WNT11, a new gene associated with early onset osteoporosis, is required for osteoblastogenesis.

Monogenic early onset osteoporosis (EOOP) is a rare disease defined by low bone mineral density (BMD) that results in increased risk of fracture in children and young adults. Although several causative genes have been identified, some of the EOOP causation remains unresolved. Whole-exome sequencing revealed a de novo heterozygous loss-of-function mutation in Wnt family member 11 (WNT11) (NM_004626.2:c.677_678dup p.Leu227Glyfs*22) in a 4-year-old boy with low BMD and fractures. We identified two heterozygous WNT11 missense variants (NM_004626.2:c.217G > A p.Ala73Thr) and (NM_004626.2:c.865G > A p.Val289Met) in a 51-year-old woman and in a 61-year-old woman, respectively, both with bone fragility. U2OS cells with heterozygous WNT11 mutation (NM_004626.2:c.690_721delfs*40) generated by CRISPR-Cas9 showed reduced cell proliferation (30%) and osteoblast differentiation (80%) as compared with wild-type U2OS cells. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells, but recombinant WNT11 treatment rescued the expression of Wnt pathway target genes. Furthermore, the expression of RSPO2, a WNT11 target involved in bone cell differentiation, and its receptor leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), was decreased in WNT11 mutant cells. Treatment with WNT5A and WNT11 recombinant proteins reversed LGR5 expression, but Wnt family member 3A (WNT3A) recombinant protein treatment had no effect on LGR5 expression in mutant cells. Moreover, treatment with recombinant RSPO2 but not WNT11 or WNT3A activated the canonical pathway in mutant cells. In conclusion, we have identified WNT11 as a new gene responsible for EOOP, with loss-of-function variant inhibiting bone formation via Wnt canonical and non-canonical pathways. WNT11 may activate Wnt signaling by inducing the RSPO2-LGR5 complex via the non-canonical Wnt pathway.

Differences in bone microarchitecture between genetic and secondary iron-overload mouse models suggest a role for hepcidin deficiency in iron-related osteoporosis.

Iron overload is one of the secondary osteoporosis etiologies. Cellular and molecular mechanisms involved in iron-related osteoporosis are not fully understood. AIM: The aim of the study was to investigate the respective roles of iron excess and hepcidin, the systemic iron regulator, in the development of iron-related osteoporosis. MATERIAL AND METHODS: We used mice models with genetic iron overload (GIO) related to hepcidin deficiency (Hfe-/- and Bmp6-/- ) and secondary iron overload (SIO) exhibiting a hepcidin increase secondary to iron excess. Iron concentration and transferrin saturation levels were evaluated in serum and hepatic, spleen, and bone iron concentrations were assessed by ICP-MS and Perl's staining. Gene expression was evaluated by quantitative RT-PCR. Bone micro-architecture was evaluated by micro-CT. The osteoblastic MC3T3 murine cells that are able to mineralize were exposed to iron and/or hepcidin. RESULTS: Despite an increase of bone iron concentration in all overloaded mice models, bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) only decreased significantly in GIO, at 12 months for Hfe-/- and from 6 months for Bmp6-/- . Alterations in bone microarchitecture in the Bmp6-/- model were positively correlated with hepcidin levels (BV/TV (ρ = +.481, p < .05) and Tb.Th (ρ = +.690, p < .05). Iron deposits were detected in the bone trabeculae of Hfe-/- and Bmp6-/- mice, while iron deposits were mainly visible in bone marrow macrophages in secondary iron overload. In cell cultures, ferric ammonium citrate exposure abolished the mineralization process for concentrations above 5 µM, with a parallel decrease in osteocalcin, collagen 1, and alkaline phosphatase mRNA levels. Hepcidin supplementation of cells had a rescue effect on the collagen 1 and alkaline phosphatase expression level decrease. CONCLUSION: Together, these data suggest that iron in excess alone is not sufficient to induce osteoporosis and that low hepcidin levels also contribute to the development of osteoporosis.

Management and outcome of native joint septic arthritis: a nationwide survey in French rheumatology departments, 2016-2017.

OBJECTIVES: To describe current management and outcome of native joint septic arthritis (NJSA) in French rheumatology departments. METHODS: For this retrospective, nationwide multicentric study, 127 French rheumatology departments were contacted to report up to 12 cases of NJSA that occurred between 1 January 2016 and 31 December 2017. Characteristics, diagnosis procedures, therapeutic management and outcome were recorded. RESULTS: Overall, 362 patients were included (mean age 64.0±18.6 years, median Charlson comorbidity index 3.5 (0-14)). Knee was the most frequent site (n=160 (38.9%)), and Staphylococcus sp (n=185 (51.4%)), the most frequent pathogen. All patients received antibiotics for a mean duration of 46.8 (±22.0) days, including intravenous route for a mean of 17.2 (±15.4) days. Management was heterogeneous. Surgical procedure was performed in 171 (48.3%), joint immobilisation in 128 (43.8%). During follow-up, 91 (28.3%) patients have had serious complications and 28 (9.2%) of them died. Factors associated with 1-year mortality were age (OR 1.08, 95% CI 1.04 to 1.13; p<0.001), Charlson's index (OR 1.30, 95% CI 1.06 to 1.58; p=0.012), presence of bacteraemia (OR 4.02, 95% CI 1.35 to 11.99; p=0.008), antibiotic use in the previous 3 months (OR 3.32, 95% CI 1.11 to 9.87; p=0.029) and Staphylococcus aureus NJSA compared with Streptococcus sp. NJSA (OR 7.24, 95% CI 1.26 to 41.68, p=0.027). The complete recovery with no adverse joint outcome at 1 year was observed in n=125/278 patients (55.0%). CONCLUSION: Prognosis of NJSA remained severe with a high rate of morbimortality. Its management was very heterogeneous. This study highlights the importance of the new French recommendations, published after the completion of the study, in order to facilitate NJSA management.

Relevance of using both aerobic and anaerobic enrichment vials for optimizing rapid diagnosis of osteoarticular infections.

The performance of a pair of blood culture vials (BACTEC® Plus Aerobic/F, and Anaerobic Lytic/F) were analyzed in 496 osteoarticular specimens (246 synovial fluids and 250 crushed bone samples), obtained in patients during routine diagnostic procedure at the Teaching Hospital of Rennes (France). The positive detection times were recorded for a 14 day-incubation period, and compared between both vials and with agar cultures. For samples from infected patients, the positive detection time was significantly shortened when vials were used compared to agar plates (p < 0.001). Median positive detection time was later with the Anaerobic Lytic/F vials (15.0 h) compared to the Plus Aerobic/F (13.0 h). Positivity rate was similar for Anaerobic Lytic/F vials (80.4%) and Plus Aerobic/F vials (83.2%) (p = 0.25). Some microorganisms were only identified from aerobic vials (15.5%) or from anaerobic vials (12.7%). The use of both atmosphere conditions for optimal positive detection time is therefore critical.

Sacroiliac joint in sarcoidosis on computed tomography: a monocentric retrospective study (SISTER).

Sacroiliitis and spondyloarthritis (SpA) have been associated to sarcoidosis. Sarcoidosis bone involvement of the sacral or iliac bones has been reported to mimic SpA. We aimed to evaluate the prevalence of structural sacroiliitis and structural changes of the sacroiliac joints (SIJ) in patients with sarcoidosis by abdominal-pelvic computed tomography (AP-CT). In this monocentric retrospective study, three blinded readers evaluated AP-CT that had already been performed on patients with sarcoidosis and classified them as normal, degenerative, or inflammatory. A consensus was reached for the divergent cases. Erosion, ankylosis, and sclerosis, classically associated with sacroiliitis, were noted. SpA was defined according to the ASAS 2009 classification criteria. We identified 217 patients with proven sarcoidosis who underwent AP-CT. Only three patients had sacroiliitis by CT and four had SpA, representing 1.38% and 1.85% of the patients, respectively. Degenerative SIJs represented 28.1% of patients and were significantly associated with age, at least one pregnancy, rural lifestyle, ankylosis, diffuse idiopathic skeletal hyperostosis, sclerosis, and the presence of osteophytes. Four patients had axial bone sarcoidosis. Sacroiliitis, SpA, and degenerative changes of the SIJ have been highlighted by AP-CT in patients with sarcoidosis. Osteoarthritis of the SIJ in sarcoidosis was associated with age, pregnancy, and rural lifestyle. Further studies are needed to assess the link between SpA and sarcoidosis.

Calcium pyrophosphate deposition (CPPD) in a liver transplant patient: are hypomagnesemia, tacrolimus or both guilty? A case-based literature review.

Calcium pyrophosphate deposition (CPPD) can be induced by a persistent hypomagnesemia. Tacrolimus is an immunosuppressive treatment especially used in organ transplant, potentially inducer of hypomagnesemia by renal loss. A 53-year-old man, liver transplant 10 months earlier, developed an acute peripheral oligoarthritis of wrist, hip and elbow with fever, associated with acute low back pain. Synovial fluid was sterile, and revealed calcium pyrophosphate crystals. Spinal imaging showed inflammatory changes. Magnesium blood level was low at 0.51 mmol/l, with high fractional excretion in favor of renal loss. Tacrolimus was changed for everolimus, proton pump inhibitor was stopped, and magnesium oral supplementation was started. After 8 months follow-up and slow prednisone tapering, he did not relapse pain. Persistent hypomagnesemia is a rare secondary cause of CPPD. In this entity, drug liability should be investigated such as tacrolimus in organ transplant patient.

Elaboration of a new synovial predictive score of septic origin for acute arthritis on the native joint (RESAS).

OBJECTIVE: To establish a new predictive score for the diagnosis of septic arthritis (SA) according to different synovial fluid (SF) variables. METHODS: First, we analysed the different clinical, biological and SF variables associated with the diagnosis of SA (according to the Newman's criteria) in a monocentric cohort of acute arthritis (<30 days) (n = 233) (SYNOLACTATE cohort). A new score predictive of SA (RESAS) was created using the independent discriminant variables after multivariate analysis. A value was attributed to each variable of the score according to the weighting based on their likelihood ratio for the diagnosis of SA. RESAS performance was then tested on the first cohort (internal validation) and then checked on a second independent cohort (n = 70) (external validation). RESULTS: After multivariate analysis, four independent variables of the SF were included for RESAS: (i) purulent SF or white blood cells count ≥70 000/mm3; (ii) absence/presence of crystals; (iii) lactate; and (iv) glucose synovial level. RESAS ranged between -4 and +13 points. The performance of RESAS to predicted SA was excellent with area under the curve (AUC)=0.928 (0.877-0.980) in internal validation and AUC=0.986 (0.962-1.00) in external validation. For a RESAS threshold ≥+4, SA was diagnosed with Se=56.0% (0.371-0.733), Sp=98.1% (0.952-0.993), LR+=29.1 (10.4-81.6) in the first cohort and with Se=91.7% (0.646-0.985), Sp=98.3% (0.909-0.997), LR+=53.2 (7.56-373) in the second cohort. CONCLUSION: RESAS is a new composite score of four SF variables with excellent performance to predicted SA in acute arthritis population.

Surgical management of MILD hyperparathyroidism.

INTRODUCTION: There is no consensus for management of Mild primary hyperparathyroidism (MILD-pHP). Specific management has been suggested by some authors. We have compared the surgical management of the patients with MILD-pHP to those with Classic primary hyperparathyroidism (C-pHP) treated by surgery according to The Fourth International Workshop on pHP. MATERIALS AND METHODS: Data of 173 patients who underwent a parathyroidectomy were reviewed and retrospectively analysed. Management of 32 patients with MILD-pHPT (18.5%) patients were compared to that of 141 (81.5%) patients with C-pHPT. RESULTS: MILD-pHP group was more often discovered after non-fractured osteoporosis (21.9% vs 7.1%, p = 0.02) and surgery for chondrocalcinosis was more often carried out (6.3% vs 0%, p = 0.03) in the MILD-pHP group. A Mini-Invasive Parathyroidectomy (MIP) was carried out in 81.3% of cases, and 87.5% of patients had a single adenoma. The rate of multiglandular pathology was not different. Same day discharge was significantly higher in MILD-pHP group (37.5% vs 17.7%, p = 0.01). Success was obtained in 87.5% in the MILD-pHP group, there was no significant difference with the C-pHP group (92.9%, p = 0.48). There was no significant difference in the imaging performances. Imaging discordance was observed in 18.8% of cases in MILD-pHP and 33.6% in C-pHP (p = 0.38) without correlation with surgical failure. CONCLUSION: This study suggests that, by selecting patients on the basis of concordant imaging and international recommendations, there is no difference in outcome between MILD-pHP and C-pHP treated surgically.

Spleen iron, molybdenum, and manganese concentrations are coregulated in hepcidin-deficient and secondary iron overload models in mice.

Iron excess increases the hepatic expression of hepcidin, the systemic iron metabolism regulator that favors iron sequestration in the spleen. Genetic iron overload related to hepcidin insufficiency decreases the spleen iron concentration and increases hepatic iron concentration, whereas during secondary iron overload, the hepcidin expression increases together with spleen iron concentration in addition to hepatic iron concentrations increase. Links between iron metabolism and other metals being suggested, our aim was to investigate, during iron overload, the relationships between the hepatic hepcidin expression level and the hepatic and splenic concentrations of iron, manganese, copper, zinc, and molybdenum, determined using inductively coupled plasma mass spectrometry. Hepcidin-deficient mice, secondary iron overload mice models, and their respective controls were studied. Spleen molybdenum and manganese concentrations paralleled the modulation of both spleen iron concentrations, increasing in secondary iron overload and decreasing in hepcidin deficiency related iron overload, as well as hepatic hepcidin mRNA expression. Our data suggest that iron, manganese, and molybdenum metabolisms could share mechanisms controlling their distribution that are associated to hepcidin modulation. In diseases with abnormal hepcidin levels, including chronic inflammation, special attention should be paid to those metals that can participate with the phenotype.-Cavey, T., Latour, C., Island, M.-L., Leroyer, P., Guggenbuhl, P., Coppin, H., Roth, M.-P., Bendavid, C., Brissot, P., Ropert, M., Loréal, O. Spleen iron, molybdenum, and manganese concentrations are coregulated in hepcidin-deficient and secondary iron overload models in mice.

Difficult-to-treat gout flares: eligibility for interleukin-1 inhibition in private practice is uncommon according to current EMA approval.

OBJECTIVE: The objective was to determine the proportion of patients with difficult-to-treat or difficult-to-prevent acute gout attacks eligible for IL-1 inhibition. METHODS: Participants included in the French cross-sectional GOSPEL cohort (n = 1003 gout patients) were examined for contraindications and intolerance to standard of care (SoC) drugs of gout flares (colchicine, non-steroidal anti-inflammatory drugs and systemic glucocorticoids). Patients were classified as definitely eligible for first-line IL-1 inhibition (canakinumab) according to European summary of product characteristics (contraindications/intolerance to SoC and at least three flares per year) without any other anti-inflammatory options (contraindications/intolerance only), or potentially eligible (precaution of use). Eligibility to receive IL-1 during an on-going flare related to insufficient efficacy was assessed (second-line eligibility). RESULTS: Definite first-line eligibility for IL-1 therapy was found in 10 patients (1%) and contraindication to all SoC therapies in nine patients who had presented <3 flares in the past 12 months. At least precaution of use for SoC therapies was noted for 218/1003 patients (21.7%). Of 487 patients experiencing flares at baseline, 114 (23.4%) were still experiencing pain scored ⩾4/10 numeric scale on day 3, one of whom could not receive further SoC drugs. Only nine of them had three or more flares in the past year and were eligible for second-line IL-1 inhibition. CONCLUSION: Despite significant numbers of patients without any SoC anti-inflammatory therapeutic options for gout flares, eligibility for IL-1 inhibition therapy according to current European approval is rare.

Genetic analysis of adults heterozygous for ALPL mutations.

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.

Worse Outcomes of Patients With HFE Hemochromatosis With Persistent Increases in Transferrin Saturation During Maintenance Therapy.

BACKGROUND & AIMS: Even if patients with hemochromatosis maintain low serum levels of ferritin, they still have an increased risk of general and joint symptoms, which reduce quality of life. This could be related to persistently increased transferrin saturation. We assessed whether duration of exposure to increased transferrin saturation during maintenance therapy is associated with more severe general and joint symptoms. METHODS: We performed a longitudinal cohort study of 266 individuals homozygous for the C282Y substitution in HFE, seen at a tertiary reference center in Rennes, France, and followed for 3 or more years after initial iron removal. Serum ferritin and transferrin saturation were measured at the same time points; values were used to calculate duration of exposure to serum ferritin 50 µg/L or more (FRT50exp) and to determine transferrin saturation 50% or greater (SAT50exp). Clinical and biochemical follow-up data were recorded from log books completed during maintenance therapy. The primary outcome was change in general and joint symptoms, determined from answers to a self-administered questionnaire. RESULTS: Patients were followed for 13.5 ± 5.9 years. FRT50exp (3.2 ± 3.5 years) and SAT50exp (4.5 ± 3.4 years) values correlated (r = 0.38; P < .0001), but each associated with different variables in multivariate analysis. We found independent associations, regardless of follow-up time, between SAT50exp ≥6 years and worsened joint symptoms (odds ratio [OR], 4.19; 95% confidence interval [CI], 1.88-9.31), and between SAT50exp ≥6 years and decreased athletic ability (OR, 2.35; 95% CI, 1.16-4.73). SAT50exp ≥8 years associated independently with decreased work ability (OR, 3.20; 95% CI, 1.40-7.30) and decreased libido (OR, 3.49; 95% CI, 1.56-7.80). CONCLUSIONS: In a longitudinal study of patients treated for hemochromatosis, we associated duration of exposure to increased transferrin saturation (longer than 6 years) with more severe general and joint symptoms. Maintenance of serum levels of ferritin at 50 µg/L or less does not indicate control of transferrin saturation, so guidelines on the management of hemochromatosis require revision.

Atypical presentation of spine bone metastasis in prostate cancer mimicking Pott's disease.

A 55-year-old man was hospitalized for a low back pain lasting for 3 months. Spinal MRI revealed a suggestive aspect of multilevel discitis L5-S1-S2 with paravertebral abscess. A thoraco-abdominal CT scan confirmed the presence of multiple pathological lymph nodes in several locations, bilateral micronodular pulmonary infiltrate; it also showed mirror bone erosions of vertebral L5 and S1 endplates, suggestive of disseminated tuberculosis with lung involvement and lymphadenopathy. A discovertebral L5-S1 biopsy was performed confirming the diagnosis of metastatic prostatic adenocarcinoma including a tumor infiltration of the intervertebral disc, without arguments for a septic processus superimposed without tuberculosis granuloma. Although rare, cases of metastases located at the disco-vertebral junction including prostatic cancer have already been described, and should be known to the clinician. The differential diagnosis with an infectious spondylodiscitis can be difficult in some case around the vertebral disc and in case of epiduritis and soft tissues involvement on MRI sequences. Disco-vertebral biopsy remains the cornerstone of the diagnosis.

Mid-infrared fibre evanescent wave spectroscopy of serum allows fingerprinting of the hepatic metabolic status in mice.

Non-alcoholic fatty liver disease is associated with obesity, diabetes, and metabolic syndrome. The detection of systemic metabolic changes associated with alterations in the liver status during non-alcoholic fatty liver disease could improve patient follow-up. The aim of the present study was to evaluate the potential of mid-infrared fibre evanescent wave spectroscopy as a minimum-invasive method for evaluating the liver status during non-alcoholic fatty liver disease. Seventy-five mice were subjected to a control, high-fat or high-fat-high carbohydrate diets. We analysed the serum biochemical parameters and mRNA levels of hepatic genes by quantitative RT-PCR. Steatosis was quantified by image analysis. The mid-infrared spectra were acquired from serum, and then analysed to develop a predictive model of the steatosis level. Animals subjected to enriched diets were obese. Hepatic steatosis was found in all animals. The relationship between the spectroscopy-predicted and observed levels of steatosis, expressed as percentages of the liver biopsy area, was not linear. A transition around 10% steatosis was observed, leading us to consider two distinct predictive models (<10% and >10%) based on two different sets of discriminative spectral variables. The model performance was evaluated using random cross-validation (10%). The hypothesis that additional metabolic changes occur beyond this transition was supported by the fact that it was associated with increased serum ALT levels, and Col1α1 chain mRNA levels. Our data suggest that mid-infrared spectroscopy combined with statistical analysis allows identifying serum mid-infrared signatures that reflect the liver status during non-alcoholic fatty liver disease.

Risk factors of mortality during the first year after low energy osteoporosis fracture: a retrospective case-control study.

INTRODUCTION: Osteoporotic fractures are a major public health problem because of the morbidity and mortality of fracture complications. The objective of this study was to examine predictive factors of mortality during the first year after an osteoporotic fracture. METHODS: It is a retrospective case-control study using data of a group of 1081 patients aged over 50 years with severe osteoporotic fractures by the Rennes university hospital emergency department from August 2007 to September 2008. Patients (cases) who died during the year following the fracture were compared with others who had survived (controls) one year after the fracture, matched on age, sex and type of fracture. Pre-fracture comorbidities and complications after the fractures were studied. RESULTS: Forty-two cases and 126 controls were analyzed without significant differences in age, sex or type of fracture. On univariate analysis, previous neoplasia, neurodegenerative disease, walking aids, thromboembolic complication, post fracture infection, post fracture heart failure, post fracture acute respiratory failure were associated with more mortality after osteoporotic fracture. After multivariate analysis, only previous neoplasia (OR = 4.63 [1.79 - 11.95]; p = 0.02) and acute respiratory failure after fracture (OR = 28.15 [5.75 - 137.9]; p<0.001) were retained as predictive factors during the year following the fracture. CONCLUSION: Patients died more often from their co-morbidities than direct complications of their fractures. Osteoporotic fracture seems to be a marker of poor health status and a factor which may hasten the death.

Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing.

Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of HPP is performed by sequencing the ALPL gene by Sanger methodology. Osteogenesis imperfecta (OI) and campomelic dysplasia (CD) are the main differential diagnoses of severe HPP, so that in case of negative result for ALPL mutations, OI and CD genes had often to be analyzed, lengthening the time before diagnosis. We report here our 18-month experience in testing 46 patients for HPP and differential diagnosis by targeted NGS and show that this strategy is efficient and useful. We used an array including ALPL gene, genes of differential diagnosis COL1A1 and COL1A2 that represent 90% of OI cases, SOX9, responsible for CD, and 8 potentially modifier genes of HPP. Seventeen patients were found to carry a mutation in one of these genes. Among them, only 10 out of 15 cases referred for HPP carried a mutation in ALPL and 5 carried a mutation in COL1A1 or COL1A2. Interestingly, three of these patients were adults with fractures and/or low BMD. Our results indicate that HPP and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases.

[Gout: what's new?]. / La goutte: quoi de nouveau?

Despite the continuing undertreatment, gout has seen something of renaissance in terms of research into epidemiology, genetics, diagnostic criteria, imaging and new treatments. In Metropolitan France, gout prevalence was estimated at 0.9 %. A recent genome-wide association study identified new loci of interest. An easy-to-use diagnostic rule for gout care shows good performance in primary care when joint fluid analysis is not available. Gout is associated with a number of comorbidities, which may have an effect on the development of gout and on the choice of therapeutic agents. Ultrasound allows non invasive and quick detection of urate microcrystals aggregates. Low-dose colchicine may be the preferred treatment option in acute gout. Agents blocking interleukin 1 (canakinumab) can be used in acute gout when NSAIDS and colchicine are contraindicated or not tolerated. Xanthine-oxydase inhibitors (allopurinol, febuxostat) are used in first line to reach the therapeutic serum urate target < 60 mg/L. Other agents under investigation are urate transporter inhibitors promoting renal uric acid excretion, such as lesinurad, and the recombinant urate pegloticase to directly catabolise urate. The combined targeting of two different modes of action has superior urate lowering effects. Patient education is essential in chronic gout management to improve adherence to treatment.

[From chondrocalcinosis to rheumatism with calcium pyrophosphate dehydrate]. / De la chondrocalcinose au rhumatisme à cristaux de pyrophosphate de calcium.

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is a joint pathology that affects joints, fibrocartilages and periarticular structures. Chondrocalcinosis refers to CPPD deposits on the X-ray that does not summarize the disease. It willingly affects the knees and the wrists, but all the joints can be affected. There are primitive and secondary forms of the disease to particularly look for in patients less than 50 years. The diagnosis is usually easy with standard radiography, ultrasound and synovial fluid analysis that shows the microcrystals. The therapeutics of the acute attacks are nonspecific and close to those used for acute attacks of gout.

Imaging of musculoskeletal disorders related to pregnancy.

OBJECTIVE: This article provides an overview of the typical appearance of biomechanical and physiologic changes in pregnancy and an update on related pathophysiology. Conditions occurring during the childbearing, delivery and postpartum periods will be reported separately. CONCLUSION: Pregnancy causes biomechanical and physiologic changes that may be responsible for a wide spectrum of musculoskeletal disorders in the mother.

Detection of hypophosphatasia in hospitalised adults in rheumatology and internal medicine departments: a multicentre study over 10 years.

INTRODUCTION: Hypophosphatasia (HPP) is a rare genetic disease caused by loss-of-function mutations in the ALPL gene encoding the tissue non-specific alkaline phosphatase (ALP). Mild HPP is usually misdiagnosed in adult age. While an elevated serum ALP value draws more attention than a low value, low serum ALP should be better recognised and may lead to HPP detection. METHODS: Patients were selected from the records of the biochemistry department of six University Hospitals in France. Patients were hospitalised in the departments of rheumatology and internal medicine between 2007 and 2017. RESULTS: 56 321 hospitalised patients had at least 2 serum ALP dosages and 664 of these patients had at least 2 low serum ALP≤35 UI/L. Among these 664 patients, 482 (72.6%) had fluctuating low values (mean age 62.9 years; 60% of women) and 182 patients (27.4%) had persistent low values below 35 IU/L (mean age 53.4 years; 67% of women). Among patients with persistent hypophosphatasaemia treated with bisphosphonates, 70.8% never had ALP measurement before treatment and 20.8% were treated despite an abnormal decrease of ALP. Genetic testing was performed in 18 patients and was positive in 11. Genetic diagnosis of HPP was at least 6.0% in persistent hypophosphatasaemia and at least 15.9% in patients with at least three symptoms suggestive of HPP. CONCLUSION: In this 10-year retrospective study, 0.32% of adult patients hospitalised in the rheumatology and internal medicine departments had persistently low serum ALP, and among them, 6% had genetically proven HPP. Reported hypophosphatasaemia represented only 3.6% of hospitalised patients.