A frameshift variant in the EXT1 gene in a feline leukemia virus-negative cat with osteochondromatosis.

Osteochondromatosis is a benign proliferative disorder characterized by cartilage-capped bony protuberances. In humans and most mammals, variants in the EXT1 or EXT2 gene are strongly correlated with the etiology of osteochondromatosis. However, in cats, osteochondromatosis has only been associated with feline leukemia virus infection. In this study, to explore other factors involved in the etiology of feline osteochondromatosis, we examined the EXT1 and EXT2 genes in a feline leukemia virus-negative cat with osteochondromatosis. Genetic analysis revealed a heterozygous single base pair duplication in exon 6 of the EXT1 gene (XM_023248762.2:c.1468dupC), leading to a premature stop codon in the EXT1 protein. Notably, this frameshift variant is recognized as one of the most common pathogenic variants in human osteochondromatosis. Our data suggest for the first time that genetic variants can have etiologic roles in osteochondromatosis in cats, as in humans and other animals.

Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas.

BACKGROUND: Multiple osteochondromas is a dysplasia characterized by growth of two or more osteochondromas. It is genetically heterogeneous, caused by pathogenic variants in EXT1 or EXT2 genes in 70%-90% of patients. The EXT1 is more often mutated than EXT2 gene, with a variable prevalence between populations. There are no data about EXT1 and EXT2 pathogenic variants in patients with multiple osteochondromas in Brazilian population. The aim of this survey is to characterize these to determine the genotype profile of this population. METHODS: DNA sequencing (Sanger Method) and MLPA analysis were performed to identify point mutations and deletions/duplications in the sample of 153 patients in 114 families. RESULTS: Germline variants were identified in 83% of families in which EXT2 variants were detected in 46% and EXT1 in 37% of cases. No variants were detected in 17% of them. We identified 50 different variants, 33 (13 frameshift, 11 nonsense, 5 missense, 2 splice site mutation, and 2 large deletions) in EXT1 and 17 (6 frameshift, 6 splice site mutation, 3 nonsense, 1 missense, and 1 large deletion) in EXT2. Of all 50 variants, 31 (62%) were novel, including 20 out of 33 (60,6%) EXT1 and 11 out of 17 (64.7%) EXT2 alleles. The vast majority of variants (88%) were "loss-of-function" and two novel hotspots in EXT2 gene were observed in our study. CONCLUSION: The prevalence of variants detected in the EXT2 gene differs from other researches from Latin America, European, and Asian population. This uncommon prevalence could be related with the newly characterized variant hotspot sites detected in EXT2 gene (p.Ala409Profs*26 and p.Ser290*). A high number of novel variants were also identified indicating that Brazilian population has a unique genetic profile. Characterizing this population and establishing its genotype is essential to understand the molecular pathogenesis of this disease in Brazil.

A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers.

BACKGROUND: We aimed to identify mutations associated with osteochondromatosis in a litter of American Staffordshire Terrier puppies. HYPOTHESIS: We hypothesized that the associated mutation would be located in a gene that causes osteochondromatosis in humans. ANIMALS: A litter of 9 American Staffordshire puppies, their sire and dam, 3 of 4 grandparents, 26 healthy unrelated American Staffordshire Terriers, and 154 dogs of 27 different breeds. METHODS: Whole genome sequencing was performed on the proband, and variants were compared against polymorphisms derived from 154 additional dogs across 27 breeds, as well as single nucleotide polymorphism database 146. One variant was selected for follow-up sequencing. Parentage and genetic mosaicism were evaluated across the litter. RESULTS: We found 56,301 genetic variants unique to the proband. Eleven variants were located in or near the gene exostosin 2 (EXT2), which is strongly associated with osteochondromatosis in humans. One heterozygous variant (c.969C > A) is predicted to result in a stop codon in exon 5 of the gene. Sanger sequencing identified the identical mutation in all affected offspring. The mutation was absent in the unaffected offspring, both parents, all available grandparents, and 26 healthy unrelated American Staffordshire Terriers. CONCLUSIONS AND CLINICAL IMPORTANCE: These findings represent the first reported mutation associated with osteochondromatosis in dogs. Because this mutation arose de novo, the identical mutation is unlikely to be the cause of osteochondromatosis in other dogs. However, de novo mutations in EXT2 are common in humans with osteochondromatosis, and by extension, it is possible that dogs with osteochondromatosis could be identified by sequencing the entire EXT2 gene.

Gammagrafía ósea de cuerpo completo con 99mTc-MDP de 3 hermanos afectos de osteocondromatosis múltiple familiar / 99mTc-MDP bone scintigraphy of three brothers affected by multiple osteochondromas

No disponible

Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma.

Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with details on molecular alterations and potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of 10 primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of the pathological subtype or the presence of IDH1 mutations, is unique among a range of cancer types, and shares significant commonalities with that of prostate cancer. Clusters of structural alterations localized within a single chromosome were observed in four cases. Combined with targeted resequencing of additional cartilaginous tumor cohorts, we identified somatic alterations of the COL2A1 gene, which encodes an essential extracellular matrix protein in chondroskeletal development, in 19.3% of chondrosarcoma and 31.7% of enchondroma cases. Epigenetic regulators (IDH1 and YEATS2) and an activin/BMP signal component (ACVR2A) were recurrently altered. Furthermore, a novel FN1-ACVR2A fusion transcript was observed in both chondrosarcoma and osteochondromatosis cases. With the characteristic accumulative process of somatic changes as a background, molecular defects in chondrogenesis and aberrant epigenetic control are primarily causative of both benign and malignant cartilaginous tumors.

Evaluation of the forearm in untreated adult subjects with multiple hereditary osteochondromatosis.

BACKGROUND: Limb-length discrepancy or angular deformities as a result of altered bone growth may lead to a decreased range of motion and impaired function as well as premature osteoarthritis in patients with multiple hereditary osteochondromatosis. The purpose of this study was to describe the function of the forearm in untreated patients in order to facilitate comparison with studies of the results of treatment of this condition. METHODS: The medical records of fifty-one pediatric patients were identified and served as the basis for identifying a cohort of adult relatives with the disorder. Participants were asked about pain and limitations in vocational or recreational activities and about concerns with regard to cosmetic appearance. Radiographs of the forearm and wrist were made to quantify the deformity. Functional outcome was assessed on the basis of a comparison with the norms for grip and pinch strength and for scores on the hand function test of Jebsen et al. Limitations in the range of motion of the upper extremities were converted to standard impairment ratings. RESULTS: Participants included twenty-two men and seventeen women with an average age of forty-two years (range, twenty to eighty years). Most of the patients were employed in careers of their choice, with only five (13%) indicating that they were limited in any way in the performance of their jobs. Twenty-six subjects (67%) participated in recreational activities, and sixty-eight arms (88%) were reported to be free of pain. Objective measurement of function demonstrated greater disability than that found from subjective reporting. Fourteen arms had an impairment rating of >10%, while twenty had decreased pinch strength and sixteen had decreased grip strength. Ten arms (13%) had decreased hand function according to the hand test of Jebsen et al. Radiographic evaluation demonstrated osteoarthritic changes in three limbs. CONCLUSIONS: Affected individuals had definite decreases in hand and wrist function, yet these did not result in major increases in pain or in limitations in daily work and recreation. This cohort provides a basis for comparison with the results of operative treatment in affected individuals with multiple hereditary osteochondromatosis.

Neuropsychological findings in two children diagnosed with hamartoses: evidence of a NLD phenotypic profile.

Hamartoses (HM) are defined as disorders involving nonneoplastic tissue overgrowth. Studies have examined the neuropsychological profiles of children with common HM, such as neurofibromatosis type 1. Limited information is known regarding neuropsychological profiles of rare HM such as Osteochondromatosis Syndrome (OS) and Klippel-Trenaunay Syndrome (KTS). The current investigation is, to our knowledge, the first attempt to define the cognitive phenotypes in two boys with OS and KTS. Results revealed significantly greater impairments involving sensorimotor and visuospatial skills, while verbal memory and language skills appeared relatively preserved. Significant neurobehavioral problems and marked social difficulties were evident. These findings suggest that these syndromes are on a Nonverbal Learning Disorder (NLD) continuum, with varying degrees of severity.

Cervical laminar exostosis in multiple hereditary osteochondromatosis: anterior stabilization and fusion technique for preventing instability.

Multiple hereditary osteochondromatosis is a genetically transmitted disorder consisting of multiple projections of bone capped by cartilage, which are called exostoses. Spinal cord compression due to expansion of a laminar osteochondroma is rare but well recognized. Surgical decompression usually improves the patient's neurological status but, in cervical exostosis, post-laminectomy kyphosis and instability problems, especially in the high-risk adolescent group, form the most significant potential difficulties in the postoperative period. We report a case of cervical laminar exostosis that was treated by anterior stabilization and fusion and discuss the benefits of this technique.

Hereditary spinal osteochondromas in diaphyseal aclasia.

We present cases of cervical cord compression in father and son with diaphyseal aclasia. Both patients were investigated with plain radiography, CT and MRI. We believe this to be the first report of spinal cord compression in first-degree relatives with diaphyseal aclasia.

Deformities and problems of the forearm in children with multiple hereditary osteochondromata.

Multiple hereditary osteochondromata is the most common benign bone tumor. Deformities of the forearm are the most frequent cause of functional impairment in these patients. The most common deformity is a combination of relative shortening of the ulna, bowing of the radius and/or ulna, increased ulnar tilt of the distal radial epiphysis, ulnar deviation of the hand, progressive ulnarward translocation of the carpus, and subluxation/dislocation of the proximal radial head. In addition to relative shortening and cosmetic displeasure, these deformities commonly produce limited forearm rotation, limited wrist motion, and, when the radial head dislocates, both elbow pain and loss of motion. This article reviews all surgical procedures currently in use, and attempts to synopsize the current thinking about how best to treat these deformities. Preventing and reducing progression of deformity and functional impairment, particularly radial head dislocation, remain paramount goals, and aggressive management is advocated.

Dominant carpotarsal osteochondromatosis.

Dominant carpotarsal osteochondromatosis is a particular disorder of the wrist and tibiotalar joints with abnormal bone proliferation and osteochondromas. Two patients, a mother and son, are described here; a similar condition has previously been described in seven affected members of a family. The upper and the lower limbs are affected in the same patient and the lesion can be bilateral. Autosomal dominant inheritance is a further criterion allowing the diagnosis of dysplasia epiphysealis hemimelica.