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PubMed1985

The treatment of hereditary multiple exostosis of the upper extremity.

Thirty of 50 patients with hereditary multiple exostosis developed significant deformities of the arm in one extremity. The degree of deformity is dependent on the location of the osteochondroma. If the osteochondroma is on the radius, deformity will usually be only minimal. If the osteochondroma is at the distal end of the ulna, the epiphysis usually stops growing. We believe that the ulnar collateral ligament then acts as a tether, very similar to that seen in the ulnar clubhand. The radius then has to either bow or dislocate at the elbow, and the wrist displaces ulnarly. We performed operations on 10 patients that consisted of cutting the ulnar collateral ligament, lengthening the ulna, osteotomizing the radius, and removing any osteochondromas. In the young, growing child, staples are placed across the lateral side of the distal radial epiphysis. The cosmetic results of the surgery were very gratifying. Nine patients also had osteochondromas removed from the hands and the forearms.

Bone Neoplasms↗
PubMedDate not supplied

Hereditary multiple exostosis and pain.

This study was undertaken to characterize pain in individuals with hereditary multiple exostosis (HME). Two hundred ninety-three patients with HME completed a questionnaire designed to assess pain as well as its impact on their life. Eighty-four percent of participants reported having pain, indicating that pain is a real problem in HME. Of those with pain, 55.1% had generalized pain. Two factors were found to be associated with pain outcome: HME-related complications and surgery. Individuals who had HME-related complications were five times more likely to have pain, while those who had surgery were 3.8 more likely to have pain. No differences were found between males and females with respect to pain, surgery, or HME-related complications. The results of this study indicate that the number of individuals with HME who have pain has been underestimated and that pain is a problem that must be addressed when caring for individuals with HME.

Adolescent↗
PubMed2007

Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas.

Mutational inactivation of EXT1 or EXT2 is the cause of hereditary multiple osteochondromas. These genes function in heparan sulphate proteoglycan (HSPG) biosynthesis in the Golgi apparatus. Loss of heterozygosity of the EXT1 locus at 8q24 is frequently found in solitary osteochondromas, whereas somatic mutations are rarely found. We investigated the expression of EXT1 and EXT2 (quantitative RT-PCR) and of different HSPGs (immunohistochemistry) in solitary and hereditary osteochondromas and in cases with malignant progression to secondary peripheral chondrosarcoma, in relation to possible mutations and promoter methylation. The mutation status of patients with multiple osteochondromas correlated with decreased EXT1 or EXT2 expression found in their resected tumours. We could not show somatic point mutations or promoter hypermethylation in 17 solitary tumours; however, EXT1 expression was decreased in 15 cases, whereas EXT2 was not. Intracellular accumulation of syndecan-2 and heparan sulphate-bearing isoforms of CD44 (CD44v3) was found in most tumours, which concentrated in the Golgi apparatus as shown by confocal microscopy. This contrasted with the extracellular expression found in normal growth plates. In conclusion, mutational inactivation of either EXT1 or EXT2 leads to loss of mRNA expression of the corresponding gene. We hypothesize that loss of EXT expression disrupts the function of the EXT1/2 complex in HSPG biosynthesis, resulting in the intracellular accumulation of HSPG core proteins that we found in these tumours.

Adolescent↗
PubMedDate not supplied

[Spinal cord compression by a cervical oseteocartilaginous exostosis: surgical strategy aspects].

AIM: The authors present the therapeutic management of a 12-year-old boy with known hereditary multiple exostosis syndrome (HME), who developed spinal cord compression symptoms caused by an exostosis of the C2 lamina. A perinatal brain lesion with tetraparesis delayed the recognition of the spinal cord compression substantially, which resulted in an extensive spur-like growth of the exostosis. METHOD: In comparison with already published cases, this growth pattern was rather unique and required consideration on the best surgical management. We decided to monitor the spinal cord function from positioning of the patient to skin closure and to modify the surgical steps of the laminectomy with initial lateral cutting of both hemilaminae. RESULTS: Electrophysiological monitoring helped to avoid spinal cord compression by inadequate head anteflexion during positioning. Lateral cutting of the hemilaminae C2 resulted in spontaneous extrusion of the exostosis with immediate improvement of the electrophysiological findings. The boy experienced a prompt improvement of his neurological deficits. CONCLUSION: The good surgical and clinical result confirm the value of the applied management concept.

Cervical Vertebrae↗
PubMed1988

[Diagnosis and surgical strategy in 3 cases of benign and unusual tumors of the occipito-cervical skeleton].

The authors report three cases of benign tumours of the occipito-cervical skeleton, remarkable for their rarity and especially by their unusual, even exceptional anatomic site: an osteoid osteoma, a pre-medullary chondroma and an extra-dural exostosis developing within a hereditary multiple disease. This presentation which allows to recall a few epidemiological and diagnostic problems is essentially focused on operative strategy and particularly on the choice of the best way to cope with surgical difficulties to be met. The osteoid osteoma whose diagnosis is difficult raises two surgical problems: the relation with the vertebral artery and the preservation of the atlanto-occipital joint. An approach through limited occipital craniotomy has allowed a perfect control of the vertebral artery and a complete removal without joint damage. Pre-medullary chondroma: a complete removal has been performed through the anterior way as described in rare observations of the literature. Post operatively, the patient had a complete neuro-orthopedic recovery. The antero-lateral exostosis has been removed through the posterior way by first resecting the basis of implantation, which has allowed the mobilization of the lesion without cord damage. Results have been good in the three cases both from neurological and orthopedic points of view.

Adult↗
PubMedDate not supplied

Natural history of multiple hereditary osteochondromatosis of the lower extremity and ankle.

In this study the authors evaluated the natural history of the ankle joint in patients with multiple hereditary osteochondromatosis. Thirty-eight subjects with an average age of 42 years completed a detailed subjective questionnaire and underwent clinical and radiographic evaluation of their ankles. Three subjects (8%) indicated their ankle involvement affected their vocation, and 12 (32%) were limited in recreational sports. Seven patients (18%) had pain in at least one ankle on a weekly basis, with an average ankle pain score of 2.2. Ankle range of motion averaged 50 degrees and subtalar motion was considered normal in two thirds of ankles. Radiographic evaluation documented an average tibiotalar tilt of 9 degrees of ankle valgus, with evidence of degenerative joint disease noted in 14 ankles (19%). Those with arthritic changes had significantly more tibiotalar tilt and diminished ankle range of motion compared with those without radiographic signs of osteoarthritis. These findings document measurable decreases in ankle function and suggest that correction or prevention of excessive tibiotalar tilt may be warranted to improve outcome.

Adult↗
PubMed2006

Cervical spinal cord compression due to an osteochondroma in hereditary multiple exostosis: case report and review of the literature.

BACKGROUND: Hereditary multiple exostosis is a benign disorder characterized by multiple osteochondromas affecting long and flat bones, although occasionally vertebral column involvement can be seen. Cervical spinal cord compression in HME is a rare condition. The objective of this manuscript is to describe a rare case of cervical myelopathy due to an exostosis arising from C7 in a patient with HME and a comprehensive review of the current literature. CASE DESCRIPTION: We describe a case of HME in an 18-year-old girl with myelopathy characterized by quadriparesis due to an osteochondroma arising from the lamina of C7. The patient underwent surgery, and a laminectomy was performed with a complete removal of the exostosis and spinal cord decompression. One month after surgery, patient presented an excellent recovery without neurologic deficits. CONCLUSIONS: Cervical spinal cord compression resulting from osteochondroma is an extremely serious complication of HME. Neurosurgical approach should be recommended in order to achieve a spinal cord decompression, which usually results in excellent functional recovery.

Adolescent↗
PubMed1986

[A simple method for high-resolution banding of chromosomes and its application to diagnosis of birth defects].

A simple method for obtaining high-resolution banding patterns on elongated chromosomes is devised as follows: Peripheral lymphocytes cultured for 3 days with phytohemagglutinin were exposed to 10 micrograms/ml ethidium bromide for 2 hours and with 0.02 micrograms/ml colcemid for 1 hour prior to harvesting. After preparation by steam-dry method, high-resolution G-bands were obtained by Giemsa staining following exposure to hydrogen peroxide and trypsin treatment. 19 cases of the Prader-Willi syndrome, 3 cases of the aniridia-Wilms' tumor syndrome, 2 cases of the Langer-Giedion syndrome, 2 cases of retinoblastoma and 6 cases with multiple congenital anomalies whose diagnosis was not made by routine chromosome analysis were examined by this method. 18 of the 19 cases of the Prader-Willi syndrome had a deletion of 15q11.2. 2 of the 3 cases of the aniridia-Wilms' tumor syndrome had a deletion of 11p13 and the other had a balanced insertion with a breakpoint at 11p13. The 2 cases of the Langer-Giedion syndrome had a deletion of 8q23.3-24.13. One of retinoblastoma had a deletion of 13q14 and the other had a balanced reciprocal X/13 translocation with breakpoints at Xp11.21 and 13q12.3. The last 6 cases had subtle chromosomal aberrations: 46, XX, del (5) (q15q22), 46, XX, del (13) (q32.3), 46, XX, inv dup (6) (p25p21.3), 46, XX, -5, +der (5), t (3; 5) (p23; p13) mat, 46, XX, -5, +der (5), t (5; 9) (p13.3p21) mat, and 46, XX, -4, +der (4), t (4; 16) (p15.2; p13.1) pat. The simple method for high-resolution banding of chromosomes is useful for diagnosis of many kinds of birth defects.

Adolescent↗
PubMed2005

Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations.

Multiple osteochondromas (MO) is an autosomal dominant condition, caused by mutations in either the EXT1 or the EXT2 gene. The DNA of a cohort of 35 patients, clinically suspected to be affected with MO, was screened for mutations by a combination of direct sequence analysis and multiplex ligation-dependent probe amplification (MLPA). In this cohort, 26 pathogenic gene alterations were found (74%). With sequence analysis mutations were detected in 22 patients (63%). In total, 10 mutations were detected in the EXT1 and 12 in the EXT2 gene. The number of the splice site mutations detected was larger than expected from the literature. In addition, with the MLPA four deletions of one or more exons were found in this cohort. Two patients, of whom one had a negative family history, showed deletions of exon 1 of the EXT1 gene, which is possibly a deletion hot spot. In patients suspected to be affected by MO, we recommend a quantitative analysis such as MLPA, followed by direct sequence analysis for the screening of the EXT1 and EXT2 genes.

Cohort Studies↗
PubMed1997

Kissing osteochondromata leading to synostoses.

Our aim was to determine the incidence of synostoses in the bones of the lower limbs in patients with multiple cartilaginous exostosis (MCE) and use the available imaging to suggest the cause and mechanism of its development. Radiographs of the lower legs of 21 patients with MCE were reviewed. With the intention of demonstrating the exact site and extent of synostoses and other bone deformities, such as bone pressure atrophy or erosions in five patients, 8 proximal and 6 distal tibiofibular joints were examined by CT scans. No synostoses were present in 11 patients and 10 patients had 1 to 4 synostoses. Of these synostoses, 14 were localized below the knee joint and 9 above the ankle joint. A growing osteochondroma arising from tibia or fibula can cause an erosion in the contagious surface of the neighbouring bone. If facing osteochondromata are present in both bones and show an interlocking growth at abutting parts, on osseous fusion can take place with formation of a synostosis in the proximal or distal tibiofibular joint region. In adult patients with MCE and abundant osteochondromata synostoses between the neighbouring bones of the lower legs are common findings; they are always caused by coalescence of "kissing" osteochondromata.

Adolescent↗
PubMedDate not supplied

A practical classification system for multiple cartilaginous exostosis in children.

Forty-one patients with multiple cartilaginous exostosis (MCE) were classified into three groups: Group I, no involvement of the distal forearm (n = 8); Group II, involvement of the distal forearm without shortening of the radius or ulna (n = 11); Group III, involvement of the distal forearm with shortening of the radius or ulna (n = 22). Groups were compared with regard to number of lesions, regional morbidity rate, age of onset, height, and presence of valgus deformity of the ankle. From these results, children in Group I were mildly affected. Further, those in Group III were severely affected, and all children in Group III had lesions of the innominate bone or proximal femur, where secondary chondrosarcoma occurs most frequently. This classification should prove useful in estimating severity and identifying cases at high risk for malignant transformation. MCE seemed to be an aberrant enchondral ossification and its mode of development to be reflected in the growth potential of each bone. Dislocation of the radial head occurred in three cases and was the initial symptom in two of these. Dislocation of the radial head may occur earlier than previously thought, hindering its prevention.

Adolescent↗
PubMed2006

Determination of the mutation spectrum of the EXT1/EXT2 genes in British Caucasian patients with multiple osteochondromas, and exclusion of six candidate genes in EXT negative cases.

We describe here the spectrum and distribution of mutations in the EXT1 and EXT2 genes in the largest reported British Caucasian multiple osteochondromas (MO) population. Furthermore, we report for the first time the screening of the EXT1 and EXT2 promoters, 5'UTRs, and 3'UTRs, and exclude six potential MO candidate genes in individuals without a detectable mutation within the coding region of EXT1 and EXT2. The coding exons of EXT1 and EXT2 were screened in 72 unrelated probands affected with MO. Forty-six different mutations were identified in 56 probands, of which 29 were novel. Mutation in the EXT1 and EXT2 genes each accounted for 50% of the mutations identified. Of the 72 probands, 42 were of British Caucasian descent, which when added to the 41 British Caucasian families previously reported from our total cohort, gave a total of 83 families. This cohort's proportional frequency for EXT1/EXT2 mutation was 53%/47%. We also validated the technique of high-resolution melting analysis in a blind study using 27 unique EXT1 or EXT2 mutations. This technique was found to be sensitive with a detection rate of 100% regarding heterozygote detection for EXT mutation scanning. Furthermore, this technique has a very high throughput and is very cost-effective.

Chromatography, High Pressure Liquid↗
PubMed1992

Insulin-like growth factor-I levels and gene expression in ovine hereditary chondrodysplasia (spider lamb syndrome).

Hereditary Chondrodysplasia or Spider Lamb Syndrome (SLS) is an inherited, semi-lethal, musculo-skeletal disease affecting lambs primarily of Suffolk or Hampshire breeding. Deformities of the limbs and spinal column along with multiple sites of ossification at the anconeal process are diagnostic for the disease. Muscle atrophy is also predominant. We have investigated the relationship between SLS and circulating levels of IGF-I and the IGF-BPs in older (50-80 d of age) animals. Serum IGF-I levels were lower (P less than 0.01) in SLS affected lambs (117 ng/ml) than in phenotypically normal lambs (188 ng/ml) while serum levels of the 32 kDa BP increased (P less than 0.01) 77% in SLS affected lambs as compared to contemporary controls. All other IGF-BPs appeared to be unaffected in this group. Gene expression of IGF-I and -II in the liver and muscle of younger (16-22 d of age) lambs was also measured. There were no differences in IGF-II expression in either muscle or liver between SLS affected and phenotypically normal control lambs. Muscle IGF-I expression also did not differ. However, liver IGF-I expression in SLS affected lambs was nearly double that of control lambs (P less than 0.01). These data suggest that the regulation of IGF-I and the IGF-BPs may be involved in the physical manifestations of this disorder.

3-Hydroxybutyric Acid↗
PubMed2000

Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice.

Mutations in the EXT1 gene are responsible for human hereditary multiple exostosis type 1. The Drosophila EXT1 homologue, tout-velu, regulates Hedgehog diffusion and signaling, which play an important role in tissue patterning during both invertebrate and vertebrate development. The EXT1 protein is also required for the biosynthesis of heparan sulfate glycosaminoglycans that bind Hedgehog. In this study, we generated EXT1-deficient mice by gene targeting. EXT1 homozygous mutants fail to gastrulate and generally lack organized mesoderm and extraembryonic tissues, resulting in smaller embryos compared to normal littermates. RT-PCR analysis of markers for visceral endoderm and mesoderm development indicates the delayed and abnormal development of both of these tissues. Immunohistochemical staining revealed a visceral endoderm pattern of Indian hedgehog (Ihh) in wild-type E6.5 embryos. However, in both EXT1-deficient embryos and wild-type embryos treated with heparitinase I, Ihh failed to associate with the cells. The effect of the EXT1 deletion on heparan sulfate formation was tested by HPLC and cellular glycosyltransferase activity assays. Heparan sulfate synthesis was abolished in EXT1 -/- ES cells and decreased to less than 50% in +/- cell lines. These results indicate that EXT1 is essential for both gastrulation and heparan sulfate biosynthesis in early embryonic development.

Animals↗
PubMed2005

A novel EXT1 splice site mutation in a kindred with hereditary multiple exostosis and osteoporosis.

CONTEXT: Hereditary multiple exostosis (HME) is an autosomal dominant disorder characterized by the development of benign cartilage-capped tumors at the juxta-epiphyseal regions of long bones. HME is usually caused by mutations of EXT1 or EXT2. OBJECTIVE: The objective of this study was to investigate a three-generation Austrian kindred with HME for EXT1 and EXT2 mutations and for abnormalities of bone mineral density (BMD). METHODS: DNA sequence and mRNA analyses were used to identify the mutation and its associated consequences. Serum biochemical and radiological investigations assessed bone metabolism and BMD. RESULTS: HME-affected members had a lower femoral neck BMD compared with nonaffected members (z-scores, -2.98 vs. -1.30; P = 0.011), and in those less than 30 yr of age, the lumbar spine BMD was also low (z-scores, -2.68 vs. -1.42; P = 0.005). However, they had normal mobility and normal serum concentrations of calcium, phosphate, alkaline phosphatase activity, creatinine, PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin, and beta-crosslaps. DNA sequence analysis of EXT1 revealed a heterozygous g-->c transversion that altered the invariant ag dinucleotide of the intron 8 acceptor splice site. RT-PCR analysis using lymphoblastoid RNA showed that the mutation resulted in skipping of exon 9 with a premature termination at codon 599. DNA sequence abnormalities of the osteoprotegerin gene, which is in close proximity to the EXT1 gene, were not detected. CONCLUSIONS: A novel heterozygous acceptor splice site mutation of EXT1 results in HME that is associated with a low peak bone mass, indicating a possible additional role for EXT1 in bone biology and in regulating BMD.

Adolescent↗
PubMed2001

[Progressive forearm lengthening in children: 14 cases].

PURPOSE OF THE STUDY: There are few indications for forearm lengthening in children. Several techniques have been proposed. We report our experience with progressive lengthening of the forearm in children using a unilateral axial external fixator and an improved technique consisting in initial insertion of an intramedullary guide wire. MATERIAL AND METHODS: Since 1990, we performed 14 forearm lengthenings in 9 children. Radial agenesia (5 forearms in 4 children), and hereditary multiple exostosis (3 forearms in 2 children) were the predominant causes. The ulna was involved in 9 cases and the radius in 5. Age at initiation of the lengthening procedure ranged from 4.5 to 14.8 years (mean 9.9). The lengthening technique consisted in a transverse subperiosteal osteotomy of the bone shaft then progressive distraction with a unilateral axial external fixator. When axial deviation had to be corrected, we used a subtraction osteotomy. In our last 10 cases, we inserted an intramedullary guide wire in the lengthened bone. The external fixation was left in place throughout the lengthening procedure and until complete bone healing. Serial radiographs were used to assess bone healing, the degree of lengthening achieved and any axial deviation at the end of lengthening. RESULTS: All 14 forearms were reviewed at a mean 50.6 months. Mean lengthening was 26.4 mm (range 10 - 52 mm). There were no nerve or vessel complications. In one case, reducible claw finger completely regressed after temporary interruption of the lengthening. There were 6 cases of late healing requiring a secondary bone graft. The healing index was 61.9 days per cm gained length. There were 3 cases with an axial deviation at the end of lengthening. DISCUSSION: Insertion of a guide wire in the bone being lengthened reduced the risk of late healing compared with lengthening procedures without a guide wire, avoiding axial deviation. In addition, this technique led to more rapid bone healing so the fixator could be removed earlier. We have found this method to be easier to perform on a normally axed segment. This would require an initial subtraction osteotomy for prior alignment. CONCLUSION: Forearm lengthening is a difficult procedure. Use of an intramedullary guide wire associated with an external fixation and an initial osteotomy for axial correction when needed and possibly stabilization of the wrist is an important contribution, particularly for malformed forearms.

Adolescent↗
PubMed1976

Congenital generalized fibromatosis. An African case with gingival hypertrophy and other unusual features.

What is believed to be the first reported case of congenital generalized fibromatosis in an African infant is described. Features in our patient, which were not noted in previous reports of the disease, include gingival hypertrophy, ankylosis of joints, skeletal hyperostosis, and lymphatic dilation of the ileal villi. Corticosteroid therapy was tried in the patient, but did not produce any beneficial effect.

Ankylosis↗