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We report on a further case of a recently described type of spondylo-metaphyseal dysplasia in a 12(10/12)-year-old Polish boy. The original paper described the disorder in five relatives in an Algerian family.
Endothelial cell division in the metaphyseal capillaries of growing rats was studied by serial sectioning and electron microscopic examination. The endothelium of these capillary sprouts forms a continuous attenuated squamous lining. During endochondral bone formation these growing vessels possess a region of endothelial cell division which is located behind the sprout tip in an area where the microvascular wall consists of an endothelium and a discontinuous layer of perivascular cells. Examination of this region has shown the presence of junctional attachments between daughter cells even before cell separation is complete. Thus, the integrity of the vascular wall is not compromised during cell division. Junctional complexes with adjacent endothelial cells are also formed along the cleavage plane prior to the completion of cytokinesis. Numerous microvilli and from both the daughter cells and adjacent endothelial cells often make contact and form junctions with the plasma membrane of the dividing cells. A model for endothelial junction formation between daughter cells during cytokinesis and the role that microvilli play in the process is proposed.
Schmid metaphyseal chondrodysplasia (SMCD) has previously been shown to be the result of mutations in the type X collagen gene, COL10A1. A further three mutations have been identified, including two nonsense mutations (Y268X, W651X) and a frameshift mutation (1856delCC). Each of the 10 SMCD mutations identified to date is within the C-terminal noncollagenous domain of type X collagen and three of five deletions initiated around the same nucleotide. This domain is believed to be involved in the initiation of collagen trimerization. The concentration of mutations within this domain is consistent with the hypothesis that the phenotype is the result of a reduction in the level of mature type X collagen due to the mutant polypeptide's inability to participate in trimer formation, although a dominant-negative mechanism cannot be discounted, on the basis of current evidence.
Schmid metaphyseal chondrodysplasia (SMCD) is a dominantly inherited cartilage disorder caused by mutations in the gene for the hypertrophic cartilage extracellular matrix structural protein, collagen X (COL10A1). Thirty heterozygous mutations have been described, about equally divided into two mutation types, missense mutations, and mutations that introduce premature termination signals. The COL10A1 mutations are clustered (33/36) in the 3' region of exon 3, which codes for the C-terminal NC1 trimerization domain. The effect of COL10A1 missense mutations have been examined by in vitro expression and assembly assays and cell transfection studies, which suggest that a common consequence is the disruption of collagen X trimerization and secretion, with consequent intracellular degradation. The effect of COL10A1 nonsense mutations in cartilage tissue has been examined in two patients, demonstrating that the mutant mRNA is completely removed by nonsense mediated mRNA decay. Thus for both classes of mutations, functional haploinsufficiency is the most probable cause of the clinical phenotype in SMCD.
Schmid metaphyseal chondrodysplasia (SMCD) is an autosomal dominant disorder affecting the growth plate cartilage of long bones caused by heterozygous mutations in the gene for collagen X (COL10A1), a short-chain collagen expressed by hypertrophic chondrocytes of growth plate cartilage. In this paper we analyzed six unrelated patients clinically determined as affected by SMCD, and characterized four missense mutations, c.52G>A (p.G18R), c.1744T>G (p.Y582D), c.1792T>G (p.Y598D) and c.1958A>C (p.Q653P). These mutations were clustered in the two regions of the collagen X protein shown to contain all previous SMCD mutations; the signal sequence cleavage site (p.G18R), or the C-terminal NC1 trimerization domain (p.Y582D, p.Y598D and p.Q653P). To determine the functional effect of the mutations we produced engineered p.Y582D, p.Y598D and p.Q653P cDNA and expressed these in vitro. Our data showed that while the wild-type collagen X assembled in vitro into trimers that were stable to SDS-PAGE analysis, p.Y582D (the most N-terminal of the SMCD NC1 mutations described), p.Q653P, and the previously analyzed p.Y598D impair collagen X trimerization. However, in two patients no mutations were detected despite complete sequence analysis of the COL10A1 coding region, the exon-intron splice consensus sequences and the 500bp gene promoter region. Heterozygosity for known polymorphisms ruled out major COL10A1 gene deletions and Southern analysis excluded major rearrangements. The data suggest that in these two patients, SMCD results from mutations at another gene locus. No mutations were detected in RMRP, the gene for cartilage-hair hypoplasia that has phenotypic overlap with SMCD.
The purpose of this study was to evaluate the biological properties of idealized, morsellised impacted Corglaes, a soluble silicate-free glass. Twenty-two sheep underwent implantation of pellets in six metaphyseal defects in both rear limbs. Particle size distribution of all aggregates (except the autograft) approached the ideal logarithmic grading line and all implants were impacted to a standard compactive effort. Treatment groups consisted of (1) empty defect (negative control), (2) autograft (positive control), (3) allograft (clinical control), (4) allograft idealized with Corglaes, (5) 50/50 allograft/Corglaes and (6) Corglaes. Defects were sealed with polymethylmethacrylate. Healing of the defects was evaluated at 7 weeks (n=6) and 14 weeks (n=16) with computed tomography, histology, and histomorphometry. Remnants of Corglaes were found within one of the defects 7 weeks after implantation. Defects filled with mixtures containing 50% or 100% Corglaes were less dense, contained less bone and more fibrous tissue than defects with allograft, autograft, or allograft idealized with Corglaes. Allograft idealized with Corglaes may be considered for impaction grafting in revision hip arthroplasty, as well as local delivery of antibiotics. However, further studies and potential revision of the agent are required before mixtures containing concentrations of Corglaes equal to or higher than 50% can be recommended.
A model for the free allograft microvascular transplantation of rabbit proximal tibial epiphyseal plate allografts was developed, validated, and tested in an in vivo animal model. Transplants contained the minimum amount of adjacent epiphyseal and metaphyseal bone compatible with preservation of the epiphyseal-plate vascular supply, as determined by corrosion casting. Perfusion to this graft was evaluated quantitatively using radioactive microspheres, and qualitatively using India-ink injection. Female New Zealand White rabbits at 12 weeks of age were utilized. Vascularized transplantation of epiphyseal plate allografts was performed either into a defect of matched size in the iliac crest or into a soft-tissue pocket without bone contact. Cyclosporine A immunosuppression (CSA) was administered daily for 6 weeks. Two control groups underwent identical surgical procedures, but had no postoperative immunosuppression. Epiphyseal plates both with and without bone contact, in rabbits immunosuppressed postoperatively with CSA, demonstrated longitudinal growth and preserved viability as determined by positive bromodeoxyuridine uptake. Control epiphyseal plates transferred without postoperative immunosuppression were uniformly nonviable. This new model has value as a basis for further studies into the clinical applicability of isolated epiphyseal-plate transplants.
Three major vessel types--metaphyseal, epiphyseal and transphyseal vessels--were identified in the region of the growth plate following perfusion of the vasculature of the chicken leg with a solution of Berlin Blue. Following the production of osteomyelitis, obstruction to the blood supply adjacent to the abscess was rapid and was clearly demonstrated due to a lack of perfusion of the involved vessels with Berlin Blue. The extent of disturbance to the blood supply was dependent on the type of vessel involved in the inflammatory process. The efficacy of bloodstream therapy is discussed in relation to these findings.
We present the first confirmed case by molecular analysis of a metaphyseal chondrodysplasia, McKusick type, in a 22-week fetus. Two novel compound heterozygous mutations, 64T> A and 79G > T, were found in the highly conserved regions of the RMRP gene. Twenty-two heterozygous g.1018 T> C mutations, two homozygous g.1018 T> C mutations, two heterozygous insertion mutations g.799_g.800insC and one heterozygous insertion mutation g.849_g.850insT were found among 100 normal controls. Careful radiological examination of the fetus for skeletal dysplasia allowed definitive diagnosis, proper genetic counselling and future prenatal diagnosis.
A novel nucleotide change in the collagen X gene was identified in a Japanese family with Schmid metaphyseal chondrodysplasia (SMCD). The T to C change at nucleotide 1951 resulted in replacement of tryptophan by arginine at residue 651 (W651R). This missense mutation is considered to be responsible for SMCD because 1, the same mutation was not be identified in the collagen X gene from normal individuals; 2, the mutation segregated with the SMCD phenotype in the index family; 3, the substituted amino acid is highly conserved in type X collagens, and 4, the mutation causes a marked change in the hydrophobicity profile of the surrounding region in the NC1 domain. This novel mutation (W651) seems to have the same impact on bone development as W651X mutation.
Schmid metaphyseal chondrodysplasia (SMCD; MIM 156500) is an autosomal dominant disorder of the skeleton that is manifested in early childhood by short stature, coxa vara, and a waddling gait. Patients with SMCD have mutations in the gene that codes for the alpha-1 chain of collagen X (COL10A1); however, mutation analysis of this gene is hampered by its size. We studied a family with SMCD: the mother, a 36-year-old woman with a height of 149 cm, had mild bilateral coxa vara. Her two sons presented with short stature, bowed legs, and coxa vara in early childhood. DNA was extracted from peripheral lymphocytes from the three patients and subjected to PCR amplification by COL10A1 gene-specific primers. In addition to single-strand conformational polymorphism (SSCP) analysis of the COL10A1 gene, we used a novel method, dideoxy fingerprinting (ddF). The genetic defect in this family was found to be a previously unreported missense mutation (T-to-C transition) at nucleotide 2011. This change resulted in a Ser-to-Pro substitution at position 671 of the carboxy-terminus of the COL10A1 protein. In addition, the two boys, but not the mother, were found to carry a trinucleotide (CCC) deletion at position 2048 of the 3' untranslated region, a polymorphism of the COL10A1 gene. We conclude that ddF can be used in the analysis of the COL10A1 gene along with SSCP. The S671P substitution is novel, but located in the same region with the other reported COL10A1 mutations, confirming type X collagen as the locus for this disease.
This study evaluated hydroxyapatite-glass (HA-G) composite as a filler material when implanted into a proximal metaphyseal tibial cavity consisting of medullary tissue and cancellous bone in rabbits. The repair process was compared with that of autogenous bone grafts and untreated controls. Scanning electron microscopy, energy dispersive x-ray studies, radiography, histology with tetracycline fluorescence and morphometric bone measurements were used for evaluation. Equal amounts of mineralised bone were produced in both HA-G granule and autograft groups at 3 weeks; thereafter, autografts mostly resorbed, whereas there was appositional lamellar bone formation on the early woven bone in the HA-group. A relatively small proportion of the cavities was repaired by new bone. The HA-G granules were biocompatible without foreign body reaction and showed good osteoconductive potential. Mesenchymal cells were able to differentiate into osteoblasts on bioactive surfaces of the composite. Although HA-G was able to form Ca-P-rich and Si-rich layers, most of the granules underwent degradation through its glass matrix, resulting in fewer bony contacts than granules with no surface degradation.
We have used Ilazorov's method of distraction epiphyseolysis for leg lengthening since 1977 and his new method of corticotomy or compactotomy since 1983. The first method was carried out in 22 lower limbs with an average lengthening of 8.25 cm (range 4 to 18 cm); included in this group are 2 patients with achondroplasia in whom both legs were lengthened 12 cm. In the second method, a corticotomy is carried out at the metaphyseal-diaphyseal junction followed by distraction in Ilazorov's apparatus (4 x 0.25 mm a day). We lengthened 30 legs; included are 5 patients who had both legs lengthened from between 8 and 12 cm. In the remainder an average of 7.9 cm of lengthening was achieved (range from 4 to 15 cm). The index for the treatment time per cm achieved (time from operation until full weight-bearing per cm of lengthening) was shorter after distraction epiphyseolysis than after corticotomy. Complications were also a little less after the latter procedure. Distraction epiphyseolysis has to be limited to children from aged 12 years until growth ceases. The advantage with corticotomy is that it can be done at any age from 5 to 30 years. Care is needed in both cases to avoid complications.
An extremely rare case of bilateral, symmetrical involvement of distal femoral metaphyses by the solid variant of aneurysmal bone cyst (ABC) in a boy aged 13 years is described. Although there is no difference between the conventional ABC and the solid variant in terms of clinical and radiological presentation, the lesion is solid, composed of fibrohistiocytic cells with abundant giant cells and/or areas of florid, heterotopic ossification, while aneurysmal channels are sparse or absent. The lesion needs to be differentiated from giant cell tumour of bone, when the osteoclastic component predominates, while fibrous dysplasia, osteoblastoma and even osteosarcoma need to be excluded any time ossification is prominent. Careful evaluation of the clinical, radiological and pathological findings is necessary.
In summary, a case is reported of a patient with the radiographic findings of diffuse, symmetrical metaphyseal osteopenia of long bones. A constellation termed neo-osseous porosis, associated with polyendocrine failure (Schmidt syndrome) involving the thyroid gland, adrenal glands, and gonads has been described in this case. Neo-osseous porosis has been observed previously in idiopathic juvenile osteoporosis. This case represents the first instance in which this distinctive radiographic picture has been observed in the setting of specific (multiple) endocrine dysfunction disorders.
A tentative classification of Perthes' disease according to the extent of epiphyseal and metaphyseal involvement in lateral radiographs of the hip was applied to 61 hips in 55 patients. Forty-four hips were treated by containment (Tachjian's trilateral socket hip abduction orthosis) and 17 hips were treated surgically either by intertrochanteric or sub-trochanteric osteotomy. The results correlated well with the classification of the authors. The greater the extent of involvement of the epiphysis and metaphysis, the severer the resulting deformity. The choice of method of treatment is also discussed. It is concluded that this classification may be of prognostic value and may be useful to differentiate atypical cases.
The effects of long-term prostaglandin E2 (PGE2) on cancellous bone in proximal tibial metaphysis were studied in 7-month-old male Sprague-Dawley rats given daily subcutaneous injections of 0, 1, 3, and 6 mg PGE2/kg/day and sacrificed after 60, 120, and 180 days. Histomorphometric analyses were performed on double fluorescent-labeled undecalcified bone specimens. After 60 days of treatment, PGE2 produced diffusely labeled trabecular bone area, increased trabecular bone area, eroded and labeled trabecular perimeter, mineral apposition rate, and bone formation rate at all dose levels when compared with age-matched controls. In rats given PGE2 for longer time periods (120 and 180 days), trabecular bone area, diffusely labeled trabecular bone area, labeled perimeter, mineral apposition, and bone formation rates were sustained at the elevated levels achieved earlier at 60-day treatment. The eroded perimeter continued to increase until 120 days, then plateau. The observation that continuous systemic PGE2 administration to adult male rats elevated metaphyseal cancellous bone mass to 3.5-fold of the control level within 60 days and maintained it for another 120 days indicates that the powerful skeletal anabolic effects of PGE2 can be sustained with continuous administration.
Fibronectin is a well known glycoprotein of extracellular connective tissue matrices due to a specific amino acid-sequence (RGD) suggested to act as an attachment factor in cell-cell or cell-matrix interactions. Although also present in bone, little is known about the role of fibronectin in this tissue. To obtain data for discussions on function we used ultrastructural immunolocalization techniques to quantitatively examine the distribution of fibronectin in various bone matrix compartments. The study was focused on three different stages of endochondral ossification in growing long bones of young rats. The results show large amounts of fibronectin in mature bone tissue. At a higher magnification, an obvious fibronectin association to individual fibrils of collagen type I was demonstrated. Intracellular labeling was observed in Golgi-related vesicles in some active osteoblasts of metaphyseal bone, indicating local synthesis of fibronectin. In contrast to previous suggestions based on light microscopic observations, the labeling of bone or cartilage matrices facing the surface of all cell types were low. The pattern is clearly different from that of osteopontin and bone sialoprotein, two other bone matrix proteins with the same cell-binding sequence. Our results indicate that fibronectin at these stages of development participates in matrix organization rather than being an important link between cartilage or bone matrix and adjacent cells.