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Prague Medical Report 2017Hereditary multiple exostoses (HME) represents a heterogeneous group of diseases often associated with progressive skeletal deformities. Most frequently, mutations in...
Hereditary multiple exostoses (HME) represents a heterogeneous group of diseases often associated with progressive skeletal deformities. Most frequently, mutations in EXT1 and EXT2 genes with autosomal dominant inheritance are responsible for HME. In our group of 9 families with HME we evaluated the clinical course of the disease and analysed molecular background using Sanger sequencing and MLPA in EXT1 and EXT2 genes. The mean age in our group of patients, when the first exostosis was recognised was 4.5 years (range 2-10 years) and the number of exostoses per one patient documented on X-ray ranged from 2 to 54. Most of the exostoses developed before the growth was completed and they were dominantly localised in the distal femurs, proximal tibia, proximal humerus and distal radius. In all patients, at least one to 8 surgeries were necessary due to complaints and local complications, but neither patient developed malignant transformation. In half of the patients, the disease resulted in short stature. DNA analyses were positive in 7 families. In five probands, different EXT1 gene mutations resulting in premature stop-codon (p.Gly124Argfs*65, p.Leu191*, p.Trp364Lysfs*11, p.Val371Glyfs*10, p.Leu490Profs*31) were found. In two probands, nonsense mutations were found in EXT2 gene (p.Val187Profs*115, p.Cys319fs*46). Five mutations have been novel and two mutations have occurred de novo in probands. Although the risk for malignant transformation is usually low, especially in patients with low number of exostoses, early diagnostics and longitudinal follow up of patients is of a big importance, because early surgery can prevent progression of secondary bone deformities.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Czech Republic; Exostoses, Multiple Hereditary; Female; Humans; Male; Middle Aged; Mutation; N-Acetylglucosaminyltransferases; Sequence Analysis, DNA; Young Adult
PubMed: 28922105
DOI: 10.14712/23362936.2017.8 -
Cureus Jul 2021Hereditary multiple exostoses (HME) are an autosomal dominant skeletal disorder characterized by the development of multiple benign osteochondromas (exostoses) that... (Review)
Review
Hereditary multiple exostoses (HME) are an autosomal dominant skeletal disorder characterized by the development of multiple benign osteochondromas (exostoses) that frequently involve long bones of the body. Less commonly, the ribs are a site of involvement, and long-term friction between an exostosis and pleura can produce a hemothorax or pneumothorax. The purpose of this study is to provide a comprehensive review of existing literature on pneumothorax or hemothorax secondary to costal exostosis in HME patients. We reviewed the databases of PubMed and Embase and included data as current as of February 15, 2021. All case reports included cases of hemothorax or pneumothorax in patients with a known personal or family history of HME. After evaluation for inclusion based on eligibility criteria, 18 cases were included. The average age at presentation was 11.7 years (range: 3-32), and most patients were male (83%). Hemothoraces occurred in 15 cases, while pneumothoraces occurred in three cases. All cases were evaluated using chest X-ray and CT scan, and the majority of the cases were treated with surgical resection of the exostosis, either with video-assisted thoracoscopic surgery (VATS; 61%) or thoracotomy (22%). Outcomes were successful with no cases of recurrence after surgical intervention. Although rare, costal exostosis should be considered as a differential in patients presenting with pneumothorax or hemothorax and past medical history or physical exam findings suggestive of HME. Immediate evaluation and surgical intervention to resect costal exostosis are essential to reduce the risk of recurrent life-threatening injury.
PubMed: 34395113
DOI: 10.7759/cureus.16326 -
Matrix Biology : Journal of the... Oct 2018Heparan sulfate (HS) is an essential component of cell surface and matrix proteoglycans (HS-PGs) that include syndecans and perlecan. Because of their unique structural... (Review)
Review
Heparan sulfate (HS) is an essential component of cell surface and matrix proteoglycans (HS-PGs) that include syndecans and perlecan. Because of their unique structural features, the HS chains are able to specifically interact with signaling proteins -including bone morphogenetic proteins (BMPs)- via their HS-binding domain, regulating protein availability, distribution and action on target cells. Hereditary Multiple Exostoses (HME) is a rare pediatric disorder linked to germline heterozygous loss-of-function mutations in EXT1 or EXT2 that encode Golgi-resident glycosyltransferases responsible for HS synthesis, resulting in a systemic HS deficiency. HME is characterized by cartilaginous/bony tumors -called osteochondromas or exostoses- that form within perichondrium in long bones, ribs and other elements. This review examines most recent studies in HME, framing them in the context of classic studies. New findings show that the spectrum of EXT mutations is larger than previously realized and the clinical complications of HME extend beyond the skeleton. Osteochondroma development requires a somatic "second hit" that would complement the germline EXT mutation to further decrease HS production and/levels at perichondrial sites of osteochondroma induction. Cellular studies have shown that the steep decreases in local HS levels: derange the normal homeostatic signaling pathways keeping perichondrium mesenchymal; cause excessive BMP signaling; and provoke ectopic chondrogenesis and osteochondroma formation. Data from HME mouse models have revealed that systemic treatment with a BMP signaling antagonist markedly reduces osteochondroma formation. In sum, recent studies have provided major new insights into the molecular and cellular pathogenesis of HME and the roles played by HS deficiency. These new insights have led to the first ever proof-of-principle demonstration that osteochondroma formation is a druggable process, paving the way toward the creation of a clinically-relevant treatment.
Topics: Animals; Bone Morphogenetic Proteins; Disease Models, Animal; Exostoses, Multiple Hereditary; Heparitin Sulfate; Humans; Mice; Mutation; N-Acetylglucosaminyltransferases; Signal Transduction
PubMed: 29277722
DOI: 10.1016/j.matbio.2017.12.011 -
Children (Basel, Switzerland) Jun 2021The hip joint involvement in multiple hereditary exostoses (MHE) occurs in 30-90%, causing pain and limitation of motion by femoroacetabular impingement, coxa valga,...
The hip joint involvement in multiple hereditary exostoses (MHE) occurs in 30-90%, causing pain and limitation of motion by femoroacetabular impingement, coxa valga, acetabular dysplasia, hip joint subluxation, and osteoarthritis. The purpose of this study was to investigate the clinical and radiographic outcomes of ten hips in seven patients treated by surgical dislocation and corrective osteotomies between 2004 and 2009. Surgical dislocation and excision of the osteochondromas and varus intertrochanteric osteotomies were performed in all cases when the neck-shaft angle was > 150°. Common sites of osteochondromas were medial, posterior, and anterior neck of the femur. Neck-shaft angle of the femur was improved from a mean of 157° to 139°, postoperatively. On an average, the center-edge angle improved from 20° to 30° postoperatively. We believe that Ganz's safe surgical dislocation technique is the preferred treatment of MHE. This safeguards the circulation of the femoral head and the osteochondromas can be resected under direct vision. It can be combined with additional corrective osteotomies because the hip affected by MHE is frequently associated with dysplastic changes which can result in premature osteoarthritis.
PubMed: 34201373
DOI: 10.3390/children8060490 -
Journal of Vascular and Interventional... Nov 2018Hereditary multiple exostoses (HME) is an inherited genetic condition, characterized by the formation of multiple osteochondromas, developing throughout childhood and...
BACKGROUND
Hereditary multiple exostoses (HME) is an inherited genetic condition, characterized by the formation of multiple osteochondromas, developing throughout childhood and into puberty. Vascular complications associated with HME are uncommon.
METHODS
A case of a patient with HME who was admitted to hospital with subarachnoid hemorrhage (SAH), as a result of acute rupture of a basilar tip aneurysm (BTA), will be presented. Relevant literature on this topic will be systematically reviewed.
RESULTS
We describe a rare case of a 48-year-old male patient presenting multiple exostoses in both upper and lower limbs, with no familial history of such lesions. The patient experienced an episode of loss of consciousness, followed by tonal seizures, after a short (five-day) history of headache, proved finally to be secondary to SAH due to rupture of a BTA. There was no antecedent of trauma, neck manipulation, or previous infection. Aneurysm was successfully treated with the intravascular procedure (aneurysm occlusion with coil). Progressively, the patient recovered from dysphasia and tetraparesis, almost completely, following the appropriate treatment and rehabilitation program.In the systematic review, eight cases (including the one presented) of vertebrobasilar vascular system stroke secondary to solitary spinal osteochondroma or multiple osteochondromas were found, but only the present case was associated with basilar artery aneurysm.
CONCLUSION
Despite the fact that the etiopathogenesis of basal artery aneurysm presentation in a patient with osteochondromas remains unknown, medical society needs to be aware of this rare condition, as SAH may be a severe complication.
PubMed: 30746007
DOI: No ID Found -
Orphanet Journal of Rare Diseases Feb 2021Hereditary Multiple Exostoses (HME), also known as Multiple Osteochondromas (MO) is a rare genetic disorder characterized by multiple benign cartilaginous bone tumors,...
BACKGROUND
Hereditary Multiple Exostoses (HME), also known as Multiple Osteochondromas (MO) is a rare genetic disorder characterized by multiple benign cartilaginous bone tumors, which are caused by mutations in the genes for exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2). The genetic defects have not been studied in the Saudi patients.
AIM OF STUDY
We investigated mutation spectrum of EXT1 and EXT2 in 22 patients from 17 unrelated families.
METHODS
Genomic DNA was extracted from peripheral leucocytes. The coding regions and intron-exon boundaries of both EXT1 and EXT2 genes were screened for mutations by PCR-sequencing analysis. Gross deletions were analyzed by MLPA analysis.
RESULTS
EXT1 mutations were detected in 6 families (35%) and 3 were novel mutations: c.739G > T (p. E247*), c.1319delG (p.R440Lfs*4), and c.1786delA (p.S596Afs*25). EXT2 mutations were detected in 7 families (41%) and 3 were novel mutations: c.541delG (p.D181Ifs*89), c.583delG (p.G195Vfs*75), and a gross deletion of approximately 10 kb including promoter and exon 1. Five patients from different families had no family history and carried de novo mutations (29%, 5/17). No EXT1 and EXT2 mutations were found in the remaining four families. In total, EXT1 and EXT2 mutations were found in 77% (13/17) of Saudi HME patients.
CONCLUSION
EXT1 and EXT2 mutations contribute significantly to the pathogenesis of HME in the Saudi population. In contrast to high mutation rate in EXT 1 (65%) and low mutation rate in EXT2 (25%) in other populations, the frequency of EXT2 mutations are much higher (41%) and comparable to that of EXT1 among Saudi patients. De novo mutations are also common and the six novel EXT1/EXT2 mutations further expands the mutation spectrum of HME.
Topics: DNA Mutational Analysis; Exons; Exostoses, Multiple Hereditary; Humans; Mutation; N-Acetylglucosaminyltransferases; Saudi Arabia
PubMed: 33632255
DOI: 10.1186/s13023-021-01738-z -
Medicina 2023
Topics: Humans; Exostoses, Multiple Hereditary; Spinal Canal
PubMed: 37379552
DOI: No ID Found -
Molecular Cytogenetics May 2023Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple, circumscript and usually symmetric bony...
BACKGROUND
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple, circumscript and usually symmetric bony protuberances called osteochondromas. Most HME are caused by EXT1 and EXT2 loss of function mutations. Most pathogenic mutations are nonsense followed by missense mutations and deletions.
CASE PRESENTATION
Here we report on a patient with a rare and complex genotype resulting in a typical HME phenotype. Initial point mutation screening in EXT1 and EXT2 genes by Sanger sequencing did not reveal any pathogenic variants. The patient along with the healthy parents was subsequently referred for karyotype and array-Comparative Genomic Hybridization (CGH) analyses. Chromosomal analysis revealed two independent de novo apparently balanced rearrangements: a balanced translocation between the long arms of chromosomes 2 and 3 at breakpoints 2q22 and 3q13.2 and a pericentric inversion with breakpoints at 8p23.1q24.1. Both breakpoints were confirmed by Fluorescence In Situ Hybridization (FISH). Subsequently, array-CGH revealed a novel heterozygous deletion within the EXT1 gene at one of the inversion breakpoints, rendering the inversion unbalanced. The mode of inheritance, as well as the size of the deletion were further investigated by Quantitative Real-time PCR (qPCR), defining the deletion as de novo and of 3.1 kb in size, removing exon 10 of EXT1. The inversion in combination with the 8p23.1 deletion most likely abolishes the transcription of EXT1 downstream of exon 10 hence resulting in a truncated protein.
CONCLUSIONS
The identification of a rare and novel genetic cause of HME, highlights the importance of additional comprehensive investigation of patients with typical clinical manifestations, even when EXT1 and EXT2 mutation analysis is negative.
PubMed: 37217936
DOI: 10.1186/s13039-023-00638-0 -
Orphanet Journal of Rare Diseases Dec 2019Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment... (Review)
Review
BACKGROUND
Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials.
METHODS
A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review.
RESULTS
Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP.
DISCUSSION
It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.
Topics: Animals; Bone Diseases; Female; Humans; Male; Myositis Ossificans; Osteogenesis Imperfecta; Osteopetrosis; Rare Diseases
PubMed: 31888683
DOI: 10.1186/s13023-019-1222-2 -
Turkish Neurosurgery 2021To investigate the underlying conditions in children with torticollis.
AIM
To investigate the underlying conditions in children with torticollis.
MATERIAL AND METHODS
Between May 2016 and December 2019, 24 patients (10 girls and 14 boys; mean age, 8 years) presenting with twisted neck, neck pain, weakness of extremities, imbalance, and gait disorder were evaluated retrospectively.
RESULTS
Five of the patients had cranial pathologies (cerebellar anaplastic ependymoma and medulloblastoma, brain stem glioma, atypical teratoid rhabdoid tumor, and acute disseminated encephalomyelitis), and five of the patients had spinal pathologies (idiopathic intervertebral disc calcification, vertebral hemangiomatosis, compression fracture, multiple hereditary exostoses, and Langerhans cell histiocytosis at C4). Six of the patients had ocular pathologies (strabismus, Duane syndrome, and Brown syndrome each in two patients). Four patients had otorhinolaryngological infections (Sandifer syndrome, esophageal atresia, reflux, and spasmus nutans, with one patient each). Detailed clinical physical examination and necessary laboratory investigation were performed for all patients.
CONCLUSION
Torticollis is a sign that is not always innocent and may herald an underlying severe disease. Misdiagnosis can lead to wrong and unnecessary surgical procedures and treatments, and sometimes, the results can be damaging due to underlying severe conditions if diagnosed late. In addition, we first report a case of vertebral hemangiomatosis and temporomandibular joint ankylosis that presented with torticollis in the English medical literature.
Topics: Adolescent; Brain Neoplasms; Calcinosis; Child; Child, Preschool; Ependymoma; Eye Diseases; Female; Humans; Infant; Male; Neck Pain; Physical Examination; Retrospective Studies; Spinal Diseases; Torticollis
PubMed: 33759163
DOI: 10.5137/1019-5149.JTN.31359-20.2