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.
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.
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.
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.
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 IV.
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.
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.
Classic Rett Syndrome (RS) is a disabling condition mainly caused by MECP2 mutations. Girls with RS are at risk of developing bone fragility and fractures at a young age which results in pain and may ...seriously impair quality of life.
To retrospectively assess the safety and efficacy of IV bisphosphonates on fracture, bone mineral density (BMD) and bone markers in RS girls with bone fragility.
RS girls received either IV pamidronate (n = 19) or IV zoledronate (n = 1) for 2 years.
Of 20 patients studied (age: 12.5 years 6; 39), 14 were non-ambulatory. The incidence of fracture decreased from 37 fractures in 20 patients, to 1 fracture during or after treatment (follow-up: 3.1 years 1.5; 5). The spine BMD Z-score improved from -3.2 -5.6; -0.1 to -2.2 -3.8; 0.0, p = 0.0006. Most parents reported decreases in chronic pain and 2 patients started to walk. Urinary calcium excretion decreased from 0.7 0.18; 1.5 to 0.2 0.03; 0.67 mM/mM of creatinine (p = 0.0001). Pamidronate was well tolerated.
RS girls should be screened for impaired bone mineralization and preventive measures should be taken. In girls experiencing fractures, IV bisphosphonates constitute a beneficial adjuvant treatment to diminish the risk of fracture and restore bone density.
Abstract 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.
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.
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.
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.
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).
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.
III; Case-control study.
The aim of the present study was to define indications for talectomy in congenital paralytic, dystrophic or idiopathic, inveterate or recurrent, clubfoot.
Talectomy is a valid option for paralytic, ...dystrophic or idiopathic, inveterate or recurrent, clubfoot.
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).
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.
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.
IV, retrospective series.
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.
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.
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.
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.
The tibiocalcaneal angle is a relevant radiological criterion for the PAT indication in children with clubfoot. PAT has a positive impact on the outcomes.
II; prospective study.
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