[The Schwartz-Jampel syndrome]. / Le syndrome de Schwartz-Jampel.

The Schwartz-Jampel syndrome (SJS, OMIM #255800) is an ultra-rare genetic disease characterized by myotonic manifestations combined with bone and cartilage abnormalities. Following an autosomal recessive mode of inheritance, its prevalence is more significant in highly-inbred areas. The unraveling of the HSPG2 gene encoding a protein of the basal lamina enabled a better nosological delineation of the syndrome. The diagnosis is usually strongly suspected at the clinical level and then confirmed by molecular biology. To date, the treatment remains essentially symptomatic.

Title: Le syndrome de Schwartz-Jampel. Abstract: Le syndrome de Schwartz-Jampel (SJS, OMIM #255800) est une affection génétique ultra-rare définie par des manifestations myotoniques et des anomalies ostéo-articulaires. Transmis selon un mode autosomique récessif, sa prévalence est plus élevée dans les zones de forte endogamie. La découverte du gène HSPG2 codant une protéine de la lame basale a permis de mieux en délimiter les contours nosologiques. Le diagnostic est généralement très fortement suspecté cliniquement puis confirmé en biologie moléculaire. Le traitement reste à ce jour essentiellement symptomatique.

Chlorogenic acid suppresses miR-460a in the regulation of Bcl-2, causing interleukin-1ß reduction in thiram exposed chondrocytes via caspase-3/caspase-7 pathway.

BACKGROUND: Apoptosis is thought to be involved in all processes, including normal cell cycle, immune system, atrophy, embryonic development, and chemical-induced cellular damage. However, if the normal apoptotic process fails, the results might be disastrous, e.g., chondrocytes damage in tibial dyschondroplasia (TD). TD is a worldwide issue in the poultry sector due to thiram toxicity. Thiram (Tetramethyl thiuram disulfide) is a dithiocarbamate pesticide and fungicide commonly used in horticulture to treat grains meant for seed protection and preservation. PURPOSE: According to prior studies, chlorogenic acid (CGA) is becoming essential for regulating apoptosis. But still, the specific role of CGA in chondrocyte cells remains unclear. The present study explored the molecular mechanism of CGA on chondrocytes' apoptosis with B-cell lymphoma 2 signaling under the effect of miR-460a. METHODS: An in vivo and in vitro study was performed according to our previously developed methodology. Flow cytometry, western blotting, reverse transcription-quantitative polymerase chain reaction, and immunofluorescence assay were used to investigate the involvement of apoptosis and inflammasome related pathways. RESULTS: The CGA decreased the apoptosis rate with the deactivation of miR-460a, accompanied by the activation of Bcl-2. The high expression of miR-460a reduced the cell viability of chondrocytes in vitro and in vivo, that led to the interleukin-1ß production. While the apoptotic executioners (caspase-3 and caspase-7) acted upstream in miR-460a overexpressing cells, and its depletion downgraded these executioners. The CGA administrated cells negatively regulated miR-460a expression and thus indicating the deactivation of the apoptotic and inflammasome related pathways. CONCLUSION: Chlorogenic acid had a negative effect on miR-460a, setting off specific feedback to regulate apoptotic and inflammasome pathways, which might be a key feature for chondrocytes' survival.

Cluster of differentiation 147 (CD147) expression is linked with thiram induced chondrocyte's apoptosis via Bcl-2/Bax/Caspase-3 signalling in tibial growth plate under chlorogenic acid repercussion.

Tibial dyschondroplasia (TD) is a metabolic disease of young poultry that affects bone andcartilage's growth. It mostly occurs in broilers due to thiram toxicity in the feed. In this disease, tibial cartilage is not yet ripe for ossification, but it also results in lameness, death, and moral convictions of commercial poultry due to numerous apoptotic changes on cell level. These changes serve a cardinal role in this situation. Many potential problems indicate that chlorogenic acid (CGA) performs an extensive role in controlling apoptosis's perception. However, the actual role of CGA in TD affected chondrocytes in-vitro is still unidentified. The current study investigates the imperceptible insight of CGA on chondrocyte's apoptosis via B-cell lymphoma 2 (Bcl-2), Bcl-2 associated x-protein (Bax), and Caspase-3 with CD147 signalling. The expression of these markers was investigated by Immunofluorescence, western blot analysis, and reverse transcription-quantitative polymerase chain (RT-qPCR). Chondrocytes from the growth plate of tibia were isolated, cultured, and processed. A sub-lethal thiram (2.5 µg/mL) was used to induce cytotoxicity and then treated with an optimum dose (40 µg/ mL) of CGA. According to the results, thiram distorted chondrocyte cells with enhanced apoptotic rate. But, in case of CGA, high expression of CD147 enhanced cell viability of chondrocytes, accompanied by downregulation of Bax/Caspase-3 signalling with the upregulation of Bcl-2. The first possibility has ruled out in the present study by the observation that the cells apoptosis marker, Caspase-3 showed a significant change in CD147 overexpressing cells. Conversely, immunodepletion of CD147 with enhanced cleavage of Caspase-3, indicating the activation of apoptosis in chondrocytes cells. Therefore, these findings suggest a novel insight about CD147 in thiram induced TD about the regulation of Bcl-2/Bax/Caspase-3 apoptosis-signalling axis.

Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption.

Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases.

Novel compound heterozygous variants of TBXAS1 presenting with Ghosal hematodiaphyseal dysplasia treated with steroids.

BACKGROUND: Homozygous or compound heterozygous pathogenic variants in the thromboxane A synthase 1 (TBXAS1) gene are associated with Ghosal hematodiaphyseal dysplasia (GHDD) which is characterized by defective hematopoiesis and increased bone density of long bones. METHODS: Patients 1 and 2 are identical twins, who presented with red blood cell transfusion-dependent normocytic anemia and thrombocytopenia with bone marrow fibrosis and cortical bone thickening of long bones on plain radiograph. To clarify the etiology of their anemia and thrombocytopenia, whole blood was used for the DNA extraction and analyzed using next-generation sequencing (NGS) on an in-house bone marrow failure syndrome panel. RESULTS: The NGS results indicated that these two patients carried two heterozygous variants in TBXAS1, exon7, c.583_584del, p.Ala195Leufs*12, and exon12, c.1420G>T, p.Gly474Trp, which were inherited from their mother and father, respectively. Patients 1 and 2 have been on chronic oral steroids with normalization of hemoglobin and platelet count after steroid initiation. Patient 3 is their sister who has normal blood counts but also has the same variants in TBXAS1 as her brothers. Radiographs showed cortical bone thickening and she has not required any treatment or transfusion. CONCLUSION: We report three Caucasian siblings from non-consanguineous parents with novel compound heterozygous variants of TBXAS1 presenting with the phenotypes of GHDD. These three cases illustrate the variable clinical expressivity of the GHDD from two-compound heterozygous pathogenic variants of TBXAS1.

Glutathione-S-transferase A3 protein suppresses thiram-induced tibial dyschondroplasia by regulating prostaglandin-related genes expression.

Tibial dyschondroplasia (TD) is an intractable avian cartilage disease in which proximal growth plates of tibia lack blood vessels and contain nonviable cells, and it leads to the inflammatory response. Prostaglandins (PGs) genes have not been studied yet in TD chicken, and they might play role in skeletal metabolism, therefore we planned to explore the role of recombinant glutathione-S-transferase A3 (rGSTA3) protein and PG-related genes. In this study, qRT-PCR, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) analysis were used to identify the expression patterns of eight PG-related genes in the tibial growth plate of broiler chicken. The results showed that the expression of PG-related genes glutathione-S-transferase A3 (GSTA3), cyclooxygenase 2 (COX-2), prostaglandin D2 synthase (PTGDS), prostaglandin E synthase (PTGES), prostaglandin E2 receptor (PTGER) 3, PTGER4, prostaglandin reductase 1 (PTGR1) and hematopoietic prostaglandin D synthases (HPGDS) expression were identified and could significantly respond to thiram-induced TD chicken. Interestingly, the expression of rate-limiting enzyme COX-2 and PGE2 were induced after the treatment of rGSTA3 protein. These findings demonstrated that the occurrence of TD is closely related to the inhibition of PGs. Moreover, rGSTA3 protein participated in the recovery of TD by strengthening the expression of PG-related genes.

Multiple epiphyseal dysplasia and related disorders: Molecular genetics, disease mechanisms, and therapeutic avenues.

For the vast majority of the 6000 known rare disease the pathogenic mechanisms are poorly defined and there is little treatment, leading to poor quality of life and high healthcare costs. Genetic skeletal diseases (skeletal dysplasias) are archetypal examples of rare diseases that are chronically debilitating, often life-threatening and for which no treatments are currently available. There are more than 450 unique phenotypes that, although individually rare, have an overall prevalence of at least 1 per 4000 children. Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous disorder characterized by disproportionate short stature, joint pain, and early-onset osteoarthritis. MED is caused by mutations in the genes encoding important cartilage extracellular matrix proteins, enzymes, and transporter proteins. Recently, through the use of various cell and mouse models, disease mechanisms underlying this diverse phenotypic spectrum are starting to be elucidated. For example, ER stress induced as a consequence of retained misfolded mutant proteins has emerged as a unifying disease mechanisms for several forms of MED in particular and skeletal dysplasia in general. Moreover, targeting ER stress through drug repurposing has become an attractive therapeutic avenue.

Treatment of tibial dyschondroplasia with traditional Chinese medicines: "Lesson and future directions".

Tibial dyschondroplasia (TD) is a metabolic tibiotarsal bone disease in rapidly growing birds throughout the world, which is characterized by gait disorders, reduced growth, and in an unrecoverable lameness in many cases. The short production cycle in chickens, long metabolism cycle in most of the drugs with the severe drug residue, and high treatment cost severely restrict the enthusiasm for the treatment of TD. Traditional Chinese medicine (TCM) has been used for the prevention, treatment, and cure of avian bone diseases. Previously, a couple of traditional Chinese medicines has been reported being useful in treating TD. This review will discuss the TCM used in TD and the alternative TCM to treat TD. Selecting a TCM approach and its pharmacologic effects on TD chickens mainly focused on the differentiation, proliferation, and apoptosis of chondrocytes, angiogenesis, matrix metabolism, oxidative damage, cytokines, and calcification of cartilage in tibia.

Use of Growth Hormone Treatment in Skeletal Dysplasia - A Review.

Skeletal dysplasias are the disorders of the skeletal and cartilaginous tissues. Short stature is the hallmark presentation. Achondroplasia is the commonest skeletal dysplasia. Growth hormone (GH) has been widely used in children with achondroplasia. Various studies have shown 1st year increase in height velocity is about 2-3cm. Apart from achondroplasia, studies have also shown positive effect of GH in hypochondroplasia children. However, in hypochondroplasia GH treatment seems to give better results when administered at puberty. Other forms of skeletal dysplasias are rare, so no conclusion on GH use in such patients can be drawn.

"Electrifying dysmorphology": Potassium channelopathies causing dysmorphic syndromes.

Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.

Diabetes management in Wolcott-Rallison syndrome: analysis from the German/Austrian DPV database.

BACKGROUND: Wolcott-Rallison syndrome (WRS) is characterized by permanent early-onset diabetes, skeletal dysplasia and several additional features, e.g. recurrent liver failure. This is the first multicentre approach that focuses on diabetes management in WRS. We searched the German/Austrian Diabetes-Patienten-Verlaufsdokumentation (DPV) registry and studied anthropometric characteristics, diabetes treatment, glycaemic control and occurrence of severe hypoglycaemia (SH) and diabetic ketoacidosis (DKA) in 11 patients with WRS. Furthermore, all local treatment centres were personally contacted to retrieve additional information on genetic characteristics, migration background and rate of consanguinity. RESULTS: Data were analysed at diabetes onset and after a median follow-up period of 3 (1.5-9.0) years (time from diagnosis to latest follow-up). Median age at diabetes onset was 0.2 (0.1-0.3) years, while onset was delayed in one patient (aged 16 months). Seventy percent of patients manifested with DKA. At follow-up, 90% of patients were on insulin pump therapy requiring 0.7 [0.5-1.0] IU of insulin/kg/d. More than two third of patients had HbA1c level ≥ 8%, 40% experienced at least one episode of SH in the course of the disease. Three patients died at 0.6, 5 and 9 years of age, respectively. To the best of our knowledge three patients carried novel mutations in EIF2AK3. CONCLUSION: Insulin requirements of individuals with WRS registered in DPV appear to be comparable to those of preschool children with well-controlled type 1 diabetes, while glycaemic control tends to be worse and episodes of SH tend to be more common. The majority of individuals with WRS in the DPV registry does not reach glycaemic target for HbA1c as defined for preschool children (< 7.5%). International multicentre studies are required to further improve our knowledge on the care of children with WRS.

Acquired cutis laxa secondary to Sweet syndrome in a child (Marshall syndrome): A rare case report.

Sweet syndrome is rare in the pediatric population and usually responds well to treatment, resolving without sequelae. Marshall syndrome is a rare pediatric skin disease characterized by loss of elastic tissue (cutis laxa) secondary to acquired, localized neutrophilic dermatitis without any internal organ involvement. Only few cases of Marshall syndrome (acquired cutis laxa type II) have been reported. Systemic steroids and dapsone show excellent results in Sweet syndrome. Although there is no satisfactory treatment for cutis laxa, dapsone can be used in the acute phase for control of swelling.

Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity.

Cantu syndrome (CS) is a complex disorder caused by gain-of-function (GoF) mutations in ABCC9 and KCNJ8, which encode the SUR2 and Kir6.1 subunits, respectively, of vascular smooth muscle (VSM) KATP channels. CS includes dilated vasculature, marked cardiac hypertrophy, and other cardiovascular abnormalities. There is currently no targeted therapy, and it is unknown whether cardiovascular features can be reversed once manifest. Using combined transgenic and pharmacological approaches in a knockin mouse model of CS, we have shown that reversal of vascular and cardiac phenotypes can be achieved by genetic downregulation of KATP channel activity specifically in VSM, and by chronic administration of the clinically used KATP channel inhibitor, glibenclamide. These findings demonstrate that VSM KATP channel GoF underlies CS cardiac enlargement and that CS-associated abnormalities are reversible, and provide evidence of in vivo efficacy of glibenclamide as a therapeutic agent in CS.

An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen's Metaphyseal Chondrodysplasia.

Jansen's metaphyseal chondrodysplasia (JMC) is a rare disease of bone and mineral ion physiology that is caused by activating mutations in PTHR1. Ligand-independent signaling by the mutant receptors in cells of bone and kidney results in abnormal skeletal growth, excessive bone turnover, and chronic hypercalcemia and hyperphosphaturia. Clinical features further include short stature, limb deformities, nephrocalcinosis, and progressive losses in kidney function. There is no effective treatment option available for JMC. In previous cell-based assays, we found that certain N-terminally truncated PTH and PTHrP antagonist peptides function as inverse agonists and thus can reduce the high rates of basal cAMP signaling exhibited by the mutant PTHR1s of JMC in vitro. Here we explored whether one such inverse agonist ligand, [Leu11 ,dTrp12 ,Trp23 ,Tyr36 ]-PTHrP(7-36)NH2 (IA), can be effective in vivo and thus ameliorate the skeletal abnormalities that occur in transgenic mice expressing the PTHR1-H223R allele of JMC in osteoblastic cells via the collagen-1α1 promoter (C1HR mice). We observed that after 2 weeks of twice-daily injection and relative to vehicle controls, the IA analog resulted in significant improvements in key skeletal parameters that characterize the C1HR mice, because it reduced the excess trabecular bone mass, bone marrow fibrosis, and levels of bone turnover markers in blood and urine. The overall findings provide proof-of-concept support for the notion that inverse agonist ligands targeted to the mutant PTHR1 variants of JMC can have efficacy in vivo. Further studies of such PTHR1 ligand analogs could help open paths toward the first treatment option for this debilitating skeletal disorder. © 2019 American Society for Bone and Mineral Research.

Plastrum Testudinis Extract Mitigates Thiram Toxicity in Broilers via Regulating PI3K/AKT Signaling.

Tibial dyschondroplasia (TD) negatively affects broilers all over the world, in which the accretion of the growth plate (GP) develops into tibial proximal metaphysis. Plastrum testudinis extract (PTE) is renowned as a powerful antioxidant, anti-inflammatory, and bone healing agent. The current study was conducted to evaluate the efficacy of PTE for the treatment of thiram-induced TD chickens. Broilers (day old; n = 300) were raised for 3 days with normal feed. On the 4th day, three groups (n = 100 each) were sorted, namely, the control (normal diet), TD, and PTE groups (normal diet+ thiram 50 mg/kg). On the 7th day, thiram was stopped in the TD and PTE group, and the PTE group received a normal diet and PTE (30 mg/kg/day). Plastrum testudinis extract significantly restored (p < 0.05) the liver antioxidant enzymes, inflammatory cytokines, serum biochemicals, GP width, and tibia weight as compared to the TD group. The PTE administration significantly increased (p < 0.05) growth performance, vascularization, AKT (serine/threonine-protein kinase), and PI3K expressions and the number of hepatocytes and chondrocytes with intact nuclei were enhanced. In conclusion, PTE has the potential to heal TD lesions and act as an antioxidant and anti-inflammatory drug in chickens exposed to thiram via the upregulation of AKT and PI3K expressions.