MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells.

Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1-deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1-deficient SSPCs adopted a fibrotic fate, NF1-deficient Schwann cells produced critical paracrine factors including transforming growth factor-ß and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1-deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.

MRI quantitative muscle characterization in children with X-linked hypophosphatemia.

INTRODUCTION: Children with X Linked Hypophosphatemia (XLH) suffer from carential ricket, bone deformities and lameness. No previous study demonstrated a morphological distinction in muscles in these patients. The aim of this prospective study was to characterize, using Magnetic Resonance Imaging (MRI), the muscle morphology of pelvis, thigh and leg in children with XLH and to compare it with typically developed (TD) children. HYPOTHESIS: We hypothesized that lower limbs muscles in children with XLH are different from TD children and could explain limp walking. MATERIAL AND METHODS: Three-dimensional reconstructions of the muscles were performed in 11 patients with XLH and 15 TD children. Muscle lengths, sections and volumes were calculated and normalized with height and weight. Mean age was 10. RESULTS: Lengths were all smaller in children with XLH except for the Medius/minimus gluteus muscles (p=0.64). The difference seemed higher in muscles with a long tendinous part as semitendinosus (0.139 vs 0,164; p<0.01). All volumes were significantly inferior in children with XLH. This preliminary study showed significant differences in muscle structures between patients with XLH and TD children. DISCUSSION: Medius/minimus gluteus seemed to be particularly developed in children with XLH. Nevertheless it is not possible to conclude if it is related to XLH or a consequence of bone deformities. LEVEL OF PROOF: IV.

Results of talectomy for inveterate or recurrent clubfoot.

INTRODUCTION: The aim of the present study was to define indications for talectomy in congenital paralytic, dystrophic or idiopathic, inveterate or recurrent, clubfoot. HYPOTHESIS: Talectomy is a valid option for paralytic, dystrophic or idiopathic, inveterate or recurrent, clubfoot. PATIENTS AND METHODS: A single-center retrospective series comprised 52 clubfeet in 31 patients. Etiology was paralytic in 34 feet (65%) (17 arthrogryposes, 10 myelomeningoceles, 4 encephalopathies, 3 peripheral neuropathies), dystrophic in 6 (12%) and idiopathic in 12 (23%). In 27 feet, there was history of surgery (52%). Mean age at talectomy was 4.7 years. In 45 feet (87%), there were associated procedures (soft-tissue release, tendon surgery, calcaneal or lateral arch osteotomy, tibiocalcaneal fusion) and talectomy was isolated in 7 feet (13%). Mean follow-up was 9 years. Final assessment was based on the modified Ghanem and Seringe classification (G&S) and the Ankle-Hindfoot Scale (AHS). RESULTS: All feet required at least one complementary procedure, either in the same step or as revision. Revision surgery was performed in 17 cases (33%), including all 7 feet with isolated talectomy (7 calcaneal tendon lengthenings, 10 mid- or hind-foot osteotomies, 6 tibiocalcaneal fusions, one calcaneocuboid fusion, and 2 progressive corrections by external fixator). Finally, 33 feet (63%) had good G&S results, 44 (85%) were pain-free, and 40 (77%) were plantigrade. DISCUSSION: Talectomy for paralytic or dystrophic inveterate or recurrent clubfoot provided satisfactory medium-term results. Associated to other procedures, it achieves a pain-free plantigrade foot in most cases. Tibiocalcaneal fusion has an analgesic effect. Talectomy may, however, not be indicated in idiopathic clubfoot, given the patients' high functional demand and the existence of alternative treatments. LEVEL OF EVIDENCE: IV, retrospective series.

Quantitative analysis of lower limb and pelvic deformities in children with X-linked hypophosphatemic rickets.

INTRODUCTION: X-linked hypophosphatemia (XLH) rickets mainly causes leg deformities in children that can worsen as they grow. We hypothesized that quantifying the bone parameters will help to document and monitor these deformities in children with XLH. METHODS: Thirty-five growing children affected by XLH were included in this cross-sectional study. Biplanar radiographs were taken with an EOS system allowing three-dimensional (3D) reconstructions of the pelvis and legs. Sixteen geometric parameters were calculated for the legs and pelvis. A control group of 40 age-matched patients was used to define the reference values for these geometric parameters. RESULTS: For the legs, significant differences (p<0.05) appeared between the XLH patients and the control group in the neck-shaft angle, femur/tibia length ratio and HKS. Among the 70 legs in the XLH group, 23 were in genu varum, 25 were in genu valgum and 22 were straight. There were significant differences between the genu varum and genu valgum subgroups in the femoral mechanical angle and the HKS. A strong correlation was found between the femoral mechanical angle and femorotibial angle (r2=0.73) and between the femoral mechanical angle and HKS (r2=0.69) The sacral slope and acetabular anteversion were significant different from the reference values. DISCUSSION: Quantitative radiological parameters derived from 3D reconstructions show that the deformities in XLH patients are (1) mainly in - but not limited to - the femoral shaft; (2) highly variable from one person to another. Some of these radiological parameters may be useful for the diagnosis and monitoring of XLH patients. LEVEL OF EVIDENCE: III; case control study.

Well though-out introduction of percutaneous Achilles tenotomy during functional treatment of congenital talipes equinovarus: Which indications produce the best results?

INTRODUCTION: Percutaneous Achilles tenotomy (PAT) was recently added to functional treatment of congenital talipes equinovarus (aka clubfoot). The aim of this study was to determine the relevance of a carefully chosen radiological criterion for the PAT indication and to evaluate its results. HYPOTHESIS: When the tibiocalcaneal angle (aTiCa) is larger than 75° at 4 months, doing PAT will improve the results of the functional method in the medium term and will reduce the surgery rate. PATIENTS AND METHODS: This prospective study involved 101 patients (151 feet) born between 2011 and 2014 with clubfoot who were treated with the French functional method and had at least 4 years' follow-up. The initial severity of the deformity was evaluated using the Diméglio scoring system. In our sample, 30 feet had a Diméglio rating of II (20%), 61 had a Diméglio rating of III (40%) and 60 feet had a Diméglio rating of IV (40%). The indication for PAT was made at 4 months of age when the aTiCa on a lateral radiograph of the foot in maximum correction was greater than 75°. The mean follow-up was 5 years. The final assessment was done using the modified Ghanem and Seringe classification. RESULTS: In the entire cohort, PAT was done in 113 feet (75%). None of the feet required a repeat PAT. Surgical release of the soft tissues was done in 20 feet (13%). None of the feet developed a rocker bottom deformity. Two feet were operated in the absence PAT (out of 38 in this subgroup) and 18 feet after PAT (out of 113 in this subgroup). The aTiCa angle did not vary in the PAT group based on whether surgical release was indicated afterwards or not. At the final assessment, 140 feet (93%) were classified as very good and 11 feet (7%) as good. DISCUSSION: The tibiocalcaneal angle is a relevant radiological criterion for the PAT indication in children with clubfoot. PAT has a positive impact on the outcomes. LEVEL OF EVIDENCE: II; prospective study.

Changes in adipose bone marrow and bone morphology in X-linked hypophosphatemic rickets.

INTRODUCTION: X-linked hypophosphatemic (XLH) rickets causes significant bone deformities in the lower limbs resulting from a bone mineralization defect. According to Frost's Mechanostat theory, compensatory modeling of the bones takes place during increased mechanical loads. In addition, mechanical stimuli modulate the differentiation of mesenchymal stem cells; common precursors to bone marrow adipocytes and osteoblasts. HYPOTHESIS: Bone deformities of the lower limbs lead to increased femoral bone mass and decreased fatty infiltration of the bone marrow (FIBM) in children with XLH rickets compared to a control group. PATIENTS AND METHODS: Eleven children (10.3years [6-17]) with XLH rickets and 22 healthy children (10.2years [5-15.5]) underwent lower limb Magnetic Resonance Imaging. A calculation of FIBM was performed at the mid-femur, as well as a calculation of the total bone cross-sectional area (CSA), the cortical CSA, the anteroposterior and mediolateral axes of the femur, bone marrow and the thickness of the femoral cortices. RESULTS: Total bone CSA, total cortical CSA and bone marrow CSA were higher in the XLH group than in the control group (p<0.05). The mid-lateral diameters of the femur and bone marrow were more elongated than those of the control group (p<0.001). Only the anterior cortex was thinned in the XLH group (p=0.001), while there was no difference with the control group for the posterior, medial and lateral cortices. The total percentage of FIBM was 72.81% [±3.95] and 77.4% [±5.52] for the XLH and control groups respectively (p<0.001). DISCUSSION: The increase in bone mass in the XLH population reflects an adaptation of bone tissue to the bone deformities present in this pathology. The decrease in FIBM indicates a lower risk of osteoporosis in the XLH population and may constitute a new monitoring parameter in this pathology. LEVEL OF STUDY: III; Case-control study.

Orthopedic and neurosurgical care of X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is due to mutations in the PHEX gene leading to unregulated production of FGF23 and uncontrollable hypophosphatemia. XLH is characterized in children by rickets, short stature, waddling gait, and leg bowing of variable morphology and severity. Phosphate supplements and oral vitamin D analogs partially or, in some cases, fully restore the limb straightness. XLH patients may also be affected by premature, complete, or partial ossification of sutures between cranial bone, which could eventually result in cranial dysmorphia, decreased intracranial volume, and secondary abnormally high intracranial pressure with a cerebral compression. Our goal is to address the criteria and the management of the skeletal complications associated with XLH, mainly orthopedic and neurosurgical care, and reflect on decision-making and follow-up complexities.

Mineral and Bone Consequences of High Dose Denosumab Therapy to Treat an Aneurysmal Bone Cyst, a Child Case Report.

Aneurysmal bone cysts (ABCs) are rare benign pseudotumoral bone lesions with potential aggressive behavior due to the extensive destruction of surrounding bone. Traditionally, these tumors were treated with open surgery, but there is more and more a shift to less invasive procedures. In particular, treatment for spinal ABCs is generally unsatisfactory due to the risk of morbidity, neurological impairment and recurrence, and there is a need for innovative therapies. Denosumab has been reported as a useful treatment in giant cell tumors of bone (GCTB), so its efficacy has been tested also in other fibro-osseus lesions affecting children and adolescents, such as spinal aneurysmal bone cysts. The pediatric literature is limited to case reports and small series, all of which highlight the efficacy of this treatment on lesions growth and associated bone pain. Some of these reports have already reported well known side effects associated with denosumab, such as hypocalcemia at the beginning of the treatment, and rebound hypercalcemia at the discontinuation. The latter seems to be more frequent in children and adolescents than in adults, probably due to the higher baseline bone turnover in children. In addition, the use of denosumab in young patients could affect both bone modeling and remodeling, even if the consequences on the growing skeleton have not been reported in detail. Here we describe the case of a spinal ABC diagnosed in an 8-year old young boy which was not accessible to surgery but responded favorably to denosumab. Our aim is to describe the rapid changes in mineral and bone homeostasis in this patient, that required advice from the experts of the European Reference Network (ERN) for rare bone and endocrine diseases.

Magnetic resonance imaging is a valuable tool to evaluate the therapeutic efficacy of burosumab in children with X-linked hypophosphatemia.

PURPOSE: To examine the MRI diagnostic performance in the assessment of therapeutic response to burosumab in children with X-linked hypophosphatemia (XLH). DESIGN: Prospective longitudinal open cohort. PATIENTS: Seventeen children with XLH, average age of 10.2 ± 2.7 years, had a knee MRI at baseline and after 1 year of burosumab. INTERVENTION: Children received burosumab at an average dose of 1.4 ± 0.5 mg/kg during 1 year for the treatment of severe rickets (the target serum phosphate ≥ 1.2 mmol/L (≥3.7 mg/dL). The primary endpoint was the change from baseline to 12 months in rachitic lesions on knee MRI. Secondary endpoints were changes in biochemical parameters of phosphate and alkaline phosphatase (ALP). RESULTS: One year of treatment with burosumab significantly reduced radiological disease activity on knee MRI (by 44 ± 29% in the transverse extent of widening) which was accompanied by a significant reduction in biochemical activity, namely in serum ALP activity, by 28 ± 17%. Additionally, MRI parameters after 1 year of treatment with burosumab (the maximum width of medial physis at 12 months and the change from baseline in the maximum width of lateral physis) were associated with ALP activity at 12 months. CONCLUSION: We suggest that MRI is a valuable and quantitative tool to evaluate the therapeutic response to burosumab. MRI could be an excellent alternative to standard bone radiographs for evaluation of the rachitic lesions in a clinical setting avoiding repeated exposition to ionizing radiation.

Can Chiari Osteotomy Favorably Influence Long-term Hip Degradation in Multiple Epiphyseal Dysplasia and Pseudoachondroplasia?

BACKGROUND: Multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH) are congenital skeletal disorders characterized by irregular epiphyses, mild or severe short stature and early-onset osteoarthritis which frequently affect the hips. The current study evaluates the long-term results of the Chiari osteotomy in MED and PSACH patients. METHODS: Twenty patients (14 MED and 6 PSACH) were retrospectively included. Clinical assessment used the Postel Merle d'Aubigné (PMA) score and the Hip disability and Osteoarthritis Outcome Score (HOOS). Risser index, Sharp angle, acetabular depth index, center-edge angle, Tönnis angle, and femoral head coverage were measured on the preoperative radiographs and at last follow-up. The Treble index, which identifies the hip at risk in MED patients, was also determined. Stulberg classification (grades I to V) was used to evaluate the risk of osteoarthritis in the mature hips.Statistical analyses determined differences between preoperative and postoperative data. The Kaplan Meier method was used to calculate the survival rate of the operated hips using total hip arthroplasty as the endpoint. RESULTS: Thirty-three hips which underwent a Chiari osteotomy were reviewed. The average follow-up was 20.1 years. The PMA scores were significantly better at last follow-up than preoperatively. All radiographic parameters significantly improved. Moreover, the Sharp angle, center-edge angle, and femoral head coverage improved to a normal value at hip maturity. All of the operated hips had a Treble index of type I. At hip maturity, a majority of hip were aspherical congruent (Stulberg grades of III and IV). The survival rate of the operated hips was 80.7% at 24 years postoperative. CONCLUSIONS: The Chiari osteotomy is a satisfying solution for severe symptomatic hip lesions in MED and PSACH patients. At long-term follow-up, this procedure lessens pain and improves hip function, which delays total hip arthroplasty indication. LEVEL OF EVIDENCE: Level IV.

Combined 3D analysis of lower-limb morphology and function in children with idiopathic equinovarus clubfoot: A preliminary study.

INTRODUCTION: In children treated for idiopathic equinovarus clubfoot (EVCF), the relation between morphologic defects on clinical examination and standard X-ray on the one hand and functional abnormalities on the other is difficult to objectify. The aim of the present study was to demonstrate the feasibility of combined 3D analysis of the foot and lower limb based on biplanar EOS radiographs and gait analysis. The study hypothesis was that this provides better understanding of abnormalities in form and function. METHODS: Ten children with unilateral EVCF and "very good" clinical results were included. They underwent gait analysis on the Rizzoli Institute multisegment foot model. Kinematic data were collected for the hip, knee, ankle and foot (hindfoot/midfoot, midfoot/forefoot and hindfoot/forefoot). Biplanar EOS radiographs were taken to determine anatomic landmarks and radiological parameters. RESULTS: Complete acquisition time was around 2hours per patient. No significant differences were found between EVCF and healthy feet except for calcaneal incidence, tibiocalcaneal angle and hindfoot/midfoot and hindfoot/forefoot inversion. DISCUSSION: The feasibility of the combined analysis was confirmed. There were no differences in range of motion, moment or power between EVCF and healthy feet in this series of patients with very good results. The functional results are related to radiological results within the normal range. The protocol provided anatomic and kinematic reference data. A larger-scale study could more objectively assess the contribution of EOS radiography using optoelectronic markers. LEVEL OF EVIDENCE: II, low-power prospective study.

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia.

X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care.

Long-Term Results of the "Horseman" Procedure for Severe Idiopathic Flatfoot in Children: A Retrospective Analysis of 41 Consecutive Cases With Mean 8.9 Year Duration of Follow-Up.

The "horseman" procedure is a surgical technique used to correct the talocalcaneal joint displacement of severe idiopathic flatfoot in children while maintaining the reduction with a temporary talocalcaneal screw. While this technique has been used since the early 1960s, very little has been reported on its results. Our objectives were to estimate the correction, functional results, and postoperative complications of the "horseman" procedure. We conducted a retrospective study on 23 consecutive patients (41 cases) who underwent the "horseman" procedure for a talocalcaneal joint displacement. Mean follow-up was 8.9 (range 1 to 28) years, and 8 patients (12 feet) had reached bone maturity at last follow-up. Mean age at surgery was 6.6 (range 4 to 9.5) years. At last follow-up, all the patients were asymptomatic except 2 [8.7%] (4 [9.8%] cases). The talocalcaneal divergence on anteroposterior and lateral radiographic views was reduced by 8.9° and 11.4°, respectively, after the surgery, and the correction was maintained with loss of 0.7° and 2.9°, respectively, at final follow-up. The talonavicular coverage angle was reduced by 25° without loss of correction at last follow-up. The calcaneal pitch angle did not change after the surgery. Mean American Orthopedic Foot and Ankle Society score increased from 88.7 of 100 (63 of 100 to 93 of 100) preoperatively to 99 of 100 (97 to 100 of 100) at last follow-up. No major complication occurred. The "horseman" procedure allows an immediate and lasting correction of severe idiopathic flatfoot in children.

Long term results of the revisited Meary closing wedge tarsectomy for the treatment of the fixed cavo-varus foot in adolescent with Charcot-Marie-Tooth disease.

BACKGROUND: Various techniques have been proposed for the treatment of cavovarus feet (CVF). The aim of this study was to report outcomes of the revisited Meary's dorsal closing wedge tarsectomy for fixed CVF secondary to Charcot-Marie-Tooth (CMT) disease. METHODS: All CVF operated on between 1977 and 2011 were included. The tarsectomy design was modified from its original description and systemically combined with a plantar fascia release, a Dwyer osteotomy and a proximal extension osteotomy of the 1st metatarsal bone if required. Outcomes were assessed by 2 functional scores and radiographically. RESULTS: Among the 26 feet (20 patients), the Wicart and Seringe score was very good or good, fair and poor in respectively 58%, 23% and 19% of the feet. Hindfoot and midfoot AOFASs were of 95.5 and 75 respectively. All radiographic measures were significantly improved. CONCLUSIONS: This complete revisited procedure is an efficient and safe surgical technique for the treatment of the CMT disease CVF. LEVEL OF EVIDENCE: Level IV.

Assessing 3D paediatric foot morphology using low-dose biplanar radiography: Parameter reproducibility and preliminary values.

BACKGROUND: The physical examination and weight-bearing radiography are the two main available methods for assessing the feet and lower limbs. The anatomy and function of these two structures interact with each other. These two assessment methods are affected by subjectivity and projection bias. Low-dose biplanar radiography (LDBR) is now a promising alternative for evaluating the lower limbs in children. At present, however, the foot cannot be assessed using LDBR. The objective of this study was to work towards developing a new method for 3D radiographic analysis of the paediatric foot during weight-bearing, first by determining the reproducibility of landmarks defined by LDBR then by reporting the values of the calculated radiographic parameters. HYPOTHESIS: A new radiographic method based on LDBR can be used to obtain a 3D evaluation of the foot in paediatric patients. PATIENTS AND METHODS: Two biplanar radiographs in perpendicular planes were obtained simultaneously in a standardised position using the EOS system (EOS® Imaging, Paris, France) in each of 10 healthy children. To assess measurement uncertainty, two observers performed 3D reconstructions of each of the 10 feet three times (60 reconstructions). The standard error of reproducibility of the anatomic landmarks and clinical parameters was computed. Measurement uncertainty was then estimated based on the 95% confidence interval (95%CI). To obtain reference values, the mean±SD of each variable was computed after checking that the data were normally distributed. RESULTS: Reproducibility was high for the anatomical landmarks of interest, calcaneal pitch angle, tibio-calcaneal angle on the lateral view, and first metatarsal pitch angle (95%CI<5%). The values of these angles in the study population are reported. DISCUSSION AND CONCLUSION: The data reported here pave the way towards developing new parameters for describing 3D foot morphology and for simultaneously assessing the lower limb and foot in the standing position. LEVEL OF EVIDENCE: I.

Three-Dimensional Reconstruction of Foot in the Weightbearing Position From Biplanar Radiographs: Evaluation of Accuracy and Reliability.

The initial assessment and postoperative monitoring of patients with various abnormalities of the foot in clinical routine practice is primarily based on the analysis of radiographs taken in the weightbearing position. Conventional x-ray imaging, however, only provides a 2-dimensional projection of 3-dimensional (3D) bony structures, and the clinical parameters assessed from these images can be affected by projection biases. In the present work, we addressed this issue by proposing an accurate 3D reconstruction method of the foot in the weightbearing position from low-dose biplanar radiographs with clinical index measurement assessment for clinical routine practice. The accuracy of the proposed reconstruction method was evaluated for both shape and clinical indexes by comparing 3D reconstructions of 6 cadaveric adult feet from computed tomographic images and from biplanar radiographs. For the reproducibility study, 3D reconstructions from the biplanar radiographs of the foot of 6 able-bodied subjects were considered, with 2 observers repeating each measurement of anatomic landmarks 3 times. Baseline assessment of important 3D clinical parameters was performed on 17 subjects (34 feet; mean age 27.7, range 20 to 52 years). The average point to surface distance between the 3D stereoradiographic reconstruction and the computed tomographic scan-based reconstruction was 1 mm (range 0mm to 6mm). The selected radiographic landmarks were highly reproducible (95% confidence interval <2.0 mm). The greatest interindividual variability for the clinical parameters was observed for the twisting angle (mean 87°, range 73° to 100°). Such an approach opens the way for routine 3D quantitative analysis of the foot in the weightbearing position.

Long-term results of ankle arthrodesis in children and adolescents with haemophilia.

INTRODUCTION: Ankle arthrodesis in patients with haemophilia is a joint-non-preserving treatment option often resulting in substantial pain relief and termination of haemarthrosis by osseous consolidating of the joint. However, limited data are available regarding ankle arthrodesis in young patients. AIM: The aim of this study was to evaluate the long-term clinical and radiographic results with a minimum follow-up of ten years in children with haemophilia who underwent ankle arthrodesis. METHODS: We retrospectively reviewed the results of ankle fusions performed in young haemophiliacs in our department between 1980 and 2006. The Méary procedure was used for arthrodesis, performed on patients with closed growth plates. Only one patient had no fixation, due to being only six years old. The modified American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot score was calculated at last follow-up, and standard radiographic evaluations were performed. RESULTS: A total of 22 ankles were analysed from 17 patients. The mean follow-up was 19.7 ± 8 years. The mean age of the patients was 15.5 (6-23) years at the time of index surgery. There were no intra-operative or peri-operative complications related to ankle arthrodesis. The mean modified AOFAS score at last follow-up was 83 ± 10.5. Radiographic assessment demonstrated solid osseous fusion at the arthrodesis site, with no axis deformities. Two patients developed secondary subtalar arthrosis, treated by subtalar arthrodesis six years after initial ankle arthrodesis in one case. CONCLUSION: In our study, tibiotalar arthrodesis in young patients with haemophilia resulted in good long-term functional outcome with a low surgery-related complication rate.

Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia.

Seven young patients with X-linked hypophosphatemia (XLH, having inactivating PHEX mutations) were discovered to accumulate osteopontin (OPN) at the sites of defective bone mineralization near osteocytes - the so-called hallmark periosteocytic (lacunar) "halos" of XLH. OPN was also localized in the pericanalicular matrix extending beyond the osteocyte lacunae, as well as in the hypomineralized matrix of tooth dentin. OPN, a potent inhibitor of mineralization normally degraded by PHEX, is a member of a family of acidic, phosphorylated, calcium-binding, extracellular matrix proteins known to regulate dental, skeletal, and pathologic mineralization. Associated with the increased amount of OPN (along with inhibitory OPN peptide fragments) in XLH bone matrix, we found an enlarged, hypomineralized, lacuno-canalicular network - a defective pattern of skeletal mineralization that decreases stiffness locally at: i) the cell-matrix interface in the pericellular environment of the mechanosensing osteocyte, and ii) the osteocyte's dendritic network of cell processes extending throughout the bone. Our findings of an excess of inhibitory OPN near osteocytes and their cell processes, and in dentin, spatially correlates with the defective mineralization observed at these sites in the skeleton and teeth of XLH patients. These changes likely contribute to the dento-osseous pathobiology of XLH, and participate in the aberrant bone adaptation and remodeling seen in XLH.

Therapeutic management of hypophosphatemic rickets from infancy to adulthood.

In children, hypophosphatemic rickets (HR) is revealed by delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, and growth failure. If undiagnosed during childhood, patients with hypophosphatemia present with bone and/or joint pain, fractures, mineralization defects such as osteomalacia, entesopathy, severe dental anomalies, hearing loss, and fatigue. Healing rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counter the 1,25-diOH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of HR. Besides vitamin D analogs and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical, and contributions of various expertises to the treatment of HR are described, with an effort to highlight the importance of coordinated care.

Ischiovertebral dysplasia: a retrospective analysis of 30 consecutive cases pointing out the specifics and risks of the spine management.

STUDY DESIGN: A review of clinical publications, current knowledge, and recent developments regarding the etiology of ischiovertebral dysplasia was combined with a clinical review of the condition. OBJECTIVE: To acquaint orthopedic spine surgeons with identification patterns of ischiovertebral dysplasia in order to provide them with guidelines about spine management and which complications to expect. SUMMARY OF BACKGROUND DATA: Ischiovertebral dysplasia is a rare skeletal dysplasia that may appear in a sporadic fashion or be inherited with an autosomal dominant inheritance pattern. It is defined by the association of an ischiopubic ramus hypoplasia and a vertebral dysplasia. It leads to a specific spine deformity whose management and complications should be clarified. METHODS: Thirty consecutive patients from 0 to 31 years of age with ischiovertebral dysplasia were included from 5 centers specialized in congenital spinal deformities. Frontal and sagittal Cobb angles before treatment, natural history of the curves, therapeutic options, and their complications were systematically analyzed. RESULTS: All the patients had a vertebral dysplasia and 28 of them developed a spinal deformity. This deformity was an extremely severe thoracic kyphoscoliosis in 25 cases. The other deformities were a thoracolumbar scoliosis in 1 case and a thoracolumbar kyphosis in 2 cases. The management of the thoracic kyphoscoliosis was always challenging and complications included death by respiratory failure (3 cases) and neurological impairment (9 cases). CONCLUSION: Recognizing the occurrence of ischioverterbral dysplasia is very important to allow for dedicated treatment. The authors advocate preoperative distraction and circumferential fusion to prevent progression of the curve and to avoid the potentially fatal sequelae associated with this disorder. LEVEL OF EVIDENCE: 4.