Contracture Syndrome Research Articles

“Syndrome of Contractures and Deformities” According to Prof. Hans Mau as the Primary Cause of Hip, Neck, Shank and Spine Deformities in Babies, Youth and Adults

“Syndrome of Contractures and Deformities” According to Prof. Hans Mau as the Primary Cause of Hip, Neck, Shank and Spine Deformities in Babies, Youth and Adults

Possible involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of the Dupuytren's contracture: a novel target for a future therapeutic strategy?

Dupuytren’s contracture (DC) is a benign fibroproliferative disease causing fibrotic nodules and fascial cords with resultant debilitating flexion contracture deformities. The present study was designed to characterize pro-inflammatory cytokines and growth factors involved in the genesis, progression and recurrence of the disease to optimize therapeutic agents and strategies for controlling Dupuytren’s disease. The expression of pro-inflammatory cytokines and other growth factors was detected by immunohistochemistry and immunofluorescence in the fibrotic nodules and normal palmar fascia resected respectively from patients affected by Dupuytren’s contracture and Carpal Tunnel Syndrome (as negative controls). RT-PCR analysis was performed to quantify the expression of TGF-β1, IL-1β and VEGFa in the myofibroblasts and fibroblasts isolated from Dupuytren’s nodules. Histological analysis showed the high cellularity and rate of proliferation of Dupuytren’s tissue with the presence of myofibroblastic isotypes. Our data showed the strong expression of TGF-β1, IL-1β and VEGFa in Dupuytren’s fibromatosis nodules suggesting a direct role of these markers in the onset, progression and recurrence of the disease. Our observations suggest that TGF-β1, IL-1β and VEGFa may be considered potential therapeutic targets in the treatment of Dupuytren’s disease. Moreover, a new innovative therapy may be represented by the combined use of specific inhibitors of these growth factors.

Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.

ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6).

Lethal congenital contracture syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis multiplex congenita (AMC). LCCS is genetically heterogeneous with mutations in five genes identified to date, all with a role in the innervation or contractile apparatus of skeletal muscles. In a consanguineous Saudi family with multiple stillbirths presenting with LCCS, we excluded linkage to all known LCCS loci and combined autozygome analysis and whole-exome sequencing to identify a novel homozygous variant in ZBTB42, which had been shown to be enriched in skeletal muscles, especially at the neuromuscular junction. Knockdown experiments of zbtb42 in zebrafish consistently resulted in grossly abnormal skeletal muscle development and myofibrillar disorganization at the microscopic level. This severe muscular phenotype is successfully rescued with overexpression of the human wild-type ZBTB42 gene, but not with the mutant form of ZBTB42 that models the human missense change. Our data assign a novel muscular developmental phenotype to ZBTB42 in vertebrates and establish a new LCCS6 type caused by ZBTB42 mutation.

Frozen shoulder contracture syndrome – Aetiology, diagnosis and management

Frozen shoulder is a poorly understood condition that typically involves substantial pain, movement restriction, and considerable morbidity. Although function improves overtime, full and pain free range, may not be restored in everyone. Frozen shoulder is also known as adhesive capsulitis, however the evidence for capsular adhesions is refuted and arguably, this term should be abandoned. The aim of this Masterclass is to synthesise evidence to provide a framework for assessment and management for Frozen Shoulder. Although used in the treatment of this condition, manipulation under anaesthetic has been associated with joint damage and may be no more effective than physiotherapy. Capsular release is another surgical procedure that is supported by expert opinion and published case series, but currently high quality research is not available. Recommendations that supervised neglect is preferable to physiotherapy have been based on a quasi-experimental study associated with a high risk of bias. Physiotherapists in the United Kingdom have developed dedicated care pathways that provide; assessment, referral for imaging, education, health screening, ultrasound guided corticosteroid and hydro-distension injections, embedded within physiotherapy rehabilitation. The entire pathway is provided by physiotherapists and evidence exists to support each stage of the pathway. Substantial on-going research is required to better understand; epidemiology, patho-aetiology, assessment, best management, health economics, patient satisfaction and if possible prevention.

“Syndrome of contractures and deformities” according to Prof. Hans Mau as the primary cause of motoric deformities in children. Case studies including deformities of hips, neck, shank and spine

Authors claim that the problem of deformities in children and pain in adult patients can be connected to shortening of soft tissues followed by contractures of joints. The „syndrome of contractures” (SofC) described by Prof. Hans Mau – as “Syndrome…Read more ›

Prolonged Relaxation Kinetics in Distal Arthrogryposis Skeletal Muscle Myofibrils with a MYH3 R672C Mutation

The mechanisms underlying most forms of Distal Arthrogryposis (DA), a group of congenital contracture syndromes, are unknown. Our previous functional studies from adult individuals with DA caused by the heterozygous myosin heavy chain mutation, MYH3 R672C, showed that the time required by DA skinned skeletal myofibers to relax completely after calcium-induced contraction was several-fold longer than controls (Racca et al. (2010) Biophys J 98:542-3a). Here we measured force and kinetics of activation & relaxation, and compared chemomechanical analysis using myofibrils and myofibers sampled from gastrocnemius muscle from two affected individuals vs. three control (non-DA) individuals. The prolonged relaxation was reflected in isolated myofibrils from DA patients, as 50% relaxation time from maximal activation was 36% longer, and 90% relaxation time was prolonged by 58%. The kinetics of the slow phase of relaxation were significantly slower, in both the rate and duration (DA: kREL,SLOW=0.36±0.07s−1;tREL,SLOW=285±21ms vs. Control: 0.79±0.18s−1;199±23ms), implying slower cross-bridge release. Use of ADP prolonged relaxation of control samples to a greater extent than DA preparations, suggesting that slower ADP release from myosin in DA myofibrils may be the mechanism of slower relaxation and cross-bridge release. We also found that both mRNA and protein for this embryonic myosin (gene MYH3) were present in adult skeletal muscle, such that a small amount of this slower myosin may prolong relaxation. Although the mechanism that leads to the congenital contractures must begin prenatally, these results suggest that MYH3 R672H also affects ongoing function of adult skeletal muscle. Understanding the mechanism by which myosin mutations affect muscle cell contractility could provide a model for exploring the pathogenesis of more common contractures such as idiopathic clubfoot and facilitate the development of novel therapeutic approaches. Supported by F31AR06300(A.R.), 5K23HD057331(A.B.), HD048895(M.B.,M.R.).

Insights into mRNA export-linked molecular mechanisms of human disease through a Gle1 structure–function analysis

A critical step during gene expression is the directional export of nuclear messenger (m)RNA through nuclear pore complexes (NPCs) to the cytoplasm. During export, Gle1 in conjunction with inositol hexakisphosphate (IP6) spatially regulates the activity of the DEAD-box protein Dbp5 at the NPC cytoplasmic face. GLE1 mutations are causally linked to the human diseases lethal congenital contracture syndrome 1 (LCCS-1) and lethal arthrogryposis with anterior horn cell disease (LAAHD). Here, structure prediction and functional analysis provide strong evidence to suggest that the LCCS-1 and LAAHD disease mutations disrupt the function of Gle1 in mRNA export. Strikingly, direct fluorescence microscopy in living cells reveals a dramatic loss of steady-state NPC localization for GFP-gle1 proteins expressed from human gle1 genes harboring LAAHD and LCCS-1 mutations. The potential significance of these residues is further clarified by analyses of sequence and predicted structural conservation. This work offers insights into the perturbed mechanisms underlying human LCCS-1 and LAAHD disease states and emphasizes the potential impact of altered mRNA transport and gene expression in human disease.

Expanding the phenotypic spectrum of ECEL1‐related congenital contracture syndromes

Using a combination of homozygosity mapping and whole-exome sequencing (WES), we identified a novel missense c.1819G>A mutation (G607S) in the endothelin-converting enzyme-like 1 (ECEL1) gene in a consanguineous pedigree of Turkish origin presenting with a syndrome of camptodactyly, scoliosis, limited knee flexion, significant refractive errors and ophthalmoplegia. ECEL1 mutations were recently reported to cause recessive forms of distal arthrogryposis. This report expands on the molecular basis and the phenotypic spectrum of ECEL1-associated congenital contracture syndromes.

MYBPC1 mutations impair skeletal muscle function in zebrafish models of arthrogryposis

Myosin-binding protein C1 (MYBPC1) is an abundant skeletal muscle protein that is expressed predominantly in slow-twitch muscle fibers. Human MYBPC1 mutations are associated with distal arthrogryposis type 1 and lethal congenital contracture syndrome type 4. As MYBPC1 function is incompletely understood, the mechanism by which human mutations result in contractures is unknown. Here, we demonstrate using antisense morpholino knockdown, that mybpc1 is required for embryonic motor activity and survival in a zebrafish model of arthrogryposis. Mybpc1 morphant embryos have severe body curvature, cardiac edema, impaired motor excitation and are delayed in hatching. Myofibril organization is selectively impaired in slow skeletal muscle and sarcomere numbers are greatly reduced in mybpc1 knockdown embryos, although electron microscopy reveals normal sarcomere structure. To evaluate the effects of human distal arthrogryposis mutations, mybpc1 mRNAs containing the corresponding human W236R and Y856H MYBPC1 mutations were injected into embryos. Dominant-negative effects of these mutations were suggested by the resultant mild bent body curvature, decreased motor activity, as well as impaired overall survival compared with overexpression of wild-type RNA. These results demonstrate a critical role for mybpc1 in slow skeletal muscle development and establish zebrafish as a tractable model of human distal arthrogryposis.

Congenital contractural arachnodactyly (Beals-Hecht syndrome): a rare connective tissue disorder

Congenital contractural arachnodactyly (CCA) or Beals-Hecht syndrome (BHS) presents a very rare connective tissue disorder characterized by narrow body habitus, crumpled ears, arachnodactyly, contractures, and scoliosis. In our case report, the physical examination revealed typical physical findings to determine the physical diagnosis of BHS in contrast to negative finding on DNA analysis. From clinical point-of-view, it is important to include a complex clinical approach in making the diagnosis.

Novel Role for Perinatal Myosin in Skeletal Muscle Development

Previously, we identified an R674Q missense mutation in the MYH8 gene encoding the myosin heavy chain perinatal isoform (MyHCpn) in individuals with a rare Carney complex syndrome (CNC) variant. In CNC, familial cardiac myxomas occur in the setting of spotty skin pigmentation, extracardiac myxomas, endocrinopathy, and other neoplasms. Individuals with R674Q MYH8 mutations exhibit a typical CNC phenotype along with trismus pseudocamptodactyly limb contracture syndrome. To define the role of MyHCpn in mammalian development, we established a genetically engineered mouse line carrying the orthologous R674Q mutant MYH8 allele. Mice with ubiquitous knockin of R476Q Myh8 (Myh8R674Q/+;EIIa-Cre mice) die within minutes after birth due to respiratory failure. Gross examination of these mice at embryonic day (E)18.5 revealed smaller embryos with abdominal bulges. Upon histological examination of E18.5 Myh8R674Q/+;EIIa-Cre skeletal muscles, we observed fiber size variability, signs of apoptosis and increased muscle degeneration/regeneration. Electron microscopic images of striated muscles showed enlarged mitochondria, focal absence of myofibrils, loosely arrayed fiber bundles, and regional Z-line irregularities. We also observed the presence of nemaline rods indicative of nemaline myopathy. These findings suggest a novel and crucial role of MyHCpn in proper skeletal muscle development.

Developmental Dysplasia of the Hip

1. Blaise A. Nemeth, MD, MS* 2. Vinay Narotam, MD† 1. *Associate Professor, Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, Madison, WI. 2. †Assistant Professor, Department of Orthopaedics, University of North Carolina School of Medicine, Chapel Hill, NC. * Abbreviations: AVN: : avascular necrosis DDH: : developmental dysplasia of the hip Early detection of developmental dysplasia of the hip is essential because restoration of the normal relationship of the femoral head and acetabulum increases the likelihood of normal development. Pediatricians must be aware of the American Academy of Pediatrics guidelines for early detection. After completing this article, readers should be able to: 1. Acknowledge the spectrum of hip pathology included in developmental dysplasia of the hip (DDH). 2. Identify newborns at risk for DDH. 3. Diagnose hip dislocations by using appropriate physical examination maneuvers. 4. Appropriately use imaging modalities to screen for DDH in infants who have normal or equivocal physical findings. 5. Recognize the presentation of hip dislocation in the older child. Developmental dysplasia of the hip (DDH) encompasses the spectrum of hip abnormalities involving the relationship between the femoral head and the acetabulum during early growth and development. A hip may be dislocated at rest, dislocatable (but in a normal position at rest), subluxed (incomplete contact between the femoral head and acetabulum), subluxable (incomplete contact induced with provocative maneuvers), or appear normal on physical examination yet have an abnormally shaped acetabulum or femoral head radiographically. The previously used term, “congenital hip dislocation,” has been abandoned in recognition of this spectrum, acknowledging as well the fact that a child may have normal examination findings at birth but progress to dislocation later in life. Strictly speaking, the term DDH does not apply to abnormal development of the hip due to other diseases, such as cerebral palsy, Legg-Calve-Perthes disease, or slipped capital femoral epiphysis, in which “hip dysplasia” is a sufficient term, nor does the term include traumatic dislocation. In addition, the term “teratologic dislocation” is reserved …

The diagnosis and treatment of Dupuytren' s contracture combined with carpal tunnel syndrome

Objective To investigate the correlation of Dupuytren's contracture and carpal tunnel syndrome and evaluate the clinical outcomes of treating both diseases in one surgery. Methods From March 2003 to August 2011,8 cases of Dupuytren's contracture combined with carpal tunnel syndrome were surgically treated.Through an M-shaped palm incision and a Y-shaped incision extended to the finger,the palmar aponeurosis was partially removed and the flexor retinaculum was cut open to release the median nerve at the same time. Results Primary wound healing was achieved in all of the eight cases.There were no flap edge necrosis and hematoma formation.Numbness of the thumb,index finger and middle finger gradually reduced postoperatively.The numbness disappeared after 3 months.All patients were follow-up for 6 months to 2 years with no recurrence. Conclusion When more predisposing factors of both diseases occur in one patient,the probability of the occurrence of both Dupuytren' s contractue and carpal tunnel syndrome in one patient also increases significantly.The two diseases can be treated in one surgery. Key words: Dupuytren's contracture; Carpal tunnel syndrome; Surgical procedures,operative

Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a mutation in MYBPC1

Autosomal recessive lethal congenital contractural syndrome (LCCS) is a severe form of neuromuscular arthrogryposis. We previously showed that this phenotype is caused in two unrelated inbred Bedouin tribes by different defects in the phosphatidylinositol pathway. However, the molecular basis of the same phenotype in other tribes remained elusive. Whole exome sequencing identified a novel LCCS founder mutation within a minimal shared homozygosity locus of approximately 1 Mb in two affected individuals of different tribes: a homozygous premature stop producing mutation in MYBPC1, encoding myosin-binding protein C, slow type. A dominant missense mutation in MYBPC1 was previously shown to cause mild distal arthrogryposis. We now show that a recessive mutation abrogating all functional domains in the same gene leads to LCCS.

Pharmacological vitrectomy with urokinase: description of the method and review of a case series.

BackgroundPharmacological vitrectomy (PV) with autologous plasmin is used to detach the vitreous, with or without subsequent surgical vitrectomy, in several pathologies such as proliferative diabetic retinopathy, proliferative vitreoretinopathy, macular hole,...

A zebrafish model of lethal congenital contracture syndrome 1 reveals Gle1 function in spinal neural precursor survival and motor axon arborization

In humans, GLE1 is mutated in lethal congenital contracture syndrome 1 (LCCS1) leading to prenatal death of all affected fetuses. Although the molecular roles of Gle1 in nuclear mRNA export and translation have been documented, no animal models for this disease have been reported. To elucidate the function of Gle1 in vertebrate development, we used the zebrafish (Danio rerio) model system. gle1 mRNA is maternally deposited and widely expressed. Altering Gle1 using an insertional mutant or antisense morpholinos results in multiple defects, including immobility, small eyes, diminished pharyngeal arches, curved body axis, edema, underdeveloped intestine and cell death in the central nervous system. These phenotypes parallel those observed in LCCS1 human fetuses. Gle1 depletion also results in reduction of motoneurons and aberrant arborization of motor axons. Unexpectedly, the motoneuron deficiency results from apoptosis of neural precursors, not of differentiated motoneurons. Mosaic analyses further indicate that Gle1 activity is required extrinsically in the environment for normal motor axon arborization. Importantly, the zebrafish phenotypes caused by Gle1 deficiency are only rescued by expressing wild-type human GLE1 and not by the disease-linked Fin(Major) mutant form of GLE1. Together, our studies provide the first functional characterization of Gle1 in vertebrate development and reveal its essential role in actively dividing cells. We propose that defective GLE1 function in human LCCS1 results in both neurogenic and non-neurogenic defects linked to the apoptosis of proliferative organ precursors.

Evaluation and Treatment of Disorders of the Infrapatellar Fat Pad

The infrapatellar fat pad (IFP), also known as Hoffa's fat pad, is an intracapsular, extrasynovial structure that fills the anterior knee compartment, and is richly vascularized and innervated. Its degree of innervation, the proportion of substance-P-containing fibres and close relationship to its posterior synovial lining implicates IFP pathologies as a source of infrapatellar knee pain. Though the precise function of the IFP is unknown, studies have shown that it may play a role in the biomechanics of the knee or act as a store for reparative cells after injury. Inflammation and fibrosis within the IFP, caused by trauma and/or surgery can lead to a variety of arthrofibrotic lesions including Hoffa's disease, anterior interval scarring and infrapatellar contracture syndrome. Lesions or mass-like abnormalities rarely occur within the IFP, but their classification can be narrowed down by radiographical appearance. Clinically, patients with IFP pathology present with burning or aching infrapatellar anterior knee pain that can often be reproduced on physical exam with manoeuvres designed to produce impingement. Sagittal MRI is the most common imaging technique used to assess IFP pathology including fibrosis, inflammation, oedema, and mass-like lesions. IFP pathology is often successfully managed with physical therapy. Passive taping is used to unload or shorten an inflamed IFP, and closed chain quadriceps exercises can improve lower limb control and patellar congruence. Training of the gluteus medius and stretching the anterior hip may help to decrease internal rotation of the hip and valgus force at the knee. Gait training and avoiding hyperextension can also be used for long-term management. Injections within the IFP of local anaesthetic plus corticosteroids and IFP ablation with ultrasound guided alcohol injections have been successfully explored as treatments for IFP pain. IFP pathology refractory to physical therapy can be approached through a variety of operative treatments. Arthroscopic partial resection for IFP impingement and Hoffa's disease has showed favourable results; however, total excision of the IFP performed concomitantly with total knee arthroplasty (TKA) resulted in worse results when compared with TKA alone. Arthroscopic debridement of IFP fibrosis has been successfully used to treat extension block following anterior cruciate ligament reconstruction, and arthroscopic anterior interval release has been an effective treatment for pain associated with anterior interval scarring. Arthroscopic resection of infrapatellar plicae and denervation of the inferior pole of the patella have also been shown to be effective treatments for refractory infrapatellar pain.

Digital Flexion Contracture and Severe Carpal Tunnel Syndrome Due to Tophaceus Infiltration of Wrist Flexor Tendon: First Manifestation of Gout

The authors report an unusual case of flexor tenosynovitis, severe carpal tunnel syndrome, and triggering at the carpal tunnel as the first manifestation of gout. A 69-year-old man presented with digital flexion contracture and severe carpal tunnel syndrome of his right hand and was treated surgically. A flexor tenosynovectomy and a median nerve neurolysis were performed through an extended carpal tunnel approach. The sublimis and the profundus tendons were involved. Partial ruptures and multiple whitish lesions suggestive of tophacceous infiltration of the flexor tendons were seen. Macroscopically, the removed synovial tissue was involved by multiple whitish nodules that were milimetric in size and was suggestive of monosodium urate crystals deposits. By light microscopy examination, numerous nonnecrotizing granulomas of different sizes were observed that were compounded by large aggregations of acellular nonpolarized material, surrounded by epithelioid histiocytes, mononuclear cells, and foreign body multinucleated giant cells. Postoperatively, the patient recovered with resolution of the median nerve symptoms and a near-to-full range of motion of the affected digits.To the authors' knowledge, this patient is the first case report with flexor tendons tophacceous infiltration as the first clinical sign of gout. Gouty flexor tenosynovitis can occur in the absence of a long history of gout. A high index of suspicion is paramount to the initiation of proper management. Operative treatment of gouty flexor tenosynovitis is mandatory to debulk tophaceous deposits, improve tendon gliding, and decompress nerves. Routine uric acid determination could be helpful in the preoperative evaluation of patients with flexor tenosynovitis.

Incomitant Strabismus

The paradigm that an "underacting" extraocular muscle is always atrophic or hypoplastic and that an overacting extraocular muscle should always be enlarged leads to inconsistencies with clinical observations. These include findings of "overacting" inferior oblique muscles, superior rectus muscle overaction or contracture syndrome, and normal extraocular muscle diameters in patients with apparent superior oblique muscle palsy, among other clinical entities. These inconsistencies can be reconciled if one accepts the possibility that extraocular muscle contractile activity may reflect a change in neural input to an anatomically normal muscle or that muscle contractile activity may be altered by shifts in fiber type and distribution within a normal-sized muscle. This remodeling may result from vergence adaptation or from any change in neural stimulus to the muscle. There is substantial evidence to suggest that both of these theoretical possibilities may likely occur.