Limb Contractures Research Articles

Identification of four TTN variants in three families with fetal akinesia deformation sequence

BackgroundTTN is a complex gene with large genomic size and highly repetitive structure. Pathogenic variants in TTN have been reported to cause a range of skeletal muscle and cardiac disorders. Homozygous or compound heterozygous mutations tend to cause a wide spectrum of phenotypes with congenital or childhood onset. The onset and severity of the features were considered to be correlated with the types and location of the TTN variants.MethodsWhole-exome sequencing was performed on three unrelated families presenting with fetal akinesia deformation sequence (FADS), mainly characterized by reduced fetal movements and limb contractures. Sanger sequencing was performed to confirm the variants. RT-PCR analysis was performed.ResultsTTN c.38,876–2 A > C, a meta transcript-only variant, with a second pathogenic or likely pathogenic variant in trans, was observed in five affected fetuses from the three families. Sanger sequencing showed that all the fetal variants were inherited from the parents. RT-PCR analysis showed two kinds of abnormal splicing, including intron 199 extension and skipping of 8 bases.ConclusionsHere we report on three unrelated families presenting with FADS caused by four TTN variants. In addition, our study demonstrates that pathogenic meta transcript-only TTN variant can lead to defects which is recognizable prenatally in a recessive manner.

Risk factors for poor outcomes in patients with acute lower leg compartment syndrome: a retrospective study of 103 cases

PurposeThe primary aim of this study was to investigate the risk factors associated with poor outcomes following acute compartment syndrome (ACS) of lower leg. The secondary objective was to determine if delayed fasciotomy is linked to poor outcomes.MethodsIn this retrospective case control study approved by the institutional review board, we identified 103 patients with ACS of the lower leg. Poor outcome was defined as a composite variable that included limb amputation, neurological deficit and contracture. Among these, 44 patients exhibited poor outcome while 59 patients demonstrated a good outcome. Patient-related factors, laboratory values, and treatment-related factors were analyzed using electronic medical records. Univariate statistical and logistic regression analyses were conducted to determine significance.ResultsBivariate analyses showed that the mechanism of injury (P = 0.021), open injury (P = 0.001), arterial injury (P<0.001), hemoglobin levels (HB) (P < 0.001), white blood cell count (WBC) (P = 0.008), albumin levels (ALB) (P<0.001), creatine kinase levels (CK) at presentation (P = 0.015), CK at peak (P<0.001), creatine kinase levels (Ca) (P = 0.004), dehydrating agent (P = 0.036), and debridement (P = 0.005) were found to be associated with the risk of poor outcomes. Logistic regression analyses revealed that arterial injury [ P< 0.001, OR = 66.172, 95% CI (10.536, 415.611)] was an independent risk factor for poor outcomes. However, HB [P = 0.005, OR = 0.934, 95% CI (0.891, 0.979)] was a protective factor against poor outcomes. Receiver operating characteristic (ROC) curve analysis showed that the cut-off values of HB to prevent poor outcome following ACS was 102.45 g/L.ConclusionsACS of the lower leg is a serious complication often associated with a poor prognosis. Patients with arterial injury or lower HB have a significantly increased risk of having poor outcomes. Poor outcomes were not found to be associated with the timing of fasciotomy in this study.

Retrograde intramedullary nailing of AO/OTA 33C femur fractures in patients with below-knee amputations: technical note and case series.

Intra-articular distal femur fractures in patients with a lower extremity amputation can present a technical challenge for the treating surgeon in what may be otherwise considered a routine procedure in non-amputees. Difficulties with positioning, fracture reduction, limb contractures, and stump osteoporosis can present challenges with treatment. Here, we describe the surgical technique and outcome of a case series of amputee patients with AO/OTA 33C femur fractures. Retrospective case series of five patients with a comminuted supracondylar distal femur fracture with intercondylar extension proximal to a below-knee amputation treated with retrograde intramedullary nail at a single Level 1 trauma center from January 1, 2021, to January 1, 2023. Baseline demographic and clinical data were recorded. Rate of bony union and complications were documented. Five patients (three females and two males) with a mean age of 48years who were treated for a comminuted supracondylar distal femur fracture with intercondylar extension proximal to a below-knee amputation were identified. At the time of final follow-up (mean 109.3days, range 29-183days), all patients had healed their incisions and were progressing to return of function with their prosthesis. All patients were treated with the surgical technique described in this article, and no postoperative complications were reported. This is an effective and safe technique for surgical treatment of comminuted intra-articular distal femur fractures in patients with an ipsilateral below-knee amputation. We believe that this technique can be utilized by any orthopedic surgeon taking trauma call and can avoid unnecessary transfers or delays to care.

A clinical study on different surgical options for management of post-burn axillary contractures

Background: Post-burn contracture is a common sequele occurring after burn. Upper limb contracture like axilla is also occurring more commonly because it is most mobile part of body and likely to involve in burn. Post-burn contracture of axilla leads to functional deficit as it limits the movement of upper extremity mainly abduction and extension. Patients with axillary contracture are unable to utilize his upper limb because he is unable to take the hand at required site. Aims and Objectives: The objective of this study was to study various operative strategies for patients presenting with post-burn axillary contracture. Materials and Methods: Twenty patients presenting with post-burn axillary contractures were taken in our study. Results: In our study of 20 patients of post-burn axillary contracture, five patients had Grade I (25%), Grade II 05 (25%), Grade III 01 (5%), and Grade IV 09 (45%) contractures. Regarding surgical procedure, Z-plasty was done in 8 patients (40%), release with skin grafting 10 patients (50%), and local flap done in 2 patients (10%). In our study, the mean degree of range of motion achieved after release of axillary contracture was 120°. In our study, 2 patients (10%) developed re-contracture, 1 patient (5%) had a graft failure while 85% of the patients had no complications. Conclusion: In the present study of 20 cases of management of post-burn axillary contracture, it is reasonable to conclude that the prevention of contracture is of utmost importance. The choice of surgical procedure for reconstruction of post-burn axillary contractures can be made according to the pattern of scar contracture and the state of the surrounding skin. The choice of a flap should have priority over the skin graft due to the superior functional and esthetic results of flaps. The results were satisfactory in our study in most cases with regard to quality of life, coverage, and range of motion.

Extracorporeal shock wave lithotripsy, ureterolithotripsy, and percutaneous nephrolithotripsy challenges in managing spinal cord neuropathy patients. Lessons learned from a scoping review.

We aim to review the outcomes of shock wave lithotripsy (SWL), ureteroscopy, and percutaneous nephrolithotripsy (PCNL) for renal and ureteral stones in spinal cord neuropathy patients (SNP). A literature search was performed on 8th March 2023 using PubMed, EMBASE, and Google Scholar with no date limit. Preclinical/animal studies, reviews, letters to the editor, case reports, and meeting abstracts were excluded. Only English papers were accepted. Thirty-five articles were accepted. Five studies focused on SWL, 17 on PCNL, and 6 on ureteroscopy. The remaining articles employed more than one procedure. Stone composition has shifted from struvite to the more common calcium phosphate. SWL showed a very poor stone-free rate (SFR) likely due to challenges in patient positioning, stone visualization, localization, and inability to pass fragments spontaneously. Flexible ureteroscopy and PCNL were associated with a high incidence of infectious complications, long hospital stays, high blood transfusion rate, and intensive care admissions. There were also cases of death. Both procedures were challenging due to genitourinary reconstruction, scoliosis and kyphosis, rib-cage deformity, lower limb contractures, and severe comorbidity which also affected anesthesia. SFR was lower than in non-neurological patients. SWL, ureterolithotripsy, and PCNL should be considered challenging procedures in SNP due to positioning issues, an increased risk of intra and peri-operative morbidity, and even mortality. Computed tomography should be recommended to assess residual fragments as it becomes imperative to minimize a re-intervention in SNP who should be preferably treated in referral centers.

The long-term neurological consequences of congenital Zika Syndrome to Zika-Infected maternal during pregnancy - A narrative review

Background. Congenital Zika Syndrome presents a significant public health concern, particularly due to its association with severe neurological complications in infants born to maternal infected with the Zika virus during pregnancy. This article offers a comprehensive overview of the risks, complications, and preventive measures associated with Zika virus infection during pregnancy. Methods. A thorough literature search was conducted, encompassing studies, case reports, and clinical observations related to neurological complications in infants with congenital Zika syndrome. The review focuses on elucidating the intricate relationship between maternal Zika virus infection and the subsequent neurological challenges faced by newborns. Results. The neurological impacts of congenital Zika syndrome are multifaceted, ranging from the well-documented microcephaly to less explored manifestations such as brain abnormalities, ventriculomegaly, intracranial calcifications, seizures, and sensory impairments. Additionally, joint and limb contractures contribute to the complexity of congenital Zika syndrome-related neurological deficits. This narrative review synthesizes current knowledge on the subject, shedding light on the diverse ways in which Zika virus infection during pregnancy can affect the developing fetal nervous system. Conclusion. Understanding the intricate neurological complications associated with congenital Zika syndrome is crucial for healthcare practitioners, researchers, and policymakers. This review provides a comprehensive overview of the current state of knowledge, emphasizing the need for continued research, surveillance, and public health interventions to mitigate the impact of the Zika virus on maternal and child health.

A novel missense variant in OTUD5 causes X-linked multiple congenital anomalies-neurodevelopmental syndrome.

The OTUD5 gene encodes a deubiquitinating enzyme (DUB) of the OTU family. Variants of OTUD5 are associated with X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND). The case described in this study expands the clinical and molecular spectrum of OTUD5. Trio-based clinical exome sequencing (trio-CES) was performed on a Chinese boy with a clinical phenotype and both of his parents. Sanger sequencing was employed for validation of the variant detected. The patient presented with characteristic facial features, intellectual disability, motor/language/cognitive, and global developmental delays, limb contractures, and kidney abnormalities, and trio-CES identified a de novo missense variant, c.1305T>A, of the OTUD5 gene. We describe OTUD5 gene variation in the Chinese population, with the first report of this variant. Additionally, we provide a comprehensive summary of all published cases of MCAND to date, in order to elucidate the primary clinical features of the syndrome and the variability in phenotype severity. This case expands the genetic and clinical phenotypic spectrum of OTUD5-associated MCAND.

Pain in Children and Adolescents with Spinal Muscular Atrophy: A Longitudinal Study from a Patient Registry.

Spinal muscular atrophy (SMA) is a devastating genetic neurodegenerative disease caused by the insufficient production of Survival Motor Neuron (SMN) protein. It presents different phenotypes with frequent contractures and dislocations, scoliosis, and pain. This study aims to report the prevalence and description of pain and how it affects daily life by analyzing a new ad hoc questionnaire. An observational study of patients under 18 years of age with SMA was conducted at two referral centers in Spain. Data were analyzed using a descriptive analysis and a Bayesian ordinal regression model to assess the association with clinical and demographic variables. Fifty-one individuals were included in this study, 27% of whom reported pain with a median duration of 5.2 years and a mean Visual Analogic Scale (VAS) score of 5. Notably, 77% were receiving disease-modifying treatment, with more than 50% receiving analgesic treatment. The Bayesian model showed that functional status, lower limb contractures, and number of visits have a high probability (>90%) of influencing pain. Thus, the prevalence of pain in the SMA population under 18 years is substantial, and its presence could be associated with lower limb contractures, better functional status, and higher RULM (Revised Upper Limb Module) scores.

New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients.

Pathogenetic mechanism recognition and proof-of-concept clinical trials were performed in our patients affected by collagen VI-related myopathies. This study, which included 69 patients, aimed to identify innovative clinical data to better design future trials. Among the patients, 33 had Bethlem myopathy (BM), 24 had Ullrich congenital muscular dystrophy (UCMD), 7 had an intermediate phenotype (INTM), and five had myosclerosis myopathy (MM). We obtained data on muscle strength, the degree of contracture, immunofluorescence, and genetics. In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion. These findings should be considered when recruiting BM patients for future trials. All the MM patients had axial and limb contractures that limited both the flexion and extension ranges of motion, and a limitation in mouth opening. The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype. However, biopsies from the same patient or from patients with the same mutation taken at different times showed a progressive increase in protein expression with age. The new finding of the time-dependent modulation of collagen VI expression should be considered in genetic correction trials.

Relative contributions of positive, negative, and adaptive features to limitations in upper-limb function three months after stroke

PurposeTo investigate the contributions of motor impairments to limitations in upper-limb function three months after stroke. DesignCross-sectional, exploratory study. MethodsDependent variable was upper-limb function, measured by the Motor Assessment Scale (MAS), which scores range from 0 to 18. Independent variables included measures of strength, dexterity, spasticity, and contracture of the paretic upper limb. Multiple linear regression analysis was employed to identify which of the independent variables could explain the MAS scores (p<0.05). Analysis was performed with the whole sample and with a sub-group of participants, who had high function (MAS≥12). ResultsSixty-nine individuals participated. Out of them, 63 had high upper-limb function. Regression analysis with the whole sample revealed that strength and dexterity were retained in the models. Together they explained 64% of the variance of the MAS scores (p<0.001), being strength the greater relative contributor. When the regression analysis included only participants with high upper-limb function, dexterity had a greater relative contribution, than strength. Together they explained 52 % of the variance (p< 0.001). ConclusionsStrength was the main contributor to upper-limb function in individuals three months after stroke. However, in individuals, who already had higher upper-limb function, dexterity showed to be the major contributor.

“Confounding Contractures” A Non-Lethal Presentation of a Lethal Disorder (P11-9.010)

<h3>Objective:</h3> N/A <h3>Background:</h3> The arthrogryposes are a group of non-progressive conditions characterised by multiple joint contractures at birth. They are a heterogenous group of disorders with multiple neurogenic, myopathic and connective tissue aetiologies. The Lethal Congenital Contracture Syndromes (LCCS) are a rare cause of arthrogryposis and are associated with significant perinatal pulmonary abnormalities such as pulmonary hypolasia and high mortality in the neonatal period. <h3>Design/Methods:</h3> We report the case of a 25 year old female who presented at birth with multiple lower limb contractures, bilateral talipes and hip fractures/dislocations. There was no evidence of any cardiorespiratory compromise in the neonatal period. The patient’s early life was dominated by extensive orthopaedic interventions for lower limb contractures and scoliosis, but she had an otherwise unremarkable development with no evidence of cardiac or pulmonary complications and no evidence of intellectual disability. There was a history of an early neonatal death in a brother with a similar phenotype, however no underlying cause was established. Examination demonstrated areflexia but no discernible weakness. <h3>Results:</h3> A muscle biopsy at 3 months showed non-specific myopathic features, but was normal on repeat biopsy aged 21. EMG showed subtle chronic myopathic features. Targeted genetic analysis with congenital myopathy and arthrogryposis panel was unrevealing. Proceeding to whole exome sequencing revealed a homozygous pathogenic variant in the GLDN gene, confirming the diagnosis of Lethal Congenital Contracture Syndrome type 11. <h3>Conclusions:</h3> Despite the diagnosis, which is commonly fatal in the neonatal period, the patient has survived well into adulthood and functioning at a high level independently with no evidence of any pulmonary complications. This highlights a previously unreported case of an adult patient with LCCS 11 without evidence of respiratory compromise, while also highlighting the value of broad genetic testing in this cohort. <b>Disclosure:</b> Dr. Mullane has nothing to disclose. Dr. Donlon has nothing to disclose. Dr. Smyth has nothing to disclose.

FACTORS FAVORING PREFERENCE OF ARTERIOGRAPHY OVER CT ANGIOGRAPHY FOR PERIPHERAL ARTERIAL DISEASE EVALUATION

Despite many advances in the quality and availability of less invasive arterial imaging modalities, arteriography remains the “gold standard.” This is a Prospective study which analyzes the factors favoring the preference of DSA over CTA in patients with peripheral vascular disease. Those patients with peripheral vascular disease undergoing DSA, who were initially planned for CTA and could not undergo CTA for various reasons were included. This study consists of 38 patients with most of them were males 29 (76%). In our study common factor for referral over CTA was renal dysfunction patients 18 out of 38 ( 47%), as contrast required in standard CTA for lower limb runoff is around 100ml and in our DSA average volume required is only 30ml because of target lesion arteriography with magnication. Next common factor was presence of heavy calcications in tibial vessel walls which hampers the evaluation of the CTA who were 37% of our study patients (14). Other factors were severe congestive Cardiac Failure, Previous Bone Plating/Nailing in leg bones and limb Contracture. With increasing incidences of diabetic patients with their associated diabetic nephropathy and heavy calcicated arteries, makes these patients more preferred for DSA than CTA due to its low contrast dose requirements and images free of calcication artefacts

Arthrogryposis Multiplex Congenita (AMC): Functional Improvement of a Seven-Year-Old Girl after 3 Years of Physical Medical Rehabilitation Intervention

Arthrogryposis multiplex congenita (AMC) is a genetic disease typified by non-progressive and multiple congenital limb contractures. The incidence of AMC is 1 in 3,000 live births, occurring in two or more areas of the body. The etiology of the syndrome is largely unknown and is multifactorial. The aim of this article is to report a patient diagnosed with arthrogryposis multiplex congenita who received physical medical rehabilitation intervention. We report a seven-year-old girl who frequently had symptoms of joint deformities, movement limitation, and walking difficulties. The patient's fingers and toes also had muscle hypoplasia and pterygium. She was diagnosed with arthrogryposis when she was born. Several surgical interventions had been performed. Since four years old the patient started the physical medical rehabilitation programs. Owing to the integrated orthopedic and medical rehabilitation therapy, it showed some improvements. The patient could walk by holding onto a bench and eat or drink by herself. The patient had obtained the daily living exercises using the correct compensation technique using modified tools. Physical medical rehabilitation programs can improve the functional condition of AMC patients. The goals of a physical medical rehabilitation treatment are to gain the walking ability and improve the ability to independently perform activities of daily living. Stretching exercises, ROM exercises, splints, modified tools, and orthopedic surgery are essential for arthrogryposis patients.

Does patient's position count during Endoscopic Retrograde Cholangio-pancreatography? Left lateral decubitus versus prone position.

To compare the efficacy and safety of left lateral decubitus versus prone position during endoscopic retrograde cholangio-pancreaticography (ERCP). This prospective single-centre cohort study was carried out at Pak Emirates Military Hospital from January to June 2021. Patients requiring ERCP were subsequently allotted LL or PP group randomly (unequal randomization) except patients with recent abdominal surgery, in-dwelling catheters, raised intra-abdominal pressure, cervical spine abnormalities and limb contractures. Qualitative data was analysed using frequencies and chi square statistics whereas, quantitative data was analysed using mean±SD and student T or Mann Whitney U-test. A total of 114 patients were enrolled according to the inclusion criteria with 62(54%) males and majority of the patients (42%) belonging to the age group 31-45 years. The most common ERCP indication was choledocholithiasis (36%). Technical success was achieved in 109(96%) patients with no statistically significant difference between the two groups. The total time of procedure, time for deep cannulation, time for acquiring therapeutic goal and ERCP complexity level were all similar between the two groups. The rate of inadvertent PD cannulation and PEP were relatively higher for the PP group but were statistically non-significant through univariate and logistic regression analyses and the only outcome measure that showed significance was multiple cannulations in the PP group. The study concludes that LL is non-inferior to PP and both positions have comparable outcomes with non-significant differences in terms of technical success rate, complications (specifically PEP), total procedure time, time required for deep cannulation and attainment of goal, ERCP complexity level and inadvertent PD cannulation.

Elementary mechanisms underlying activation of leak sodium channels.

The sodium-leak channel (NALCN) are weakly voltage-dependent ion channels responsible for background Na+ permeability that controls resting membrane potential in neurons and other excitable cells. Although homologous to voltage-gated Na+ and Ca2+ channels, NALCN is distinct in associating with auxiliary subunits FAM155A, UNC-79, and UNC-80 which augment its function. Precise regulation of this channel's activity is physiologically crucial, as gain of function mutations in humans lead to severe congenital neurodevelopmental disorders in humans, including infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) and congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD). Here we performed cell-attached low noise single-channel recordings to dissect elementary properties of NALCN gating. Expression of NALCN with its canonical subunits revealed a largely non-selective channel with ∼27 pS conductance and a reversal potential of ∼5.7 mV. Scrutiny of single channel recordings showed distinct gating modes and low open probabilities. As extracellular Ca2+ block of NALCN is fundamental to its physiological function, we further probed underlying single channel mechanisms. In all, these results provide a framework to establish regulatory mechanisms in physiology and to contextualize altered channel function in pathophysiology.

Distal arthrogryposis in a girl arising from a novel TNNI2 variant inherited from paternal somatic mosaicism.

TNNI2 at 11p15.5 encodes troponin I2, fast skeletal type, which is a member of the troponin I gene family and a component of the troponin complex. Distal arthrogryposis (DA) is characterized by congenital limb contractures without primary neurological or muscular effects. DA is inherited in an autosomal dominant fashion and is clinically and genetically heterogeneous. Exome sequencing identified a causative variant in TNNI2 [NM_003282.4:c.532T>C p.(Phe178Leu)] in a Japanese girl with typical DA2b. Interestingly, the familial study using Sanger sequencing suggested a mosaic variant in her healthy father. Subsequent targeted amplicon-based deep sequencing detected the TNNI2 variant with variant allele frequencies of 9.4-17.7% in genomic DNA derived from peripheral blood leukocytes, saliva, hair, and nails in the father. We confirmed a disease-causing variant in TNNI2 in the proband inherited from her asymptomatic father with its somatic variant. Our case demonstrates that careful clinical and genetic evaluation is required in DA.

THE ULTRASONOGRAPHY EXAMINATION OF SKELETAL MUSCLES IN TRAUMATIC ISCHEMIA (EXPERIMENTAL STUDY).

The aim: To establish indicators and significance of sonography in the evaluation of muscle necrosis in ischemia of the limb acording to quantitative ultrasonographic indicators and density of collagen by histological method. Materials and methods: In experiments, rabbits modeled with 6-hour limb ischemia by applying an elastic tourniquet. On days 5, 15, and 30, ultrasound and histological studies of the muscles and correlation analysis were performed between the muscles' entropy and the degree of their damage (atrophy, fibrosis and necrosis). Results: The relative amount of structurally altered tissue was estimated morphometrically and compared with entropy. A high correlation of muscle damage with vertical δ-entropy indicates that sonography is highly likely to detect areas of necrosis and, to a lesser extent, fibrosis in the development of ischemic limb contracture in the early stages. Conclusions: Vertical δ-entropy in sonography is a significant indicator of muscle damage after traumatic ischemia and has strong relationship with muscle fibrosis.

OA25 Constitutional trisomy 8 mosaicism is associated with a paediatric incomplete Bechet’s-like phenotype

Introduction/BackgroundBehcet’s disease is a rare paediatric diagnosis and to date there is no single confirmatory gold-standard test or approach. Instead, decisions are clinician-led based on experience, pattern recognition and categorisation according to international criteria. Diagnostic dilemmas arise when patients present at early ages with an incomplete or atypical phenotype. Such cases should prompt clinicians to consider Bechet-like mimics with emphasis of monogenetic and chromosomal causes in younger children.Description/MethodA 5-year-old boy with constitutional Trisomy 8 mosaicism was referred to a Bechet’s disease National Centre of Excellence paediatric clinic with cyclical episodes of fever, mouth ulcers, pseudofolliculitis and headaches.During the initial outpatient assessment period (6-12 months) symptoms were reported every 2-3 months and would last for around 1-2 weeks at a time. Physical examination and a photo diary reveal oral ulcers and rashes. He had pre-existing skeletal dysmorphism with severe pectus carinatum, scoliosis and widespread limb contractures secondary to Trisomy 8. Serial blood testing around episodes showed an associated inflammatory response.Although his phenotype was incomplete; with evidence of recurrent autoinflammation a trial of immunosuppression with colchicine was commenced. He displayed a dose-dependent improvement as evidenced by reduction in the frequency and severity of episodes.His Behcet’s-like disease remains well controlled and to date there has been no amyloidosis, ocular, gastrointestinal or cardiovascular complications.Discussion/ResultsBehcet’s disease is a multisystem chronic vasculitis presenting with widespread mucosal involvement occurring in a relapsing-remitting fashion. Classic manifestations are recurrent sterile aphthous ulcers, genital ulcers, mucosal eye involvement and a positive Pethargy test.It usually presents with all of these classic features by the 3rd or 4th decade of life; children can be affected but usually present with paucity of symptoms not reaching diagnostic criteria. As such, the accumulation of symptoms during a follow-up period may lead to a diagnostic lag of around 3-5 years. The young age of this patient therefore raised clinical suspicion for an alternative diagnosis.The aetiology of Bechet’s disease has elucidated rheumatologists since the first description in 1937. An association with HLA-B51 antigen is well documented but not fully understood. The advent of widely available next-generation genetics provides important clues to its aetiology and helps delineate monogenic and chromosomal mimics. To date 21 genetic loci have been identified through genome-wide association studies and least 11 monogenic and chromosomal mimics been described in the literature.Constitutional Trisomy 8 mosaicism has been shown to be a chromosomal-driven mimic of Behcet disease. It is rare (1-25.000 to 1-50.000 live births) with a 5:1 male predilection; those affected present with a spectrum of abnormal facies, vertebral and limb anomalies including contractures.Interestingly a similar Bechet-like disease is also seen in patients who acquire Trisomy 8 mosaicism in cells affected by myeloid malignancies. Such cases are more numerous and predate those associated with the constitutional form.The final common pathogenesis is thought to be activation of the NF-κB pathway. Reports postulate overexpression of several cytokine genes, production of proinflammatory cytokines and reactive oxygen species. The exact pathogenesis is not fully understood, further research may reveal clues to understanding both Constitutional Trisomy 8 mosaicism and Behcet Disease.Key learning points/ConclusionLearning points:1. Consider monogenic and chromosomal Behcet Disease mimics in those patients who present at young ages or at any time with atypical or incomplete features.2. Our patient with Constitutional Trisomy 8 Mosaicism with Behcet-like disease showed a dose-dependent improvement with colchicine.

Amelioration of muscle and nerve pathology of Lama2-related dystrophy by AAV9-laminin-αLN linker protein.

LAMA2 deficiency, resulting from a defective or absent laminin α2 subunit, is a common cause of congenital muscular dystrophy. It is characterized by muscle weakness from myofiber degeneration and neuropathy from Schwann cell amyelination. Previously it was shown that transgenic muscle-specific expression of αLNNd, a laminin γ1–binding linker protein that enables polymerization in defective laminins, selectively ameliorates the muscle abnormality in mouse disease models. Here, adeno-associated virus was used to deliver linker mini-genes to dystrophic dy2J/dy2J mice for expression of αLNNd in muscle, or αLNNdΔG2′, a shortened linker, in muscle, nerve, and other tissues. Linker and laminin α2 levels were higher in αLNNdΔG2′-treated mice. Both αLNNd- and αLNNdΔG2′-treated mice exhibited increased forelimb grip strength. Further, αLNNdΔG2′-treated mice achieved hind limb and all-limb grip strength levels approaching those of WT mice as well as ablation of hind limb paresis and contractures. This was accompanied by restoration of sciatic nerve axonal envelopment and myelination. Improvement of muscle histology was evident in the muscle-specific αLNNd-expressing mice but more extensive in the αLNNdΔG2′-expressing mice. The results reveal that an αLN linker mini-gene, driven by a ubiquitous promoter, is superior to muscle-specific delivery because of its higher expression that extends to the peripheral nerve. These studies support a potentially novel approach of somatic gene therapy.

Sequence of flexion contracture development in the lower limb: a longitudinal analysis of 1,071 children with cerebral palsy

BackgroundTo prevent severe contractures and their impact on adjacent joints in children with cerebral palsy (CP), it is crucial to treat the reduced range of motion early and to understand the order by which contractures appear. The aim of this study was to determine how a hip–knee or ankle contracture are associated with the time to and sequence of contracture development in adjacent joints.MethodsThis was a longitudinal cohort study of 1,071 children (636 boys, 435 girls) with CP born 1990 to 2018 who were registered before 5 years of age in the Swedish surveillance program for CP and had a hip, knee or ankle flexion contracture of ≥ 10°. The results were based on 1,636 legs followed for an average of 4.6 years (range 0–17 years). The Cox proportional-hazards model adjusted for Gross Motor Function Classification System (GMFCS) levels I–V was used to compare the percentage of legs with and without more than one contracture.ResultsA second contracture developed in 44% of the legs. The frequency of multiple contractures increased with higher GMFCS level. Children with a primary hip or foot contracture were more likely to develop a second knee contracture. Children with a primary knee contracture developed either a hip or ankle contracture as a second contracture.ConclusionsMultiple contractures were associated with higher GMFCS level. Lower limb contractures appeared in specific patterns where the location of the primary contracture and GMFCS level were associated with contracture development in adjacent joints.