Ullrich (DMCU), e relatar o caso de um paciente diagnosticado com DMCU após uma exaustiva investigação, que incluiu análise imuno-histoquímica e genômica do colágeno tipo VI. DESCRIÇÃO: Este estudo baseou-se na avaliação clínica e imuno-histoquímica do tecido muscular e na análise genômica dos fibroblastos dérmicos de um menino de 7 anos e meio, e do DNA dos seus pais. São discutidos aspectos clínicos e o diagnóstico diferencial com outras doenças. COMENTÁRIOS: O melhor conhecimento das distrofias musculares congênitas aumentará o número de diagnósticos corretos e abrirá novos horizontes para o tratamento dessas doenças. A avaliação genética dos pacientes com DMCU tem implicações relevantes para o prognóstico e o aconselhamento genético da família. É aconselhável divulgar essa doença na comunidade pediátrica, devido ao início precoce das manifestações clínicas e o fato de ser frequentemente mal diagnosticada ou não ser diagnosticada.

OBJECTIVES: To describe genetic and clinical features of Ullrich congenital muscular dystrophy (UCMD), and to report the case of a patient diagnosed with UCMD after an exhaustive investigation, which included collagen VI immunohistochemical and genomic analyses. DESCRIPTIONS: This study was based on clinical, immunohistochemical assessment of muscle tissue and genomic analysis of dermal fibroblasts of a 7 1/2-year old boy and of the DNA of his parents. Clinical aspects and differential diagnosis with other disorders are discussed. COMMENTS: A better knowledge of congenital muscular dystrophies will improve the number of correct diagnoses and open new horizons for the treatment of such diseases. Genetic evaluation of UCMD patients has relevant implications for prognosis and genetic counseling of the family. The divulgation of this disorder in the pediatric community is advisable, because of the early onset of clinical manifestations and the fact that it is frequently misdiagnosed or not diagnosed at all.