Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin.

The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here, we report that the multisubunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha-tubulin. Reduction of alpha-tubulin acetylation via expression of a nonacetylatable alpha-tubulin mutant leads to comparable defects in cortical neurons and suggests that alpha-tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha-tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons.

Optical imaging (HandScan) can identify ultrasound remission in rheumatoid arthritis.

BACKGROUND: Identifying remission is of high importance in rheumatoid arthritis (RA) because remission is associated with less structural progression. We investigated the efficacy of a new optical imaging device, HandScan, to identify RA remission, as defined by ultrasound (US). METHODS: 61 RA patients were included. Disease activity was evaluated by clinical assessment and US, using gray-scale (GS) and Power Doppler (PD). HandScan determined unitary optical spectral transmission (OST) values for wrists, metacarpophalangeal and proximal interphalangeal joints. At the patient level, three composite HandScan (HS) scores were calculated: total HS score; disease activity score OST (DAS-OST) and DAS-OST without patient global assessment (PtGA). Using ROC curves, we determined HS cut-offs to identify US-defined remission. RESULTS: At the joint level, unitary OST values significantly correlated with GS synovitis [odds ratio (OR) 2.43, p < 0.0001] and PD positivity (OR 3.72, p = 0.0002 ). At the patient level, total HS score and DAS-OST were significantly associated with all gray-scale US (GSUS) and power doppler US (PDUS) parameters evaluated (synovitis number and grade, synovial thickness, PD grade) (p < 0.05). The cut-off to identify US-defined remission at the joint level was of 0.92, giving an 81% sensitivity and a 96% positive predictive value (PPV). At the patient level, ROC-curves failed to identify a robust cut-off for the total HS score, but did identify a cut-off (3.68) for DAS-OST to identify US-defined remission, but with lower sensitivity (75%), specificity (56%) and PPV (67%). CONCLUSIONS: HandScan is a non-invasive optical imaging technique providing OST values that correlate with GSUS and PDUS parameters. In addition, HandScan is able to reliably identify US-defined remission in RA at the joint level, with a good sensitivity and high PPV. At the patient level, HandScan DAS-OST can also determine US remission (while total HS score failed to do so), but with lower performance.

[What to do to prevent osteoporosis ? Between myths and scientific reality]. / Que faire pour prévenir l'ostéoporose ? Entre mythes et réalité scientifique.

Osteoporosis is a skeletal disease characterized by low bone density and altered microarchitecture, exposing to bone fragility and an increased risk of fracture. Several therapeutic modalities can effectively reduce the risk of fractures both vertebral and non-vertebral. While a significant part of bone strength and structure is genetically determined, it should be recalled that the environment also plays a significant role in these parameters and the risk of fracture, thus offering preventive opportunities thanks to lifestyle. In this article, we review the common misconceptions and myths about the influence of diet and physical activity on bone mineral density and fracture risk.

L'ostéoporose est une maladie du squelette caractérisée par une densité osseuse basse et une microarchitecture altérée, exposant à une fragilité osseuse et à un risque accru de fracture. Plusieurs classes thérapeutiques existent, capables de réduire efficacement le risque de fracture à la fois vertébrale et non vertébrale. Si une partie importante de la force et de la structure osseuse est déterminée génétiquement, il faut garder en mémoire que l'environnement joue aussi un rôle non négligeable sur ces paramètres et le risque de fracture, offrant donc des opportunités de prévention grâce au style de vie. Dans cet article, nous passons en revue les idées préconçues et les mythes qui circulent à propos de l'influence de l'alimentation et de l'activité physique sur la densité minérale osseuse et le risque de fracture.

CEMIP (KIAA1199) regulates inflammation, hyperplasia and fibrosis in osteoarthritis synovial membrane.

Osteoarthritis (OA) synovial membrane is mainly characterized by low-grade inflammation, hyperplasia with increased cell proliferation and fibrosis. We previously underscored a critical role for CEMIP in fibrosis of OA cartilage. However, its role in OA synovial membrane remains unknown. An in vitro model with fibroblast-like synoviocytes from OA patients and an in vivo model with collagenase-induced OA mice were used to evaluate CEMIP-silencing effects on inflammation, hyperplasia and fibrosis. Our results showed that i. CEMIP expression was increased in human and mouse inflamed synovial membrane; ii. CEMIP regulated the inflammatory response pathway and inflammatory cytokines production in vitro and in vivo; iii. CEMIP induced epithelial to mesenchymal transition pathway and fibrotic markers in vitro and in vivo; iv. CEMIP increased cell proliferation and synovial hyperplasia; v. CEMIP expression was increased by inflammatory cytokines and by TGF-ß signaling; vi. anti-fibrotic drugs decreased CEMIP expression. All these findings highlighted the central role of CEMIP in OA synovial membrane development and underscored that targeting CEMIP could be a new therapeutic approach.

[A breakthrough in the management of postmenopausal osteoporosis with very high fracture risk : romosozumab (Evenity®), a humanized monoclonal anti-sclerostin antibody]. / Une nouveauté dans la prise en charge de l'ostéoporose post-ménopausique à très haut risque fracturaire : le romosozumab (Evenity®), un anticorps monoclonal anti-sclérostine.

Romosozumab (Evenity®) is a humanized monoclonal anti-sclerostin antibody. It represents a major breakthrough in the treatment of osteoporosis: while most treatments inhibit bone resorption, romosozumab has a dual effect, by increasing bone formation and reducing bone resorption. It is reimbursed in postmenopausal osteoporosis in patients with very high fracture risk (i.e. after a recent major fracture, occurring within two years). Its ideal use, in the therapeutic sequence for post-menopausal women, is as first line treatment in case of a recent major fracture. It is contraindicated in case of hypocalcemia and personal history of stroke or myocardial infarction.

Le romosozumab (Evenity®) est un anticorps monoclonal humanisé anti-sclérostine. Il représente une avancée majeure dans le traitement de l'ostéoporose : alors que la majorité des traitements remboursés inhibent la résorption osseuse, le romosozumab présente un effet «mixte¼, en augmentant la formation osseuse et en réduisant la résorption. Il est remboursé dans l'ostéoporose post-ménopausique chez les patientes à très haut risque fracturaire (c'est-à-dire après une fracture majeure récente, survenue dans les deux ans). Son utilisation idéale, dans la séquence thérapeutique chez la femme ménopausée, le positionne en première ligne en cas de fracture majeure récente. Il est contre-indiqué en cas d'hypocalcémie et d'antécédent personnel d'accident vasculaire cérébral ou d'infarctus du myocarde.

[Diagnosis of osteoporosis]. / Vignette diagnostique de l'étudiant. Prise en charge diagnostique de l'ostéoporose.

We here describe the case of a post-menopausal woman presenting with a recent vertebral fracture and cortical osteopenia on bone dual energy X-ray absorptiometry. Based on this case, we will discuss the definition and diagnosis of osteoporosis as well as the indications to treat, which go beyond the densitometric-based definition of osteoporosis. We will also address the osteoporosis screening recommendations, and the blood workup required before treatment initiation. The choice of the treatment, its duration and the non-pharmacological measures will be discussed in another article.

Nous décrivons le cas d'une patiente ménopausée présentant un tassement vertébral récent et une ostéopénie corticale sur la densitométrie osseuse. Nous discutons, à partir de ce cas clinique, la définition et le diagnostic de l'ostéoporose, ainsi que les indications thérapeutiques, qui dépassent le cadre de la simple définition densitométrique. Nous abordons ensuite les indications de dépistage de l'ostéoporose, ainsi que le bilan biologique et étiologique à réaliser avant l'instauration du traitement. Le choix du traitement reminéralisateur, la durée du traitement et la prise en charge non médicamenteuse de l'ostéoporose seront discutés dans une autre vignette.

[The management of gout]. / Vignette thérapeutique de l'étudiant. Prise en charge de la goutte.

We describe the case of a patient with a history of gout, who presents with a new episode of acute gout. Based on this clinical case, we will discuss the management of acute gout. We will then address the management of chronic gout, i.e., the indications for a hypouricemic treatment and the caution required when starting this treatment. Finally, we will address the need for a holistic care, discussing the change of certain co-medications, screening for cardiovascular comorbidities and providing diet and life-style recommendations.

Nous décrivons le cas d'un patient, goutteux connu, qui présente un nouvel accès aigu. Nous discutons tout d'abord, à partir de ce cas clinique, la prise en charge aiguë de la crise de goutte. Nous abordons ensuite les indications de mise en place d'un traitement de fond hypo-uricémiant et les précautions à prendre lors de cette introduction. Enfin, nous détaillons la prise en charge holistique, en évoquant les modifications de certaines thérapeutiques, le dépistage des comorbidités cardiovasculaires et les conseils hygiéno-diététiques.

[Lung disease associated with rheumatoid arthritis]. / La pathologie pulmonaire associée à la polyarthrite rhumatoïde.

Rheumatoid arthritis is a chronic inflammatory systemic disease. Pulmonary manifestations are the most common extra-articular involvements and can impact all components of the respiratory system: parenchyma, pleura, vessels and airways, all complications that are briefly described in this article. Interstitial lung disease is the most common of these and is associated with significant morbidity and mortality. Its detection and monitoring are based on spirometry and thoracic imaging. Specific treatments are initiated in order to reduce the risk of disease flare up but may themselves in case of toxicity be associated with respiratory manifestations, either directly or by promoting infectious complications.

La polyarthrite rhumatoïde est une pathologie systémique inflammatoire chronique. Les manifestations pulmonaires représentent l'atteinte extra-articulaire la plus fréquente et peuvent affecter tous les composants du système respiratoire : le parenchyme, la plèvre, les vaisseaux et les voies aériennes, complications décrites brièvement dans cet article. La pneumopathie interstitielle diffuse en est la plus commune et associée à une morbi-mortalité importante. Son dépistage et son suivi reposent sur les épreuves fonctionnelles et l'imagerie thoracique. Des traitements spécifiques sont initiés afin de limiter au mieux l'évolution pulmonaire, mais peuvent eux-mêmes être associés à des manifestations respiratoires, soit directement, soit en favorisant des complications infectieuses.

TFEB phosphorylation on Serine 211 is induced by autophagy in human synovial fibroblasts and by p62/SQSTM1 overexpression in HEK293 cells.

Autophagy receptor p62/SQSTM1 signals a complex network that links autophagy-lysosomal system to proteasome. Phosphorylation of p62 on Serine 349 (P-Ser349 p62) is involved in a cell protective, antioxidant pathway. We have shown previously that P-Ser349 p62 occurs and is rapidly degraded during human synovial fibroblasts autophagy. In this work we observed that fingolimod (FTY720), used as a medication for multiple sclerosis, induced coordinated expression of p62, P-Ser349 p62 and inhibitory TFEB form, phosphorylated on Serine 211 (P-Ser211 TFEB), in human synovial fibroblasts. These effects were mimicked and potentiated by proteasome inhibitor MG132. In addition, FTY720 induced autophagic flux, LC3B-II up-regulation, Akt phosphorylation inhibition on Serine 473 but down-regulated TFEB, suggesting stalled autophagy. FTY720 decreased cytoplasmic fraction contained TFEB but induced TFEB in nuclear fraction. FTY720-induced P-Ser211 TFEB was mainly found in membrane fraction. Autophagy and VPS34 kinase inhibitor, autophinib, further increased FTY720-induced P-Ser349 p62 but inhibited concomitant expression of P-Ser211 TFEB. These results suggested that P-Ser211 TFEB expression depends on autophagy. Overexpression of GFP tagged TFEB in HEK293 cells showed concomitant expression of its phosphorylated form on Serine 211, that was down-regulated by autophinib. These results suggested that autophagy might be autoregulated through P-Ser211 TFEB as a negative feedback loop. Of interest, overexpression of p62, p62 phosphorylation mimetic (S349E) mutant and phosphorylation deficient mutant (S349A) in HEK293 cells markedly induced P-Ser211 TFEB. These results showed that p62 is involved in regulation of TFEB phosphorylation on Serine 211 but that this involvement does not depend on p62 phosphorylation on Serine 349.

New Proteins Contributing to Immune Cell Infiltration and Pannus Formation of Synovial Membrane from Arthritis Diseases.

An inflamed synovial membrane plays a major role in joint destruction and is characterized by immune cells infiltration and fibroblast proliferation. This proteomic study considers the inflammatory process at the molecular level by analyzing synovial biopsies presenting a histological inflammatory continuum throughout different arthritis joint diseases. Knee synovial biopsies were obtained from osteoarthritis (OA; n = 9), chronic pyrophosphate arthropathy (CPPA; n = 7) or rheumatoid arthritis (RA; n = 8) patients. The histological inflammatory score was determined using a semi-quantitative scale based on synovial hyperplasia, lymphocytes, plasmocytes, neutrophils and macrophages infiltration. Proteomic analysis was performed by liquid chromatography-mass spectrometry (LC-MS/MS). Differentially expressed proteins were confirmed by immunohistochemistry. Out of the 1871 proteins identified and quantified by LC-MS/MS, 10 proteins (LAP3, MANF, LCP1, CTSZ, PTPRC, DNAJB11, EML4, SCARA5, EIF3K, C1orf123) were differentially expressed in the synovial membrane of at least one of the three disease groups (RA, OA and CPPA). Significant increased expression of the seven first proteins was detected in RA and correlated to the histological inflammatory score. Proteomics is therefore a powerful tool that provides a molecular pattern to the classical histology usually applied for synovitis characterization. Except for LCP1, CTSZ and PTPRC, all proteins have never been described in human synovitis.

High detection rate of osteoporosis with screening of a general hospitalized population: a 6-year study in 6406 patients in a university hospital setting.

BACKGROUND: Osteoporosis is a highly prevalent disease identified by Dual Energy X-ray Absorptiometry (DEXA) that can be performed in an ambulatory (out-patient) or hospitalized population. We evaluated the use of baseline in-hospital DEXA screening to identify osteoporosis in ambulatory care and hospitalized patients; we also assessed specific risk factors for osteoporosis among these populations. METHODS: We included a baseline initial DEXA from 6406 consecutive patients at our tertiary referral University Hospital. RESULTS: Osteoporosis was diagnosed in 22.3% of the study population. In univariate analysis, osteoporosis risk factors were age, fracture history and low BMI (for all 3 sites), but also corticotherapy (lumbar spine and femoral neck) and male (lumbar spine). In multivariate analysis, age, fracture history, low BMI, and male increased osteoporosis risk. In-hospital screening yielded a higher percentage of osteoporosis positive scans than ambulatory care screening (31.8% vs 18.5%, p < 0.001). In-hospital screening targeted an older and more predominantly male population with a higher fracture history. Z-scores revealed that this difference was not only due to an older age of the population and mainly concerned cortical bone. CONCLUSIONS: In-hospital osteoporosis screening revealed more osteoporosis than screening in ambulatory practice and could be an additional tool to improve the identification and management of osteoporosis. In addition to typical risk factors, we identified male gender as associated with osteoporosis detection in our cohort.

Correction to: Learning curves of two different techniques for the intra-articular injection of the knee joint under fluoroscopic guidance.

The published version of this article contained a mistake. In Table 1 of the original article, the numbers of successful injections and failed injections were not correct. The correct Table 1 should read as given below.

Learning curves of two different techniques for the intra-articular injection of the knee joint under fluoroscopic guidance.

AIM: The aim of the study was to compare the learning curves of three beginner operators using two different techniques of intra-articular injection of the knee under fluoroscopic guidance with a superolateral approach. MATERIALS AND METHODS: In total, 177 consecutive patients (72 females (40.7%) and 105 males (59.3%), mean age 42.2 ± 15.0 years) scheduled for a computed tomography (CT) arthrography and without joint effusion on the lateral X-rays were enrolled. They underwent an intra-articular injection of the knee under fluoroscopic guidance with a superolateral approach. Patients were randomly assigned to three different operators, including a junior supervisor and two first-year residents in radiology who never performed an intra-articular injection of the knee before the present study. Procedures in lateral or supine position were randomly assigned to three operators. RESULTS: There was a higher rate of successful injections with the lateral position (92.1%) than with supine position (80.2%) (odds ratio (OR) 4.52, 95% confidence interval (CI) 1.46-14.0). A significant learning effect was observed for the supine position, while none was observed for the lateral position. Pain and time of fluoroscopy did not differ between the two procedures (p = 0.85 and p = 0.10, respectively). Junior supervisor had a higher rate of successful intra-articular injection compared with the other two operators (p = 0.0072). There was a statistically significant higher rate of extravasation with the supine position (66.3%) than with lateral position (19.7%) (p < 0.0001, OR 0.13, 95% CI 0.06-0.25). CONCLUSION: The intra-articular injection of the knee under fluoroscopic guidance with the patient in lateral position is an easy technique for operators in training with a low rate of extravasation. Lateral position does not require a supplementary irradiation and does not increase the procedural pain. Personal operator's skill is an independent factor in determining the success of the training.

Are blind injections of gleno-humeral joint (GHJ) really less accurate imaging-guided injections? A narrative systematic review considering multiple anatomical approaches.

AIM: To perform a systematic review to establish whether blind injections of the gleno-humeral (GHJ) joint may be an accurate alternative to injections performed imaging guidance, considering multiple anatomical approaches. MATERIALS AND METHODS: Our search strategy yielded 478 articles for Scopus, 815 articles for MEDLINE, 128 articles for Cochrane Central Register of Controlled Trials and 555 articles for Embase until May 2016. One hundred and sixty-seven abstracts were retrieved after duplicates removal. Two readers independently reviewed all the 1067 abstracts. They selected for the full-text analysis only the abstracts in which the accuracy of intra-articular position of the needle was confirmed on imaging (humans) or by a surgical dissection (cadavers). Thirty-eight studies were eventually selected for the full-text reading and data extraction. The selected studies included a total of 2309 patients (2690 shoulders) and 195 cadavers (299 shoulders). To objectively assess the methodological quality of the present systematic review, "Assessment of Multiple Systematic Review" (AMSTAR) tool was used. RESULTS: The overall accuracy of the intra-articular injection in GHJ varied from 42 to 100% in the 38 selected studies. Imaging guidance was used in 65% of articles and the overall accuracy of guided GHJ injections was higher than blind injection. However, five articles in which blind injection the GHJ was used (159 shoulders) reported accuracy as high as 100%. CONCLUSION: A comprehensive review of the literature confirms that guided injections of the GHJ have overall accuracy higher compared to blind injection. Nevertheless, in some studies, including a relatively large number of shoulders, blind injections have been proven to be 100% accurate. Hence, blind injections of GHJ could be proposed a cost-effective alternative to imaging-guided injection. A large prospective randomized study is needed to gauge this hypothesis and compare the cost-effectiveness of these two techniques for the most common anatomical approaches.

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis.

Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1ß (IL-1ß), Tumor Necrosis factor-α (TNF-α), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF-1α/HIF-2α imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression.

Selective glucocorticoid receptor modulator compound A, in contrast to prednisolone, does not induce leptin or the leptin receptor in human osteoarthritis synovial fibroblasts.

OBJECTIVE: Glucocorticoids are powerful anti-inflammatory compounds that also induce the expression of leptin and leptin receptor (Ob-R) in synovial fibroblasts through TGF-ßsignalling and Smad1/5 phosphorylation. Compound A (CpdA), a selective glucocorticoid receptor agonist, reduces inflammation in murine arthritis models and does not induce diabetes or osteoporosis, thus offering an improved risk:benefit ratio in comparison with glucocorticoids. Due to the detrimental role of leptin in OA pathogenesis, we sought to determine whether CpdA also induced leptin and Ob-R protein expression as observed with prednisolone. METHODS: Human synovial fibroblasts and chondrocytes were isolated from the synovium and cartilage of OA patients after joint surgery. The cells were treated with prednisolone, TGF-ß1, TNF-α and/or CpdA. Levels of leptin, IL-6, IL-8, MMP-1 and MMP-3 were measured by ELISA and expression levels of Ob-R phospho-Smad1/5, phospho-Smad2, α-tubulin and glyceraldehyde 3-phosphate dehydrogenase were analysed by western blotting. RESULTS: CpdA, unlike prednisolone, did not induce leptin secretion or Ob-R protein expression in OA synovial fibroblasts. Moreover, CpdA decreased endogenous Ob-R expression and down-regulated prednisolone-induced leptin secretion and Ob-R expression. Mechanistically, CpdA, unlike prednisolone, did not induce Smad1/5 phosphorylation. CpdA, similarly to prednisolone, down-regulated endogenous and TNF-α-induced IL-6, IL-8, MMP-1 and MMP-3 protein secretion. The dissociative effect of CpdA was confirmed using chondrocytes with no induction of leptin secretion, but with a significant decrease in IL-6, IL-8, MMP-1 and MMP-3 protein secretion. CONCLUSION: CpdA, unlike prednisolone, did not induce leptin or Ob-R in human OA synovial fibroblasts, thereby demonstrating an improved risk:benefit ratio.

Use of Tomosynthesis for Detection of Bone Erosions of the Foot in Patients With Established Rheumatoid Arthritis: Comparison With Radiography and CT.

OBJECTIVE: The purpose of this study was to compare tomosynthesis with radiography for the detection of bone erosions of the foot in patients with established rheumatoid arthritis (RA) using MDCT as a reference standard. SUBJECTS AND METHODS: Eighteen consecutive patients with established RA were included. Each patient underwent radiography, tomosynthesis, and CT examinations of the feet on the same day. Two radiologists independently determined the number of bone erosions and the Sharp-van der Heijde score with each of the three imaging modalities. RESULTS: On a total of 216 joints from 18 patients, 216 bone erosions were detected on CT, 215 on tomosynthesis, and 181 with radiography. The mean (± SD) Sharp-van der Heijde score was equivalent for tomosynthesis (18.8 ± 16.8) and CT (19.8 ± 18.5) but was statistically lower for radiography (16.4 ± 18.0) (p = 0.030). The respective overall sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for tomosynthesis were 80%, 75%, 78%, 76%, and 80%, whereas the respective corresponding values for radiography were 66%, 81%, 74%, 77%, and 71%. The radiation burden of tomosynthesis was almost equivalent to that of radiography. CONCLUSION: Tomosynthesis has a higher sensitivity than radiography to detect bone erosions of the foot in patients with established RA and imparts an almost equivalent radiation burden.

[Two spondylodiscitis due to a contamination by Brucella melitensis in a mother and daughter back from holidays]. / Deux cas de spondylodiscite a Brucella melitensis chez une mère et sa fille de retour de vacances.

We describe here a case of spondylodiscitis of brucellosis origin in one patient back from Turkey. Some weeks later, her mother, who had accompagnied her in Turkey also developped similar symptoms. A diagnosis of spondylodiscitis due to a contamination by Brucella melitensis was also proposed. Since the control of animal brucellosis in Europe, human cases are rarer. Sporadic cases still observed are mostly travellers back from aerea where animal brucellosis remains endemic. Seroprevalence of a second case of brucellosis among family members of a patient with brucellosis is significantly more elevated than in the general population. This justifies early detection among family members presenting with any medical symptom, in order to avoid chronicity. Early detection among asymptomatic family members is not clearly justified.

Hypophosphatasia Presenting as a Chronic Diffuse Pain Syndrome with Extra-Articular Calcifications.

Hypophosphatasia is a rare genetic disease characterized by abnormal alkaline phosphatase activity and deficiency of bone and teeth mineralization. Hypophosphatasia is well known in pediatrics with typical presentations in children, but mild forms can also be present in adults and are difficult to detect. We present the case of a 50-year-old woman referred for pain management, with a previous diagnosis of fibromyalgia. The association of clinical features (diffuse pain syndrome, early dental loosening, personal history of two fractures with osteoporosis, and family history of osteoporosis) with radiographic (heterotopic calcifications of the yellow and interspinous lumbar ligaments) and biological (low levels of total alkaline phosphatase) indices was suggestive of hypophosphatasia, which was confirmed by genetic analysis. We review and discuss the association between hypophosphatasia, musculoskeletal pain, and calcium pyrophosphate deposition and the importance of raising the diagnosis of adult-onset hypophosphatasia when facing these two rheumatologic entities.