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.

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.

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.

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.

Is the High Healing Index a Complication of Progressive Long Bone Lengthening? Observations from a Cohort of 178 Children Treated with Circular External Fixation for Lower Limb Length Discrepancy.

The use of external fixators (EFs) for lower limb lengthening is common for treating lower limb length discrepancy (LLD) in children. The concern at present revolves around extended treatment times, with some suggesting a healing index (HI) > 45 days/cm as a major complication. The aim of this study is to assess the factors affecting bone healing and treatment duration in children who undergo limb lengthening for LLD using circular EFs. A total of 240 lengthening procedures on 178 children affected by congenital or acquired LLDs (mean age at surgery 13.8 ± 2.8 years) were retrospectively evaluated. Complications according to Lascombes' classification and treatment duration factors were analyzed. Mean HI was 57 ± 25 days/cm for the femur and 55 ± 24 days/cm for the tibia, with an HI > 45 days/cm in 64% of the procedures. A total of 189 procedures (79%) reported complications; 85 had an HI > 45 days/cm as the sole complication. While reducing the frame time is crucial, revising the classifications is necessary to avoid the overestimation of complications.

Data collection on rare bone and mineral conditions in Europe: The landscape of registries and databases.

BACKGROUND: knowledge on the natural history of rare diseases is necessary to improve outcomes. Disease registries may play a key role in covering these unmet needs in the rare bone and mineral community. OBJECTIVE: to map existing bone and mineral conditions registries in Europe and their characteristics. METHODS: online survey about the use of registries/databases and their characteristics. This survey was disseminated among members of the European Reference Network on Rare Bone Diseases (ERN BOND) and non-ERN experts in the field of bone and mineral conditions as well as patient organisations. RESULTS: sixty-three responses from health care providers (HCPs) and 10 responses from patient groups (PGs) were collected. The response rate for ERN BOND members was 55%. Of 63 HCPs, 37 declared using a registry. Osteogenesis imperfecta (OI) was the most registered condition. We mapped 3 international registries, all were disease-specific. CONCLUSIONS: There is a need for developing a common high-quality platform for registering rare bone and mineral conditions.

Osteogenesis imperfecta: a cross-sectional study of skeletal and extraskeletal features in a large cohort of Italian patients.

Introduction: The present study aims to describe a large cohort of Italian patients affected by osteogenesis imperfecta, providing a picture of the clinical bony and non-bony features and the molecular background to improve knowledge of the disease to inform appropriate management in clinical practice. Methods: A total of 568 subjects (from 446 unrelated Italian families) affected by osteogenesis imperfecta who received outpatient care at Istituto Ortopedico Rizzoli from 2006 to 2021 were considered in the present study. Results: Skeletal and extraskeletal features were analyzed showing a lower height (mean z-scores equal to -1.54 for male patients and -1.47 for female patients) compared with the general Italian population. Half of the patient population showed one or more deformities, and most of the patients had suffered a relatively low number of fractures (<10). An alteration in the sclera color was identified in 447 patients. Similarly, several extraskeletal features, like deafness, dental abnormalities, and cardiac problems, were investigated. Additionally, inheritance and genetic background were evaluated, showing that most of the patients have a positive family history and the majority of pathogenic variants detected were on collagen genes, as per literature. Conclusion: This study supports the definition of a clear picture of the heterogeneous clinical manifestations leading to variable severity in terms of skeletal and extra-skeletal traits and of the genetic background of an Italian population of osteogenesis imperfecta patients. In this perspective, this clearly highlights the crucial role of standardized and structured collection of high-quality data in disease registries particularly in rare disease scenarios, helping clinicians in disease monitoring and follow-up to improve clinical practice.

Remodeling an existing rare disease registry to be used in regulatory context: Lessons learned and recommendations.

Disease registries have been used as an interesting source of real-world data for supporting regulatory decision-making. In fact, drug studies based on registries cover pre-approval investigation, registry randomized clinical trials, and post-authorization studies. This opportunity has been investigated particularly for rare diseases-conditions affecting a small number of individuals worldwide-that represent a peculiar scenario. Several guidelines, concepts, suggestions, and laws are already available to support the design or improvement of a rare disease registry, opening the way for implementation of a registry capable of managing regulatory purposes. The present study aims to highlight the key stages performed for remodeling the existing Registry of Multiple Osteochondromas-REM into a tool consistent with EMA observations and recommendations, as well as to lead the readers through the entire adapting, remodeling, and optimizing process. The process included a variety of procedures that can be summarized into three closely related categories: semantic interoperability, data quality, and governance. At first, we strengthened interoperability within the REM registry by integrating ontologies and standards for proper data collection, in accordance with FAIR principles. Second, to increase data quality, we added additional parameters and domains and double-checked to limit human error to a bare minimum. Finally, we established two-level governance that has increased the visibility for the scientific community and for patients and carers. In conclusion, our remodeled REM registry fits with most of the scientific community's needs and indications, as well as the best techniques for providing real-world evidence for regulatory aspects.

Secondary peripheral chondrosarcoma arising in solitary osteochondroma: variables influencing prognosis and survival.

BACKGROUND: Secondary peripheral chondrosarcomas arising in solitary osteochondromas is an unusual complication, reported in small series. In this study, we aimed to present our experience with this rare variant of chondrosarcoma and compare results with already published data in order to determine prognostic factors for overall and disease-free survival. METHODS: The case study includes retrospective data from patients diagnosed at a single institution from 1943 to 2019. Clinical data were collected reviewing all available medical records from first to last follow-up visits. To exclude the presence of the Multiple Osteochondroma Hereditary Syndrome, few patients, with a suspect of a familial form of the disease, were evaluated for the presence of germline heterozygous variants in EXT1 and EXT2 genes. Results were summarized using descriptive statistics and statistical analysis were performed to reveal associations between variables. RESULTS: Two hundred and fourteen secondary peripheral chondrosarcomas that arose exclusively from solitary osteochondromas diagnosed in a multidisciplinary setting at the IRCCS Istituto Ortopedico Rizzoli were retrospectively identified, 66.4% males and 33.6% females with a median age at diagnosis of 38 years. The local recurrence rate was 17.3%, while the metastases one was 5.1%. Besides age, a high histologic grade is the only factor associated with worse 5-year and 10-year overall survival (log-rank p = 0.0005, HR = 3.74; 95% CI 1.69-8.26). Moreover, high histological grade (HR = 3.75; 95% CI = 1.69-8.34; p = 0.001) and surgical debulking (HR = 3.71; 95% CI = 1.57-8.79; p = 0.003) were associated with a significantly worse disease-free survival. CONCLUSIONS: Our study confirm the low-grade behavior of secondary peripheral chondrosarcomas and demonstrate that the best choice of treatment for those arising in solitary osteochondromas is the wide surgical excision, when possible. Location per se is not a factor that affects prognosis, while the accurate histological grade assessment is correlated with the tumor aggressiveness and a long term follow up is necessary for this rare variant of chondrosarcoma.

Opportunities and Challenges for Machine Learning in Rare Diseases.

Rare diseases (RDs) are complicated health conditions that are difficult to be managed at several levels. The scarcity of available data chiefly determines an intricate scenario even for experts and specialized clinicians, which in turn leads to the so called "diagnostic odyssey" for the patient. This situation calls for innovative solutions to support the decision process via quantitative and automated tools. Machine learning brings to the stage a wealth of powerful inference methods; however, matching the health conditions with advanced statistical techniques raises methodological, technological, and even ethical issues. In this contribution, we critically point to the specificities of the dialog of rare diseases with machine learning techniques concentrating on the key steps and challenges that may hamper or create actionable knowledge and value for the patient together with some on-field methodological suggestions and considerations.

Patients' priorities and expectations on an EU registry for rare bone and mineral conditions.

BACKGROUND: Understanding the natural history of rare bone and mineral conditions is essential for improving clinical practice and the development of new diagnostics and therapeutics. Recruitment and long-term participation in registries are key challenges for researchers. METHODS: To understand the user needs, the European Reference Network on Rare Bone Diseases (ERN BOND) and European Patient Advocacy Groups developed and implemented a multinational survey about the patient's preferred database content and functionality through an iterative consensus process. The survey was disseminated by national and international patient groups and healthcare professionals. The findings were analysed using descriptive statistics and multivariate regression. RESULTS: There were 493 eligible responses from 378 adults, 15 children and 100 parents, guardians or carers (PGC) across 22 rare bone and mineral conditions. Osteogenesis imperfecta constituted 53.4% of responses. Contents related to improving treatment and medical services scored the highest and contents about anxiety and socializing scored less highly. Additional content was recommended by 205 respondents. Respondents preferred data entry by their Healthcare Provider (HCP). However, less than 50% of adults received followup from their specialist HCP at least annually and 29% were followed up as needed. CONCLUSIONS: This survey of individuals, their family, guardians and carers has prioritised the key components for an EU-based rare bone and mineral condition research database. The survey highlights issues around collecting psychosocial impacts as well as measures of HCP trust. The survey demonstrated that using only specialist centre visits for data collection, while preferred by patients, will miss a substantial number of individuals, limiting generalisability. Combined HCP and patient platforms will be required to collect representative and complete natural history data for this patient group.

Outcomes of Temporary Hemiepiphyseal Stapling for Correcting Genu Valgum in Children with Multiple Osteochondromas: A Single Institution Study.

BACKGROUND: Multiple osteochondromas is a rare skeletal disorder characterized by the presence of osteocartilaginous protrusions causing bony deformities, especially around the knee. Guided growth by temporary hemiepiphyseal stapling is the treatment of choice to correct the deformity by modulating the residual physeal growth of the lower limbs. Although this procedure is increasingly practiced, inconclusive evidence exists regarding its effectiveness in children with multiple osteochondromas. The study aims to compare the outcomes of temporary hemiepiphyseal stapling for correcting genu valgum in children with multiple osteochondromas vs. idiopathic cases. METHODS: In this retrospective cohort study, we included patients admitted at a single institution from 2008 to 2018. A total of 97 children (77 idiopathic, 20 multiple osteochondromas) were enclosed, accounting for 184 limbs treated by temporary hemiepiphyseal stapling. We investigated if children with multiple osteochondromas had a similar successful rate of correction, rate of complications, and correction velocity compared to children with idiopathic genu valgum. RESULTS: Overall, 151 limbs (82%) achieved complete correction or overcorrection, with idiopathic cases having a significantly higher rate of success compared to pathologic cases (88% vs. 55%; p < 0.001). In addition, multiple osteochondromas children sustained a higher rate of major complications (p = 0.021) and showed significantly lower correction velocity (p = 0.029). CONCLUSION: Temporary hemiepiphyseal stapling is effective in both idiopathic and multiple osteochondromas children, although the latter often achieved incomplete correction, had a higher risk of complications, and required a longer time of stapling. We suggest to anticipate the timing of intervention; otherwise, children with multiple osteochondromas and severe valgus deformity, approaching skeletal maturity, could undergo combined femoral and tibial stapling.

The natural history of multiple osteochondromas in a large Italian cohort of pediatric patients.

IMPORTANCE: Multiple osteochondromas is a rare hereditary skeletal disorder, characterized by bony protrusions arising from growth plates on long bones during skeletal development. The disorder frequently leads to diminished stature, deformities and functional limitations. Understanding of the natural history of multiple osteochondromas and its evolution in children and adolescents is limited. OBJECTIVE: To provide valuable information on the natural history of multiple osteochondromas, to inform recommendations for treatment and prevent impairments caused by osteochondromas. DESIGN: This retrospective cohort study in children with multiple osteochondromas includes longitudinal data collected from first to last follow-up visit for patient demographics, and over 36 months for disease evolution. SETTING: Data were collected from the Registry of Multiple Osteochondromas, which includes data from circa 1200 patients with multiple osteochondromas treated from 2003 to 2017 at IRCCS Istituto Ortopedico Rizzoli in Bologna. PARTICIPANTS: Patients ≤18 years with multiple osteochondromas, who provided written informed consent and had data for ≥1 12-month follow-up visit. MAIN OUTCOME(S) AND MEASUREMENT(S): Demographics, clinical features, incidence of surgeries, and disease evolution (progression or regression) were assessed. Results were summarized using descriptive statistics, annual rates of new clinical features and surgeries, and Kaplan-Meier estimates. Patient height was evaluated following Italian growth charts. RESULTS: 158 patients were included in these analyses. Throughout follow-up, 80.4% of patients developed new osteochondromas, 57.6% developed new deformities, 23.4% developed new functional limitation(s). New osteochondroma(s) were developed by 28.5% patients by Month 12, 39.9% at Month 24, 50% at Month 36. Most new osteochondromas were detected in the younger population; patients aged 0-4 years underwent a significantly higher number of lesions within 12, 24 and 36 months of follow-up. The overall incidence of patients with ≥1 new deformity within 12 months was 17.7%, with incidences decreasing with increasing age (p = .023). In addition, the analyses on height highlight that 13 years is a cut off age for slow growth of the stature (p < .0005). At last follow-up visit, 46.2% of patients had disease progression, while regression (spontaneous and surgical) occurred in 7.6% (p = .007). CONCLUSIONS AND RELEVANCE: This natural history study reports the main set of clinically relevant data for patients with multiple osteochondromas during skeletal development, providing insight for patient management and development of therapeutic interventions.

Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb).

Multiple osteochondromas (MO) is an autosomal dominant skeletal disease characterized by the formation of multiple cartilage-capped bone tumors growing outward from the metaphyses of long tubular bones. MO is genetically heterogeneous, and is associated with mutations in Exostosin-1 (EXT1) or Exostosin-2 (EXT2), both tumor-suppressor genes of the EXT gene family. All members of this multigene family encode glycosyltransferases involved in the adhesion and/or polymerization of heparin sulfate (HS) chains at HS proteoglycans (HSPGs). HSPGs have been shown to play a role in the diffusion of Ihh, thereby regulating chondrocyte proliferation and differentiation. EXT1 is located at 8q24.11-q24.13, and comprises 11 exons, whereas the 16 exon EXT2 is located at 11p12-p11. To date, an EXT1 or EXT2 mutation is detected in 70-95% of affected individuals. EXT1 mutations are detected in +/-65% of cases, versus +/-35% EXT2 mutations in MO patient cohorts. Inactivating mutations (nonsense, frame shift, and splice-site mutations) represent the majority of MO causing mutations (75-80%). In this article, the clinical aspects and molecular genetics of EXT1 and EXT2 are reviewed together with 895 variants in MO patients. An overview of the reported variants is provided by the online Multiple Osteochondromas Mutation Database (http://medgen.ua.ac.be/LOVD).

Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients.

Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue and 90% of cases are due to dominant mutations in COL1A1 and COL1A2 genes. To increase OI disease knowledge and contribute to patient follow-up management, a homogeneous Italian cohort of 364 subjects affected by OI types I-IV was evaluated. The study population was composed of 262 OI type I, 24 type II, 39 type III, and 39 type IV patients. Three hundred and nine subjects had a type I collagen affecting function mutations (230 in α1(I) and 79 in α2(I)); no disease-causing changes were noticed in 55 patients. Compared with previous genotype-phenotype OI correlation studies, additional observations arose: a new effect for α1- and α2-serine substitutions has been pointed out and heart defects, never considered before, resulted associated to quantitative mutations (P = 0.043). Moreover, some different findings emerged if compared with previous literature; especially, focusing the attention on the lethal form, no association with specific collagen regions was found and most of variants localized in the previously reported "lethal clusters" were causative of OI types I-IV. Some discrepancies have been highlighted also considering the "50-55 nucleotides rule," as well as the relationship between specific collagen I mutated region and the presence of dentinogenesis imperfecta and/or blue sclera. Despite difficulties still present in defining clear rules to predict the clinical outcome in OI patients, this study provides new pieces for completing the puzzle, also thanks to the inclusion of clinical signs never considered before and to the large number of OI Italian patients.

Evaluation of TP53 Pro72Arg and MDM2 SNP285-SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations.

Li-Fraumeni syndrome (LFS) is a rare genetic cancer predisposition disease, partly determined by the presence of a TP53 germline mutation; lacking thereof, in presence of a typical LFS phenotype, defines a wide group of 'LFS Suggestive' patients. Alternative LFS susceptibility genes have been investigated without promising results, thus suggesting other genetic determinants involvement in cancer predisposition. Hence, this study explores the single and combined effects of cancer risk, age of onset and cancer type of three single nucleotide polymorphisms (SNPs)-TP53 Pro72Arg, MDM2 SNP285 and SNP309-already described as modifiers on TP53 mutation carriers but not properly investigated in LFS Suggestive patients. This case-control study examines 34 Italian LFS Suggestive lacking of germline TP53 mutations and 95 tumour-free subjects. A significant prevalence of homozygous MDM2 SNP309 G in the LFS Suggestive group (p < 0.0005) confirms its contribute to cancer susceptibility, also highlighted in LFS TP53 positive families. Conversely its anticipating role on tumour onset has not been confirmed, as in our results it was associated with the SNP309 T allele. A strong combined outcome with a 'dosage' effect has also been reported for TP53 P72 and MDM2 SNP309 G allele on cancer susceptibility (p < 0.0005). Whereas the MDM2 SNP285 C allele neutralizing effect on MDM2 SNP309 G variant is not evident in our population. Although it needs further evaluations, obtained results strengthen the role of MDM2 SNP309 as a genetic factor in hereditary predisposition to cancer, so improving LFS Suggestive patients management.