p53 as a Potential Actionable Target in Myxofibrosarcoma: A Molecular and Pathologic Review of a Single-Institute Series.

Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by high-local recurrence rate, poorly understood molecular pathogenesis, lack of specific prognostic markers, and effective targeted therapies. To gain further insights into the disease, we analyzed a well-defined group of 133 primary MFS cases. Immunohistochemical (IHC) staining for p53, MET, RET, and RB was performed. Twenty-five cases were analyzed by targeted resequencing of known cancer driver hotspot mutations, whereas 66 and 64 MFSs were examined for the presence of genetic variants in TP53 and MET gene, respectively. All clinical, histologic, immunostaining, and genetic variables were analyzed for their impact on 5-years overall survival (OS) and 5-years event-free survival (EFS). In our series, no grade I tumors relapsed and high grade are related to a positive MET immunostaining (P = .034). Both local recurrence (P = .038) and distal metastases (P = .016) correlated to the presence of "single nucleotide variant (SNV) plus copy number variation (CNV)" in TP53. Multivariate analysis revealed that age (>60 years), metastasis at presentation, and positive IHC-p53 signal are risk factors for a poor OS (P = .003, P = .000, and P = .002), whereas age (>60 years), synchronous metastasis, and tumor size (>10 cm) predict an unfavorable 5-years EFS (P = .011, P = .000, and P = .023). Considering the smaller series (n = 66) that underwent molecular screening, the presence of "SNV+CNV" in TP53 represents a risk factor for a worse 5-years EFS (hazard ratio, 2.5; P = .017). The present series confirms that TP53 is frequently altered in MFS (86.4% of cases), appearing to play an important role in MFS tumorigenesis and being a potentially drugable target. A positive p53 immunostainings is related to a poor diagnosis, and it is the presence of a single nucleotide genetic alterations in TP53 that is essential in conferring MFS an aggressive phenotype, thus supporting the use of molecular profiling in MFS to better define the role of p53 as a prognostic factor.

The Role of the European Reference Network for Rare Bone Diseases (ERN BOND) and European Registries for Rare Bone and Mineral Conditions (EuRR-Bone) in the Governance of the Management of Rare Bone and Mineral Diseases.

Rare diseases (RDs) bear a significant challenge to individuals, healthcare systems, and societies. The European reference network on Rare BONe diseases (ERN BOND) is committed to improving multidisciplinary, patient-centred care for individuals with rare bone and mineral diseases (RBMDs). Its affiliated project, the European registries for rare bone and mineral conditions (EuRR-Bone) collects data using two different platforms, an electronic surveillance system (e-REC) that captures the occurrence of RBMDs and the Core Registry, a platform with the infrastructure for collecting Core data fields and longitudinal generic and condition-specific information. With emerging registries and the overlap with other ERNs, it is key to maintain the capability of the platforms to adapt to the needs of the network and the community whilst adhering to quality and FAIR (findable, accessible, interoperable, and reusable) principles. This binomial ensures long-term sustainability and potential advances in the care pathway of RBMDs whilst promoting good practice standards within Europe and beyond.

Health-related quality of life and associated risk factors in patients with Multiple Osteochondromas: a cross-sectional study.

PURPOSE: To evaluate the health-related quality of life and associated risk factors for Multiple Osteochondromas patients. METHODS: A cross-sectional, observational study was conducted from May to December 2022 during the routine visit to the referral center for rare skeletal disorders. All patients with Multiple Osteochondromas aged ≥ 3 years were included. EuroQol 5-dimension questionnaires, and demographic, clinical, and surgical history data were collected. Descriptive statistics, Fisher's exact test, One-sample t-test, Spearman's correlation, and multiple linear and logistic regression were performed to analyze the data. Results are reported following STROBE guidelines. RESULTS: A total of 128 patients were included in the study, with a mean age of 14 [SD, 10] years. The mean EQ-5D Index Value was 0.863 [SD, 0.200] and the EQ-VAS was 84 [SD, 19] with a positive correlation between two scores [r = 0.541, p < 0.001]. Patients frequently referred problems in pain/discomfort [78.8%], anxiety/depression [50%], and usual activities [38.8%] dimensions. Increasing age was the common risk factor for health-related quality of life [p < 0.000], as well as Index Value and VAS scores were significantly lower in surgical patients [p = 0.001 and p < 0.001, respectively]. CONCLUSION: Increasing age and surgical procedures were found highly associated with reduced health-related quality of life in Multiple Osteochondromas patients. Our findings provide relevant information to support the establishment of patient-centered healthcare pathways and pave the way for further research into medical and non-medical therapeutic strategies for these patients.

Cost-effectiveness of bringing a nurse into an Italian genetic day clinic: a before and after study.

BACKGROUND: Only a few studies explore the role of nurses in genetic counselling and genetic health care, and none of them is related to orphan diseases. In addition, few studies address the issue of finding variables that might affect the economy of a service or perform a cost-effectiveness analysis of a having genetic nurse at a unit. METHODS: A multidisciplinary panel of experts working in the hospital was set up to identify sensitive indicators and remove confounding variables. This panel evaluated efficiency and effectiveness indicators and drafted a questionnaire to estimate patient perception of the quality of the service. Data were captured from different sources, including the hospital patient database and a web-accessible platform for data collection. More than 600 clinical evaluations of 400 patients were considered, and economic parameters were studied by applying Porter's Time-Driven Activity-Based Costing methodology to evaluate costs and outcomes. Additionally, an anonymous, semi-structured, paper-and-pencil interview questionnaire was given to patients at their periodic follow-ups. RESULTS: The results showed an increase in the quality of patient management, more accurate data capturing, and higher quality ambulatory care. In fact, approximately 70% of the respondents reported positive changes. In addition, a parallel economic analysis explored indicators influencing economic impact, and outcomes showed positive results with the quality of outcomes improving more compared to the increase in costs. CONCLUSIONS: The variety of evaluated issues highlighted that having a nurse in a genetic service and at day clinic activities resulted in better access, better scheduling, more satisfaction, and proved to be a cost-effective solution for patients affected by rare diseases.

Vitamin D and Bone fragility in Individuals with Osteogenesis Imperfecta: A Scoping Review.

Vitamin D affects several body functions, and thus general health, due to its pleiotropic activity. It plays a key role in bone metabolism, and its deficiency impacts bone development, leading to bone fragility. In osteogenesis imperfecta (OI), a group of hereditary connective tissue disorders characterized by bone fragility, additional factors, such as vitamin D deficiency, can affect the expression of the phenotype and aggravate the disorder. The aim of this scoping review was to assess the incidence of vitamin D deficit in OI patients and the association between vitamin D status and supplementation in individuals affected by OI. We searched the PubMed Central and Embase databases and included studies published between January/2000 and October/2022 evaluating vitamin D measurement and status (normal, insufficiency, deficiency) and supplementation for OI. A total of 263 articles were identified, of which 45 were screened by title and abstract, and 10 were included after a full-text review. The review showed that low levels of vitamin D was a frequent finding in OI patients. Vitamin D supplementation was mainly indicated along with drug therapy and calcium intake. Even if widely used in clinical practice, vitamin D supplementation for OI individuals still needs a better characterization and harmonized frame for its use in the clinical setting, as well as further studies focusing on its effect on bone fragility.

Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I.

Neurofibromatosis type I, a genetic condition due to pathogenic variants in the NF1 gene, is burdened by a high rate of complications, including neoplasms, which increase morbidity and mortality for the disease. We retrospectively re-evaluated the NF1 gene variants found in the period 2000-2019 and we studied for genotype/phenotype correlations of disease complications and neoplasms 34 variants, which were shared by at least two unrelated families (range 2-11) for a total 141 of probands and 21 relatives affected by Neurofibromatosis type I. Recurrent variants could be ascribed to the most common mutational mechanisms (C to T transition, microsatellite slippage, non-homologous recombination). In genotype/phenotype correlations, the variants p.Arg440*, p.Tyr489Cys, and p.Arg1947*, together with the gross gene deletions, displayed the highest rates of complications. When considering neoplasms, carriers of variants falling in the extradomain region at the 5' end of NF1 had a lower age-related cancer frequency than the rest of the gene sequence, showing a borderline significance (p = 0.045), which was not conserved after correction with covariates. We conclude that (1) hotspots in NF1 occur via different mutational mechanisms, (2) several variants are associated with high rates of complications and cancers, and (3) there is an initial evidence toward a lower cancer risk for carriers of variants in the 5' end of the NF1 gene although not significant at the multivariate analysis.

Preanalytical DNA assessment for downstream applications: How to optimize the management of human biospecimens to support molecular diagnosis-An experimental study.

BACKGROUND: The development of next-generation sequencing approaches has accelerated the diagnostic process, although at present, there is a lack of a clear consensus on efficient management of human samples for downstream applications. This study aims to investigate timeframe (in terms of short preservation), temperature, and additional preservation procedures (i.e., freeze and thaw cycles) for human biospecimens to implement the reliability and reproducibility of molecular investigations. METHODS: Overall, 45 whole peripheral bloods, 22 peripheral blood mononuclear cells samples, 15 saliva, and 15 buccal swab biospecimens (through the extracted DNA) were investigated, assessing yield, integrity, amplifiability, and sizing accuracy via the most common molecular techniques. RESULTS: Based on the overall evaluation criteria, the results indicate that DNA extracted from all samples, shortly preserved, have suitable quality and reliable reproducibility to be used in diagnostic activities and biomedical research, even if DNA from peripheral blood mononuclear cells is more affected by the experimental conditions. CONCLUSION: Our findings confirm the reliability of peripheral blood samples in almost all the experimental conditions. Saliva and buccal swabs are efficient almost as well, while peripheral blood mononuclear cells, albeit remain a primary source of DNA for molecular screenings, represent a less efficient source.

Laniakea@ReCaS: exploring the potential of customisable Galaxy on-demand instances as a cloud-based service.

BACKGROUND: Improving the availability and usability of data and analytical tools is a critical precondition for further advancing modern biological and biomedical research. For instance, one of the many ramifications of the COVID-19 global pandemic has been to make even more evident the importance of having bioinformatics tools and data readily actionable by researchers through convenient access points and supported by adequate IT infrastructures. One of the most successful efforts in improving the availability and usability of bioinformatics tools and data is represented by the Galaxy workflow manager and its thriving community. In 2020 we introduced Laniakea, a software platform conceived to streamline the configuration and deployment of "on-demand" Galaxy instances over the cloud. By facilitating the set-up and configuration of Galaxy web servers, Laniakea provides researchers with a powerful and highly customisable platform for executing complex bioinformatics analyses. The system can be accessed through a dedicated and user-friendly web interface that allows the Galaxy web server's initial configuration and deployment. RESULTS: "Laniakea@ReCaS", the first instance of a Laniakea-based service, is managed by ELIXIR-IT and was officially launched in February 2020, after about one year of development and testing that involved several users. Researchers can request access to Laniakea@ReCaS through an open-ended call for use-cases. Ten project proposals have been accepted since then, totalling 18 Galaxy on-demand virtual servers that employ ~ 100 CPUs, ~ 250 GB of RAM and ~ 5 TB of storage and serve several different communities and purposes. Herein, we present eight use cases demonstrating the versatility of the platform. CONCLUSIONS: During this first year of activity, the Laniakea-based service emerged as a flexible platform that facilitated the rapid development of bioinformatics tools, the efficient delivery of training activities, and the provision of public bioinformatics services in different settings, including food safety and clinical research. Laniakea@ReCaS provides a proof of concept of how enabling access to appropriate, reliable IT resources and ready-to-use bioinformatics tools can considerably streamline researchers' work.

The Rizzoli Multiple Osteochondromas Classification revised: describing the phenotype to improve clinical practice.

Multiple osteochondromas (MO) is a rare disorder, characterized by benign osteocartilaginous tumors (osteochondromas), arising from the perichondrium of bones. The osteochondromas increase during growth, frequently causing deformities and limitations. Our study aims to analyze the data captured by the Registry of Multiple Osteochondromas, to refine Istituto Ortopedico Rizzoli (IOR) Classification, providing a representative picture of the phenotypic manifestations throughout the lifespan. We conducted a single-institution cross-sectional study. Patients were categorized according to IOR Classification, which identifies three patients' classes on the presence/absence of deformities and/or limitations. The present dataset was compared with our previously published data, to refine the classification. Nine hundred sixty-eight patients were included: 243 children (<10 years), 136 adolescents (10-15 years), and 589 adults. Of the entire population, half patients presented at least one deformity, and one quarter reported at least one limitation. Compared with our previous study, the amount of children was more than doubled and the percentage of mild/moderate cases was notably increased, giving a better disease overview throughout the lifespan and suggesting a different cut-off for dividing Class II in subclasses. We confirmed that MO is characterized by phenotypic heterogeneity, suggesting that an early classification of the disease may offer a useful tool to follow disease pattern and evolution, to support clinical practice, and to propose timely interventions.

Imaging of Congenital Skeletal Disorders.

Osteochondrodysplasias are the result of the expression of gene mutations. The phenotypes in osteochondrodysplasias evolve through life, with the possibility that previously unaffected bones may be involved at later stages of growth. Due to the variable time of onset, the diagnosis may be made prenatally, at birth, or later. Certainty in the diagnosis is sometimes only achieved as the patient matures and the disease evolves. Radiographic evaluation is a fundamental part of the diagnostic work-up of congenital skeletal disorders and in most cases the first tool used to arrive at a diagnosis. This review describes the imaging characteristics, specific signs, and evolution of several skeletal dysplasias in which diagnosis may be directly or indirectly suggested by radiologic findings. A definitive accurate diagnosis of a congenital skeletal abnormality is necessary to help provide a prognosis of expected outcomes and to counsel parents and patients.

Melorheostosis and Osteopoikilosis Clinical and Molecular Description of an Italian Case Series.

Melorheostosis (MEL) is an uncommon, sclerosing disease, characterised by hyperostosis of long bones, resembling the flowing of candle wax. The disease is sporadic and the pathogenesis is still poorly understood. Occasionally, the same family can include individuals with MEL and Osteopoikilosis (OPK), a disease characterised by multiple round foci of increased bone density. LEMD3 gene mutations are related to OPK and Buschke-Ollendorff Syndrome, a genetic condition in which an association between MEL, OPK and skin lesions is observed. In rare cases, LEMD3 mutations and recently mosaic MAP2K1 gene mutations have been correlated to MEL suggesting that somatic mosaicism could be causative of the disease. In this study, we described the clinical, radiological and molecular findings of 19 individuals with MEL and 8 with OPK and compared the results to the medical literature. The molecular analyses of this case series corroborate the available data in the medical literature, indicating that LEMD3 germline mutations are not a major cause of isolated MEL and reporting five further cases of OPK caused by LEMD3 germline mutations.

Nosology and classification of genetic skeletal disorders: 2019 revision.

The application of massively parallel sequencing technology to the field of skeletal disorders has boosted the discovery of the underlying genetic defect for many of these diseases. It has also resulted in the delineation of new clinical entities and the identification of genes and pathways that had not previously been associated with skeletal disorders. These rapid advances have prompted the Nosology Committee of the International Skeletal Dysplasia Society to revise and update the last (2015) version of the Nosology and Classification of Genetic Skeletal Disorders. This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes. Remarkably, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders. By providing a reference list of recognized entities and their causal genes, the Nosology should help clinicians achieve accurate diagnoses for their patients and help scientists advance research in skeletal biology.

Structural Features of Heparan Sulfate from Multiple Osteochondromas and Chondrosarcomas.

Multiple osteochondromas (MO) is a hereditary disorder associated with benign cartilaginous tumors, known to be characterized by absence or highly reduced amount of heparan sulfate (HS) in the extracellular matrix of growth plate cartilage, which alters proper signaling networks leading to improper bone growth. Although recent studies demonstrated accumulation of HS in the cytoplasm of MO chondrocytes, nothing is known on the structural alterations which prevent HS from undergoing its physiologic pathway. In this work, osteochondroma (OC), peripheral chondrosarcoma, and healthy cartilaginous human samples were processed following a procedure previously set up to structurally characterize and compare HS from pathologic and physiologic conditions, and to examine the phenotypic differences that arise in the presence of either exostosin 1 or 2 (EXT1 or EXT2) mutations. Our data suggest that HS chains from OCs are prevalently below 10 kDa and slightly more sulfated than healthy ones, whereas HS chains from peripheral chondrosarcomas (PCSs) are mostly higher than 10 kDa and remarkably more sulfated than all the other samples. Although deeper investigation is still necessary, the approach here applied pointed out, for the first time, structural differences among OC, PCS, and healthy HS chains extracted from human cartilaginous excisions, and could help in understanding how the structural features of HS are modulated in the presence of pathological situations also involving different tissues.

Nosology and classification of genetic skeletal disorders: 2015 revision.

The purpose of the nosology is to serve as a "master" list of the genetic disorders of the skeleton to facilitate diagnosis and to help delineate variant or newly recognized conditions. This is the 9th edition of the nosology and in comparison with its predecessor there are fewer conditions but many new genes. In previous editions, diagnoses that were phenotypically indistinguishable but genetically heterogenous were listed separately but we felt this was an unnecessary distinction. Thus the overall number of disorders has decreased from 456 to 436 but the number of groups has increased to 42 and the number of genes to 364. The nosology may become increasingly important today and tomorrow in the era of big data when the question for the geneticist is often whether a mutation identified by next generation sequencing technology in a particular gene can explain the clinical and radiological phenotype of their patient. This can be particularly difficult to answer conclusively in the prenatal setting. Personalized medicine emphasizes the importance of tailoring diagnosis and therapy to the individual but for our patients with rare skeletal disorders, the importance of tapping into a resource where genetic data can be centralized and made available should not be forgotten or underestimated. The nosology can also serve as a reference for the creation of locus-specific databases that are expected to help in delineating genotype-phenotype correlations and to harbor the information that will be gained by combining clinical observations and next generation sequencing results.

In vitro biosafety profile evaluation of multipotent mesenchymal stem cells derived from the bone marrow of sarcoma patients.

BACKGROUND: In osteosarcoma (OS) and most Ewing sarcoma (EWS) patients, the primary tumor originates in the bone. Although tumor resection surgery is commonly used to treat these diseases, it frequently leaves massive bone defects that are particularly difficult to be treated. Due to the therapeutic potential of mesenchymal stem cells (MSCs), OS and EWS patients could benefit from an autologous MSCs-based bone reconstruction. However, safety concerns regarding the in vitro expansion of bone marrow-derived MSCs have been raised. To investigate the possible oncogenic potential of MSCs from OS or EWS patients (MSC-SAR) after expansion, this study focused on a biosafety assessment of MSC-SAR obtained after short- and long-term cultivation compared with MSCs from healthy donors (MSC-CTRL). METHODS: We initially characterized the morphology, immunophenotype, and differentiation multipotency of isolated MSC-SAR. MSC-SAR and MSC-CTRL were subsequently expanded under identical culture conditions. Cells at the early (P3/P4) and late (P10) passages were collected for the in vitro analyses including: sequencing of genes frequently mutated in OS and EWS, evaluation of telomerase activity, assessment of the gene expression profile and activity of major cancer pathways, cytogenetic analysis on synchronous MSCs, and molecular karyotyping using a comparative genomic hybridization (CGH) array. RESULTS: MSC-SAR displayed comparable morphology, immunophenotype, proliferation rate, differentiation potential, and telomerase activity to MSC-CTRL. Both cell types displayed signs of senescence in the late stages of culture with no relevant changes in cancer gene expression. However, cytogenetic analysis detected chromosomal anomalies in the early and late stages of MSC-SAR and MSC-CTRL after culture. CONCLUSIONS: Our results demonstrated that the in vitro expansion of MSCs does not influence or favor malignant transformation since MSC-SAR were not more prone than MSC-CTRL to deleterious changes during culture. However, the presence of chromosomal aberrations supports rigorous phenotypic, functional and genetic evaluation of the biosafety of MSCs, which is important for clinical applications.

Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.

Secondary peripheral chondrosarcoma in multiple osteochondromas: a retrospective single-institution case series.

BACKGROUND: Multiple osteochondromas is genetic disorder characterized by the formation of multiple benign cartilage-capped bone tumors, named osteochondromas, during skeletal development. The most feared complication is the secondary peripheral chondrosarcoma, a malignant cartilaginous neoplasm that arises from the chondroid cap of pre-existent osteochondromas. We conducted a retrospective cohort study on patients diagnosed and followed up from 1960 to 2019 to describe the clinical and pathological features of individuals affected by peripheral chondrosarcoma in multiple osteochondromas, to evaluate follow up information and individual outcome and to compare the results with literature. Data, including age, gender, site, histological grade, cartilage cap thickness, surgical treatments, surgical margins, genotype mutational status as well as treatment details were captured from the hospital electronic health records and from Registry of Multiple Osteochondromas. In addition, a complete histological review of all hematoxylin and eosin (H&E)-stained sections has been performed by expert pathologists. RESULTS: One hundred five of the screened cases were included in the present study. The age at diagnosis of SPC ranges from 13 to 63, with median age at diagnosis of 34 years. The site most frequently affected by malignant degeneration was the pelvis (46 patients, 44%) with higher incidence in male patients (32 males vs.14 females). The second one was lower limbs (including femur, fibula, or tibia), identified in 35 patients. Histological information - available for 103 patients - showed: 59 patients with grade 1; 40 patients had a grade 2 and 4 patients had a grade 3. The most common surgical treatment was the complete resection, followed by debulking, amputation and partial resection. Most of cases did not have recurrence of the disease. Outcome in disease-free survival highlights that a worse course of the disease was associated with histological grade 2 or 3, and partial resection surgery. In most of analyzed cases (94%) a pathogenic variant was identified. CONCLUSIONS: In conclusion, the present study gives an overview of the secondary peripheral chondrosarcomas, confirming that this disease represents an impacting complication for multiple osteochondromas patients and suggests that malignant transformation can occur also in younger patient, in a not irrelevant number of cases.

ERN BOND: The key European network leveraging diagnosis, research, and treatment for rare bone conditions.

There is no universally accepted definition for rare diseases: in Europe a disease is considered to be rare when affecting fewer than 1 in 2000 people. European Reference Networks (ERNs) have been the concrete response to address the unmet needs of rare disease patients and many pan-European issues in the field, reducing inequities, and significantly increasing accessibility to high-quality healthcare across Europe. ERNs are virtual networks, involving centres and patient representatives with the general scope to facilitate discussion on complex cases requiring highly specialised competences and trained expertise. ERN BOND - the European Reference Network on rare BONe Diseases - is one of these 24 approved networks with the specific ongoing mission to implement measures facilitating multidisciplinary, holistic, continuous, patient-centred, and participative care provision to patients, and supporting them in the full realisation of their fundamental human rights. ERN BOND includes in 2023 a total of 53 centres of expertise from 20 European countries. Its governing structure installed in March 2017 includes decision-making, operative and consultative committees, which comprise experts in the field and patient representatives ensuring patient's voice and perspectives are taken into account. Over the years, ERN BOND has worked hard to achieve its mission and valuably contribute to the advancement of diagnosis, management, treatment, and research in rare diseases. The network activities are mainly related to (i) the provision of care which collectively involves averagely 2800 patients diagnosed per year, (ii) the development of education for and training of the healthcare personnel consisting until now in the realisation of 7 thematic workshops and 19 webinars, (iii) the dissemination and exchange and spread of knowledge via network's website (https://ernbond.eu/), social media channels, and newsletters, (iv) the management of related data through a disease registry currently mapping over 2300 cases and recording over 600 reported cases, and (v) the enhancement of research which now include two clinical trials endorsed by the network. ERN BOND represents therefore an unprecedented move to improve the healthcare management of patients suffering from rare bone diseases through European collaborations. This network, through the support from the European Health Programme, will continue to pursue its efforts to achieve its goals, always maintaining the patients and their families at the centre of healthcare services.

Validation of a new multiple osteochondromas classification through Switching Neural Networks.

Multiple osteochondromas (MO), previously known as hereditary multiple exostoses (HME), is an autosomal dominant disease characterized by the formation of several benign cartilage-capped bone growth defined osteochondromas or exostoses. Various clinical classifications have been proposed but a consensus has not been reached. The aim of this study was to validate (using a machine learning approach) an "easy to use" tool to characterize MO patients in three classes according to the number of bone segments affected, the presence of skeletal deformities and/or functional limitations. The proposed classification has been validated (with a highly satisfactory mean accuracy) by analyzing 150 different variables on 289 MO patients through a Switching Neural Network approach (a novel classification technique capable of deriving models described by intelligible rules in if-then form). This approach allowed us to identify ankle valgism, Madelung deformity and limitation of the hip extra-rotation as "tags" of the three clinical classes. In conclusion, the proposed classification provides an efficient system to characterize this rare disease and is able to define homogeneous cohorts of patients to investigate MO pathogenesis.

Clinical-functional features of individuals with Osteogenesis Imperfecta and Ehlers-Danlos syndromes: A scoping review of assessment tools and ICF model.

BACKGROUND: Clinical-functional assessment of patients affected by Osteogenesis Imperfecta and Ehlers-Danlos Syndromes is essential for clinical management. However, there is no clear information on disease-specific tools of assessment for clinical practice, thus limiting quantification and management of the diseases-related impairments. OBJECTIVE: The present scoping review was aimed at investigating the most common clinical-functional features and assessment tools in individuals with Osteogenesis Imperfecta and Ehlers-Danlos Syndromes, and to provide an updated International Classification of Functioning (ICF) model related to functional impairments for each disease. METHODS: The literature revision was conducted on PubMed, Scopus and Embase databases. Articles reporting an ICF model of clinical-functional features and assessment tools for Osteogenesis Imperfecta and Ehlers-Danlos Syndromes individuals were included. RESULTS: A total of 27 articles were included, 7 reporting an ICF model, and 20 reporting clinical-functional assessment tools. It was reported that patients with Osteogenesis Imperfecta and Ehlers-Danlos Syndromes show impairments in both Body Function and Structure, and Activities and Participation domains of the ICF. A heterogeneous number of assessment tools was found for both diseases regarding proprioception, pain, endurance to exercise, fatigue, balance and motor coordination, and mobility. CONCLUSION: Patients with Osteogenesis Imperfecta and Ehlers-Danlos Syndromes show several impairments and limitations in Body Function and Structure, and Activities and Participation domains of the ICF. Thus, an appropriate and ongoing assessment of the disease-related impairments is necessary to improve clinical practice. Several functional tests and clinical scales can be used to assess the patients despite the heterogeneity of assessment tools found in previous literature.