A variant in the LDL receptor-related protein encoding gene LRP4 underlying polydactyly and phalangeal synostosis in a family of Pakistani origin.

A family of Pakistani origin, segregating polydactyly, and phalangeal synostosis in an autosomal dominant manner, has been investigated and presented in the present report. Whole-exome sequencing (WES), followed by segregation analysis using Sanger sequencing, revealed a heterozygous missense variant [c.G1696A, p.(Gly566Ser)] in the LRP4 gene located on human chromosome 11p11.2. Homology protein modeling revealed the mutant Ser566 generated new interactions with at least four other amino acids and disrupted protein folding and function. Our findings demonstrated the first direct evidence of involvement of LRP4 in causing polydactyly and phalangeal synostosis in the same family. This study highlighted the importance of inclusion of LRP4 gene in screening individuals presenting polydactyly in hands and feet, and phalangeal synostosis in the same family.

Surgical Removal of Bone Bridge and Interposition of the Extensor Digitorum Brevis in the Treatment of Calcaneonavicular Coalition in Pediatric Patients: A Case Series, Short Review, and Commentary.

This study retrospectively presents a single-clinic case series of pediatric patients with calcaneonavicular coalition treated by surgical removal of the bone bridge and interposition of the extensor digitorum brevis. This technique is currently the most cited and utilized protocol in operative treatment. Clinical, functional, and radiological results are analyzed and compared with related research. This is a single-clinic retrospective study, conducted for a period of 15 years. One independent investigator reviewed medical records and conducted a de-identified preoperative, inpatient, and postoperative assessment focused on demographic data, history and clinical evaluation, imaging assessment, American Orthopedic Foot and Ankle Society (AOFAS) scoring, and complication analysis. Of 34 patients, 13 met the inclusion criteria. Mean patient age was 11.2 years; 10 were males and 3 were females. Pathology concerned the right lower limb in eight cases and the left in five. Mean time between diagnosis and surgical intervention was 4.3 months and mean postoperative follow-up was 27.2 months. Thorough overview of reported symptoms, identified signs, imaging evaluation, functional outcomes, and adverse effects was performed. Bone bridge removal and interposition of the extensor digitorum brevis is an effective method of treating the condition. Despite drawbacks, results are comparable or even, to some degree, superior to other techniques.

Measurement of compensatory wrist joint rotation using three-dimensional motion analysis in patients with unilateral proximal congenital radioulnar synostosis.

OBJECTIVE: This study aims to investigate compensatory rotational movements of the wrist joint in patients with proximal congenital radioulnar synostosis (CRUS), using a valid and reliable three-dimensional (3D) motion analysis technique. METHODS: A total of 26 patients (6 females, 14 males; mean age=15.3 years; and age range=6-32 years) who were diagnosed with unilateral proximal CRUS but were not operated were enrolled in this study. Patients were then categorized into 2 groups: Group I included 5 patients younger than 10 years, and Group II included 15 patients older than 10 years. Eighteen light-reflective skin markers were placed on the bony landmarks of both upper limbs, and both distal forearms were fixed using a U-shaped device to minimize forearm rotation. Each patient grasped the handle of an instrument that used a goniometer to measure wrist rotation; maximal passive pronation and supination angles of the wrist were measured in this manner and also using 3D motion analysis. RESULTS: There was a significant correlation between measurements by the goniometer and 3D motion analysis (r=0.985, p<0.001). The test-retest reliability of the 3D motion analysis was acceptable for both the affected side (ICC=0.992) and the contralateral normal side (ICC=0.997) with low standard measurement errors (1.3° and 0.8°, respectively). Although no significant difference was observed in the range of the wrist rotation between the affected and contralateral sides in Group I (p=0.686), there was a significant difference in the wrist rotation between the affected and contralateral sides in Group II (p=0.001). Further, the pronation angle of the wrist joint was significantly larger in the affected side than that in the contralateral normal side in Group II (p=0.001). CONCLUSION: The 3D motion analysis technique seems to be a valid and reliable method to measure the rotation of the wrist joint. Unilateral proximal CRUS patients older than 10 years of age may develop rotational hypermobility of the wrist joint compared to the contralateral normal side as a compensatory phenomenon. LEVEL OF EVIDENCE: Level III, Diagnostic Study.

Musculoskeletal abnormalities in a large international cohort of boys with 49,XXXXY.

49,XXXXY is the rarest X and Y chromosomal variation, with an incidence of 1 in 80,000-100,000 live male births and has been associated with numerous musculoskeletal abnormalities. Data was collected from an international cohort of boys with 49,XXXXY over 10 years. Children were evaluated by a multidisciplinary team consisting of a pediatric orthopedist, a neurogeneticist, a neurodevelopmentalist, and two physical therapists. Increased rates of torticollis (32.4%), hamstring tightness (42%), radioulnar synostosis (67.6%), pes planus (65.2%), and other foot abnormalities (86.9%) were observed. Several anomalies increased with age, specifically hamstring tightness, kyphosis, and scoliosis. The elucidation of the orthopedic profile of this population is necessary in order to provide healthcare providers with current medical information. This research further supports the necessity for the comprehensive multidisciplinary treatment of boys with 49,XXXXY.

Post-traumatic proximal radioulnar synostosis: results of surgical treatment and review of the literature.

BACKGROUND: Post-traumatic proximal radioulnar synostosis is a very rare and disabling condition whose surgical treatment has traditionally been viewed with pessimism. The results of the few case series in the literature are conflicting. Our aims were (1) to describe the clinical results of a case series treated surgically by a single elbow surgeon and (2) to review the literature. METHODS: Twelve patients were evaluated. Preoperative radiographs and computed tomography scans were performed. According to the Viola and Hastings classification, there was 1 case of type IC synostosis; 3, type IIA; 2, type IIIA; and 8, type IIIB. Two patients had a double synostosis. The synostosis was excised in 10 cases; in addition, radial head excision, radial head arthroplasty, and proximal radial diaphyseal resection were performed in 1, 3, and 2 cases, respectively. The Mayo Elbow Performance Score, modified American Shoulder and Elbow Surgeons score, and QuickDASH (short version of Disabilities of the Arm, Shoulder and Hand questionnaire) score were used for the preoperative and postoperative evaluation. The nonparametric Wilcoxon signed rank test was used for the statistical analysis. RESULTS: The mean follow-up period was 20.5 months. The final mean extension-flexion and pronation-supination arcs were 116° and 123°, respectively. Significant improvements were found in the Mayo Elbow Performance Score (P = .005), modified American Shoulder and Elbow Surgeons score (P = .012), and QuickDASH score (P = .002), with mean values of 24, 28, and 17, respectively. One synostosis recurrence and one late disassembly of the radial head arthroplasty were observed. CONCLUSIONS: Post-traumatic proximal radioulnar synostosis surgery is effective, but careful preoperative planning based on the pathoanatomic characteristics of each type of synostosis and associated lesions is mandatory. Synostosis excision is performed in most cases, whereas additional surgical procedures should be considered in selected cases.

H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome.

BACKGROUND: Structural variants (SVs) affecting non-coding cis-regulatory elements are a common cause of congenital limb malformation. Yet, the functional interpretation of these non-coding variants remains challenging. The human Liebenberg syndrome is characterised by a partial transformation of the arms into legs and has been shown to be caused by SVs at the PITX1 locus leading to its misregulation in the forelimb by its native enhancer element Pen. This study aims to elucidate the genetic cause of an unsolved family with a mild form of Liebenberg syndrome and investigate the role of promoters in long-range gene regulation. METHODS: Here, we identify SVs by whole genome sequencing (WGS) and use CRISPR-Cas9 genome editing in transgenic mice to assign pathogenicity to the SVs. RESULTS: In this study, we used WGS in a family with three mildly affected individuals with Liebenberg syndrome and identified the smallest deletion described so far including the first non-coding exon of H2AFY. To functionally characterise the variant, we re-engineered the 8.5 kb deletion using CRISPR-Cas9 technology in the mouse and showed that the promoter of the housekeeping gene H2afy insulates the Pen enhancer from Pitx1 in forelimbs; its loss leads to misexpression of Pitx1 by the pan-limb activity of the Pen enhancer causing Liebenberg syndrome. CONCLUSION: Our data indicate that housekeeping promoters may titrate promiscuous enhancer activity to ensure normal morphogenesis. The deletion of the H2AFY promoter as a cause of Liebenberg syndrome highlights this new mutational mechanism and its role in congenital disease.

Synostosis of the first and second ribs in six horses.

CASE DESCRIPTION Over a 2-year period, 6 horses (4 Selle Français, 1 Hanoverian, and 1 Thoroughbred) were referred for evaluation of forelimb lameness. All horses had radiographic evidence of synostosis of the first and second ribs (SFSR). CLINICAL FINDINGS For 1 horse, the SFSR was considered the probable cause of the lameness (grade 3/5), with a shortening of the cranial phase of the stride in the affected limb. For 3 horses, it was considered a possible cause of the lameness (grade 1/5) for the same reason. For 2 horses, SFSR was considered an incidental finding unassociated with any clinical signs. The 4 horses with lameness suspected as attributable to SFSR had a moderate to severe amount of irregularly marginated new bone formation at the site of the SFSR, with a cranial displacement of the first rib, compared with findings for the 2 horses in which the SFSR was considered incidental. A likely congenital abnormality of the first rib was first suspected on nuclear scintigraphy in the 1 horse for which it was performed or on radiography of the caudal cervical portion of the vertebral column (3 horses) or shoulder joint (2 horses). TREATMENT AND OUTCOME The horse in which SFSR was considered the probable cause of the lameness was retired to the field and remained chronically lame. Two of the 3 horses in which SFSR was considered a possible cause of lameness received an IV infusion of tiludronate disodium and mesotherapy over the caudal cervical and cranial thoracic regions; both returned to competition but with poor results. One of the 2 horses with subclinical SFSR never developed lameness on the affected side. No follow-up information was available for the other 2 horses. CLINICAL RELEVANCE SFSR can be an incidental finding in horses, with or without clinical manifestations. This abnormality should be considered as a differential diagnosis for horses with forelimb lameness and associated shortening of the cranial phase of the stride that fails to improve with diagnostic analgesic techniques.

Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB.

The location and/or type of variants in FLNB result in a spectrum of osteochondrodysplasias ranging from mild forms, like spondylocarpotarsal synostosis syndrome and Larsen syndrome, to severe perinatal lethal forms, such as atelosteogenesis I and III and Boomerang dysplasia. Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones. Biallelic loss-of-function variants in FLNB are known to cause spondylocarpotarsal synostosis syndrome and 9 families and 9 pathogenic variants have been reported so far. We report clinical features of 10 additional patients from 7 families with spondylocarpotarsal synostosis syndrome due to 7 novel deleterious variants in FLNB, thus expanding the clinical and molecular repertoire of spondylocarpotarsal synostosis syndrome. Our report validates key clinical (fused thoracic vertebrae and carpal and tarsal coalition) and molecular (truncating variants in FLNB) characteristics of this condition.

Further delineation of the GDF6 related multiple synostoses syndrome.

A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6-related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6-related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP-inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6-related multiple synostoses syndrome.

FGF9 mutation causes craniosynostosis along with multiple synostoses.

Craniosynostosis is commonly caused by mutations in fibroblast growth factor receptors (FGFRs), highlighting the essential role of FGF-mediated signaling in skeletal development. We set out to identify the molecular defect in a family referred for craniosynostosis and in whom no mutation was previously detected. Using next-generation sequencing, we identified a novel missense mutation in FGF9. Modeling based upon the crystal structure and functional studies confirmed its pathogenicity showing that it impaired homodimerization and FGFR3 binding. Only one FGF9 mutation has been previously reported in a multigeneration family with multiple synostoses (SYNS3) but no signs of craniosynostosis. In contrast, our family has a greater phenotypic resemblance to that observed in the Fgf9 spontaneous mouse mutant, elbow-knee-synostosis, Eks, with both multiple synostoses and craniosynostosis. We have demonstrated for the first time that mutations in FGF9 cause craniosynostosis in humans and confirm that FGF9 mutations cause multiple synostoses.

A 590 kb deletion caused by non-allelic homologous recombination between two LINE-1 elements in a patient with mesomelia-synostosis syndrome.

Mesomelia-synostoses syndrome (MSS) is a rare, autosomal-dominant, syndromal osteochondrodysplasia characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations due to a non-recurrent deletion at 8q13 that always encompasses two coding-genes, SULF1 and SLCO5A1. To date, five unrelated patients have been reported worldwide, and MMS was previously proposed to not be a genomic disorder associated with deletions recurring from non-allelic homologous recombination (NAHR) in at least two analyzed cases. We conducted targeted gene panel sequencing and subsequent array-based copy number analysis in an 11-year-old undiagnosed Japanese female patient with multiple congenital anomalies that included mesomelic limb shortening and detected a novel 590 Kb deletion at 8q13 encompassing the same gene set as reported previously, resulting in the diagnosis of MSS. Breakpoint sequences of the deleted region in our case demonstrated the first LINE-1s (L1s)-mediated unequal NAHR event utilizing two distant L1 elements as homology substrates in this disease, which may represent a novel causative mechanism of the 8q13 deletion, expanding the range of mechanisms involved in the chromosomal rearrangements responsible for MSS.

Transtibial Amputation Outcomes Study (TAOS): Comparing Transtibial Amputation With and Without a Tibiofibular Synostosis (Ertl) Procedure.

The optimal technique for a transtibial amputation in a young, active, and healthy patient is controversial. Proponents of the Ertl procedure (in which the cut ends of the tibia and fibula are joined with a bone bridge synostosis) argue that the residual limb is more stable which confers better prosthetic fit and improved function especially among high-performing individuals. At the same time, the Ertl procedure is associated with longer operative and healing time and may be associated with a higher complication rate compared with the standard Burgess procedure. The TAOS is a prospective, multicenter randomized trial comparing 18-month outcomes after transtibial amputation using the Ertl versus Burgess approach among adults aged 18 to 60. The primary outcomes include surgical treatment for a complication and patient-reported function. Secondary outcomes include physical impairment, pain, and treatment cost.

Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies.

Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. Mutations in filamin B (FLNB) and MYH3 have been reported for autosomal-recessive and autosomal-dominant SCT, respectively. We present a family with two patients suffering from autosomal-recessive SCT with rib anomalies, including malalignment, crowding, and uneven size and shape of ribs. Whole-exome sequencing revealed a novel p.S2542Lfs* 82 (c.7621dup) frameshift mutation in FLNB. This frameshift mutation lies in the C-terminal-most domain involved in FLNB dimerization and resulted in a 20-residue elongation, with complete familial segregation and absence in 376 normal controls. The mutant p.S2542Lfs* 82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells. The p.S2542Lfs* 82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus. This is the first identified mutation in the dimerization domain of FLNB. This loss-of-function frameshift mutation in FLNB causes autosomal-recessive SCT with rarely reported rib anomalies. This report demonstrates the involvement of rib anomaly in SCT and its causative mutation in the dimerization domain of FLNB.

A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGFß signaling and cause autosomal dominant spondylocarpotarsal synostosis.

Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in the gene that encodes the cytoskeletal protein filamin B (FLNB), but a subset do not have FLNB mutations. Exome sequence analysis of three SCT patients negative for FLNB mutations identified an autosomal dominant form of the disease due to heterozygosity for missense or nonsense mutations in MYH3, which encodes embryonic myosin. Cells transfected with the MYH3 missense mutations had reduced TGFß signaling, revealing a regulatory role for embryonic myosin in the TGFß signaling pathway. In wild-type mice, there was persistent postnatal expression of embryonic myosin in the small muscles joining the neural arches of the spine suggesting that loss of myosin function in these muscles contribute to the disease. Our findings demonstrate that dominant mutations in MYH3 underlie autosomal dominant SCT, identify a postnatal role for embryonic myosin and suggest that altered regulation of signal transduction in the muscles within the spine may lead to the development of vertebral fusions.

Distal tibiofibular synostosis after surgically resolved ankle fractures: An epidemiological, clinical and morphological evaluation of a patient sample.

INTRODUCTION: Ankle fractures comprise a highly morphologically and etiologically diverse group of injuries, which includes various degrees of impairment of bone and ligamentous structures. The complete synostosis and incomplete bony bridging of tibiofibular syndesmosis are among the local late complications after surgically treated ankle fractures. PATIENTS AND METHOD: 269 patients were evaluated, including 203 patients with Weber type-B fractures, and 66 patients with Weber type-C fractures. All patients underwent ankle radiography at standard intervals (post-operatively, 6 and 12 weeks, 6 and 12 months). The final assessment one year after osteosynthesis was performed. The study analyzed age, sex, fracture morphology, the location and morphology of ossification, functional outcomes and subjective evaluations of patient status. RESULTS: As risk factors there were found male sex, tibiotalar dislocation, syndesmotic screw fixation and Weber type-C fractures. The severity of subjective difficulties and objective status were not dependent on the size of distal tibiofibular synostosis. DISCUSSION AND CONCLUSION: Despite relatively extensive imaging findings of complete synostosis or incomplete bony bridging, they only limited functional outcomes to a minimal extent.