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International Journal of Molecular... 2011Rare diseases (RD) are characterized by low prevalence and affect not more than five individuals per 10,000 in the European population; they are a large and... (Review)
Review
Rare diseases (RD) are characterized by low prevalence and affect not more than five individuals per 10,000 in the European population; they are a large and heterogeneous group of disorders including more than 7,000 conditions and often involve all organs and tissues, with several clinical subtypes within the same disease. Very often information concerning either diagnosis and/or prognosis on many RD is insufficient. microRNAs are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level by either degrading or blocking translation of messenger RNA targets. Recently, microRNA expression patterns of body fluids underscored their potential as noninvasive biomarkers for various diseases. The role of microRNAs as potential biomarkers has become particularly attractive. The identification of disease-related microRNAs is essential for understanding the pathogenesis of diseases at the molecular level, and is critical for designing specific molecular tools for diagnosis, treatment and prevention. Computational analysis of microRNA-disease associations is an important complementary means for prioritizing microRNAs for further experimental examination. In this article, we explored the added value of miRs as biomarkers in a selected panel of RD hitting different tissues/systems at different life stages, but sharing the need of better biomarkers for diagnostic and prognostic purposes.
Topics: Amyotrophic Lateral Sclerosis; Biomarkers; Exostoses, Multiple Hereditary; Hepatoblastoma; Humans; MicroRNAs; Muscular Dystrophy, Duchenne; Pemphigus, Benign Familial; Rare Diseases; Rett Syndrome; Sezary Syndrome
PubMed: 22072915
DOI: 10.3390/ijms12106733 -
BMC Medical Genetics Jul 2010Osteopoikilosis is a rare autosomal dominant genetic disorder, characterised by the occurrence of the hyperostotic spots preferentially localized in the epiphyses and...
BACKGROUND
Osteopoikilosis is a rare autosomal dominant genetic disorder, characterised by the occurrence of the hyperostotic spots preferentially localized in the epiphyses and metaphyses of the long bones, and in the carpal and tarsal bones 1. Heterozygous LEMD3 gene mutations were shown to be the primary cause of the disease 2. Association of the primarily asymptomatic osteopokilosis with connective tissue nevi of the skin is categorized as Buschke-Ollendorff syndrome (BOS) 3. Additionally, osteopoikilosis can coincide with melorheostosis (MRO), a more severe bone disease characterised by the ectopic bone formation on the periosteal and endosteal surface of the long bones 456. However, not all MRO affected individuals carry germ-line LEMD3 mutations 7. Thus, the genetic cause of MRO remains unknown. Here we describe a familial case of osteopoikilosis in which a novel heterozygous LEMD3 mutation coincides with a novel mutation in EXT1, a gene involved in aetiology of multiple exostosis syndrome. The patients affected with both LEMD3 and EXT1 gene mutations displayed typical features of the osteopoikilosis. There were no additional skeletal manifestations detected however, various non-skeletal pathologies coincided in this group.
METHODS
We investigated LEMD3 and EXT1 in the three-generation family from Poland, with 5 patients affected with osteopoikilosis and one child affected with multiple exostoses.
RESULTS
We found a novel c.2203C > T (p.R735X) mutation in exon 9 of LEMD3, resulting in a premature stop codon at amino acid position 735. The mutation co-segregates with the osteopoikilosis phenotype and was not found in 200 ethnically matched controls. Another new substitution G > A was found in EXT1 gene at position 1732 (cDNA) in Exon 9 (p.A578T) in three out of five osteopoikilosis affected family members. Evolutionary conservation of the affected amino acid suggested possible functional relevance, however no additional skeletal manifestations were observed other then those specific for osteopoikilosis. Finally in one member of the family we found a splice site mutation in the EXT1 gene intron 5 (IVS5-2 A > G) resulting in the deletion of 9 bp of cDNA encoding three evolutionarily conserved amino acid residues. This child patient suffered from a severe form of exostoses, thus a causal relationship can be postulated.
CONCLUSIONS
We identified a new mutation in LEMD3 gene, accounting for the familial case of osteopoikilosis. In the same family we identified two novel EXT1 gene mutations. One of them A598T co-incided with the LEMD3 mutation. Co-incidence of LEMD3 and EXT1 gene mutations was not associated with a more severe skeletal phenotype in those patients.
Topics: Adult; DNA-Binding Proteins; Exostoses, Multiple Hereditary; Female; Humans; Male; Membrane Proteins; Middle Aged; Mutation; N-Acetylglucosaminyltransferases; Nuclear Proteins; Osteopoikilosis; Pedigree
PubMed: 20618940
DOI: 10.1186/1471-2350-11-110 -
The Journal of Biological Chemistry May 2018Hereditary multiple exostoses (HME) is a pediatric disorder caused by heparan sulfate (HS) deficiency and is characterized by growth plate-associated osteochondromas....
Hereditary multiple exostoses (HME) is a pediatric disorder caused by heparan sulfate (HS) deficiency and is characterized by growth plate-associated osteochondromas. Previously, we found that osteochondroma formation in mouse models is preceded by ectopic bone morphogenetic protein (BMP) signaling in the perichondrium, but the mechanistic relationships between BMP signaling and HS deficiency remain unclear. Therefore, we used an HS antagonist (surfen) to investigate the effects of this HS interference on BMP signaling, ligand availability, cell-surface BMP receptor (BMPR) dynamics, and BMPR interactions in Ad-293 and C3H/10T1/2 cells. As observed previously, the HS interference rapidly increased phosphorylated SMAD family member 1/5/8 levels. FACS analysis and immunoblots revealed that the cells possessed appreciable levels of endogenous cell-surface BMP2/4 that were unaffected by the HS antagonist, suggesting that BMP2/4 proteins remained surface-bound but became engaged in BMPR interactions and SMAD signaling. Indeed, surface mobility of SNAP-tagged BMPRII, measured by fluorescence recovery after photobleaching (FRAP), was modulated during the drug treatment. This suggested that the receptors had transitioned to lipid rafts acting as signaling centers, confirmed for BMPRII via ultracentrifugation to separate membrane subdomains. proximity ligation assays disclosed that the HS interference rapidly stimulates BMPRI-BMPRII interactions, measured by oligonucleotide-driven amplification signals. Our studies reveal that cell-associated HS controls BMP ligand availability and BMPR dynamics, interactions, and signaling, and largely restrains these processes. We propose that HS deficiency in HME may lead to extensive local BMP signaling and altered BMPR dynamics, triggering excessive cellular responses and osteochondroma formation.
Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein Receptors, Type II; Cells, Cultured; Chondrogenesis; Exostoses, Multiple Hereditary; Gene Expression Regulation; Heparitin Sulfate; Humans; Mice; Mice, Inbred C3H; Phosphorylation; Signal Transduction; Urea
PubMed: 29622677
DOI: 10.1074/jbc.RA117.000264 -
Cureus Jun 2022The single-bone forearm is a salvage technique for massive loss of bone due to serious trauma, malignant tumors, infections or congenital deformity. It is also...
The single-bone forearm is a salvage technique for massive loss of bone due to serious trauma, malignant tumors, infections or congenital deformity. It is also described to treat the sequelae of hereditary multiple exostoses disease that affects the distal end of the ulna. We present the case of a 29-year-old patient, operated for sequelae of hereditary multiple exostoses disease of the left forearm by a modified single-bone forearm technique. The patient, right-handed, operated on twice in childhood for a hereditary multiple exostoses disease of the left forearm: incomplete excision of the exostosis of the distal end of the ulna and lengthening of this last on external fixator, without improvement. The patient presented for a deformation of the left forearm with shortening compared to the right side. Significant limitation of prono-supination (pronation 15°, supination 20°). Elbow flexion at 110° and extension with deficit of 15°. Wrist flexion at 50° and extension at 50°, radial inclination at 25° and ulnar at 30°. The pain score was 3 according to the Visual Analogue Scale (VAS), especially on effort. Dash score was 31,82/100. We chose the forearm technique with a single bone. The immediate postoperative result found a realignment of the forearm, without neurological or vascular damages. Consolidation was obtained in four months. At five months, the patient recovered elbow flexion at 110° and full extension, wrist flexion at 45° and extension at 50°. Radial inclination at 20° and ulnar at 25°. The single-bone forearm technique has been described, not only for the treatment of hereditary multiple exostoses disease, but also for serious trauma or tumors with massive loss of bone. The technique generally consists of an osteotomy of the radius as well as the ulna, fixing the radius to the ulna creating a synostosis, with or without resection of part of one or both bones of the forearm. The most described complications of single-bone forearm procedure are pain, complications related to soft tissue secondary to the previous injury, and infections. The one-bone forearm remain a salvage technique for massive loss of bone of the forearm, or large deformities due to congenital malformations. This technique could allow the excision of massive bone and keep only a part of the ulna and the radius, with function maintenance and aesthetic forearm preservation.
PubMed: 35903567
DOI: 10.7759/cureus.26361 -
Expert Opinion on Orphan Drugs 2018Hereditary multiple exostoses (HME) is a rare congenital pediatric disorder characterized by osteochondromas forming next to the growth plates in young patients. The...
INTRODUCTION
Hereditary multiple exostoses (HME) is a rare congenital pediatric disorder characterized by osteochondromas forming next to the growth plates in young patients. The osteochondromas cause multiple health problems that include skeletal deformities and chronic pain. Surgery is used to remove the most symptomatic osteochondromas but because of their large number, many are left in place, causing life-long problems and increasing the probability of malignant transformation. There is no other treatment to prevent or reduce osteochondromas formation at present.
AREAS COVERED
Recent studies reviewable through PubMed are providing new insights into cellular and molecular mechanisms of osteochondroma development. The resulting data are suggesting rational and plausible new therapeutic strategies for osteochondroma prevention some of which are being tested in HME animal models and one of which is part of a just announced clinical trial.
EXPERT COMMENTARY
This section summarizes and evaluates such strategies and points also to possible future alternatives.
PubMed: 31448184
DOI: 10.1080/21678707.2018.1483232 -
Journal of Clinical Medicine Jun 2022Multiple hereditary exostoses (MHE) is a rare autosomal dominant skeletal disorder with a variety of clinical manifestations. We aimed to evaluate the general clinical...
Multiple hereditary exostoses (MHE) is a rare autosomal dominant skeletal disorder with a variety of clinical manifestations. We aimed to evaluate the general clinical phenotypic severity of MHE using our own scoring system and analyzed the risk factors associated with severe clinical phenotypes. In this study, 43 patients from 30 families were analyzed. The mutations were identified by direct sequencing of polymerase chain reaction-amplified genomic DNA or by multiplex ligation-dependent probe amplification. According to a new scoring system devised by the authors, the severity of the phenotype was assessed as mild, moderate, or severe based on the deformity of each segment, number of exostoses, leg length discrepancy, and functional limitations. Of 43 patients from 30 families, 39 patients (90.7%) and 24 families (80%) presented with EXT1 or EXT2 mutations. Patients with EXT1 mutations had a significantly worse phenotype than that of patients with EXT2 mutations or without any detectable mutation. The mean clinical score of patients with an EXT1 mutation (5.76; range, 2.0-8.0; SD = 1.60) was higher than that of patients with an EXT2 mutation (4.06; range, 2.0-7.0; SD = 1.47) or of those without any detectable mutation (4.63; range, 3.0-6.0; SD = 1.44; = 0.005). According to our classification system, more patients with EXT1 mutations had 'severe disease' than those with EXT2 mutations. Deformity scores were also higher in patients with EXT1 mutations ( = 0.018). In the multivariate analysis, the deformity score was found to be associated with the 'severe' class ( = 0.031). In conclusion, 90.7% of patients with MHE showed EXT mutations. Our scoring system showed reliable results. We suggest that the extent of deformity is an important factor in determining the phenotype of MHE and close monitoring for the development of severe disease is recommended in patients with high deformity scores.
PubMed: 35806987
DOI: 10.3390/jcm11133703 -
Case Reports in Dentistry 2019Gingival and osseous augmentations are reported as hypertrophic or hyperplastic reactions to different factors including chronic traumatisms and surgeries such as free...
Gingival and osseous augmentations are reported as hypertrophic or hyperplastic reactions to different factors including chronic traumatisms and surgeries such as free gingival graft (FGG) that induce an abnormal growth of both hard and soft tissues in genetically predisposed subjects. Since an imbalance in collagen turnover plays a key role in the development of gingival overgrowth leading to an accumulation of collagen in gingival connective tissue, in this study we described the histological and molecular features of three oral overgrowths obtained from a 34-year-old woman previously operated for FGG in order to evaluate a possible relationship between exostoses and overgrown tissue. Healthy and overgrown gingiva were analyzed by histological methods, and the expression of genes and proteins involved in collagen synthesis, maturation, and degradation was assessed in cultured fibroblasts obtained from gingival fragments at the molecular level. Our results show that general morphology and collagen content were similar in healthy and overgrown gingivae. However, fibroblasts obtained from the overgrown gingiva revealed an anabolic phenotype characterized by an increased collagen turnover and maturation. These findings indicate that an exostosis could act as a mechanical stimulus stretching the overlying connective tissue and triggering an anabolic phenotype of gingival fibroblasts and suggest to use minimally invasive surgical techniques to avoid traumatizing the periosteal tissues for the eradication of the exostosis with minimal relapses.
PubMed: 31263605
DOI: 10.1155/2019/3231759 -
Journal of Orthopaedics Dec 2018The purpose of this clinical case-control study was to assess the level of sports activity in children with hereditary multiple exostoses (HME) and to compare with the...
OBJECTIVE
The purpose of this clinical case-control study was to assess the level of sports activity in children with hereditary multiple exostoses (HME) and to compare with the degree of physical activity in children of the same age without pathology.
METHODS
A case-control study was designed. Cases were drawn from children with HME diagnosed on the basis of clinical and radiographic evaluation with an age less then 12 years. Controls were chosen from a group of children with the same age and a negative family history for HME. All patients and controls were completed with the help of parents using the following evaluations: Tegner Activity Level Scale and University of California Los Angeles (UCLA) activity scale.
RESULTS
A total of 154 individuals participated (54 cases and 100 controls). In the case groups, the mean age was 9.07; the mean number of exostoses resulted 29.51, while the mean value of UCLA and Tegner score resulted respectively 6.04 and 5.09. In the controls, the mean age was 8.88; mean UCLA and Tegner resulted respectively 7.17 and 5.64. Comparing the two groups, the only difference was between UCLA score (p = 0.0053). Moreover, comparing the results between female children affected by HME and female controls, we found a significant difference as regards UCLA score (p = 0.0045).
CONCLUSION
Children affected by HME reported lower sports activity, in particular as regards female patients. Moreover, physical activity is not correlated with any other independent factor leading different patients to a similar level of ability in performing sport.
STUDY DESIGN
Level III - Case Control Study.
PubMed: 30190634
DOI: 10.1016/j.jor.2018.08.029 -
Acta Reumatologica Portuguesa 2012
Topics: Child, Preschool; Exostoses, Multiple Hereditary; Humans; Male
PubMed: 22781520
DOI: No ID Found -
Hand (New York, N.Y.) Dec 2015The purpose is to determine the location and type of osteochondromas in patients with multiple osteochondroma of the hand as well as the presence of shortening and... (Review)
Review
BACKGROUND
The purpose is to determine the location and type of osteochondromas in patients with multiple osteochondroma of the hand as well as the presence of shortening and angulation. Second, it aims to establish longitudinal data on the change in tumors.
METHODS
Retrospective review of patients with multiple osteochondroma affecting the hand evaluating the location and type of tumors as well as the presence of shortening and angulation is done. We examined radiographs from final follow-up and analyzed them based on patient age at presentation (group I = ages 2-6; II = ages 7-10; III = ages 11-19), to determine changes over time and any differences in the number of tumors, location, and shortening and angulation.
RESULTS
The most affected bones were the index and small finger metacarpals with an increase seen around the metacarpophalangeal (MCP) joints. The most shortening and angulation were seen on the ulnar side. Group II had the most tumors and the most bones with angulation. Twenty-three hands had longitudinal follow-up with an overall increase of 2.7 tumors per hand with a range of loss of 8 to gain of 16. There was an increase in the number of bones with angulation and shortening. Group I showed the largest increase in tumors, shortening, and angulation.
CONCLUSIONS
The ulnar side and bones around the MCP joints are affected most commonly. The largest change was seen as the patients went from young childhood into adolescence, which may be due to rapid growth during this time. This is the largest study of these patients with the longest longitudinal data.
PubMed: 26568714
DOI: 10.1007/s11552-015-9775-6