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Human Molecular Genetics Mar 2011Craniometaphyseal dysplasia (CMD) is a rare genetic disorder with hyperostosis of craniofacial bones and widened metaphyses in long bones. Patients often suffer from...
Craniometaphyseal dysplasia (CMD) is a rare genetic disorder with hyperostosis of craniofacial bones and widened metaphyses in long bones. Patients often suffer from neurological symptoms due to obstruction of cranial foramina. No proven treatment is available and the pathophysiology is largely unknown. A Phe377 (TTC(1130-1132)) deletion in exon 9 of the pyrophosphate (PPi) transporter ANK leads to CMD-like features in an Ank(KI/KI) mouse model. Here, we investigated the effects of CMD-mutant ANK on mineralization and bone mass at a cellular level. Ank(KI/KI) osteoblast cultures showed decreased mineral deposition. Expression of bone mineralization regulating genes Mmp13, Ocn, Osx and Phex was reduced in Ank(KI/KI) osteoblasts, while the Fgf23 mRNA level was highly elevated in Ank(KI/KI) calvarial and femoral bones. Since ANK is a known PPi transporter, we examined other regulators of Pi/PPi homeostasis Enpp1 and Tnap. Significantly increased ENPP1 activity may compensate for dysfunctional mutant ANK leading to comparable extracellular PPi levels in Ank(+/+) osteoblasts. Similar to Ank(KI/KI) bone marrow-derived macrophage cultures, peripheral blood cultures from CMD patients exhibited reduced osteoclastogenesis. Cell-autonomous effects in Ank(KI/KI) osteoclasts resulted in disrupted actin ring formation and cell fusion. In addition, Ank(KI/KI) osteoblasts failed to adequately support osteoclastogenesis. Increased bone mass could partially be rescued by bone marrow transplants supporting our hypothesis that reduced osteoclastogenesis contributes at least in part to hyperostosis. We conclude that the Phe377del mutation in ANK causes impaired osteoblastogenesis and osteoclastogenesis resulting in hypomineralization and a high bone mass phenotype.
Topics: Animals; Bone Diseases, Developmental; Calcification, Physiologic; Case-Control Studies; Cell Differentiation; Cells, Cultured; Craniomandibular Disorders; Disease Models, Animal; Exons; Facial Paralysis; Female; Fibroblast Growth Factor-23; Gene Expression Regulation, Developmental; Humans; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mutation; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Phosphate Transport Proteins; Sequence Deletion; Skull
PubMed: 21149338
DOI: 10.1093/hmg/ddq541 -
Studies in History and Philosophy of... Dec 2010This article discusses the Tibetan notion of rlung, usually translated as: 'wind', but perhaps better understood as a close equivalent of pneuma in the Greek tradition,...
This article discusses the Tibetan notion of rlung, usually translated as: 'wind', but perhaps better understood as a close equivalent of pneuma in the Greek tradition, or qi in the Chinese tradition. The article focuses on the way rlung provides a useful prism through which concepts of health, illness and disease may be observed in a cross-cultural perspective. An analysis of syndromes linked with rlung in a Tibetan cultural context illuminates some of the ways in which culture determines particular syndromes. The article raises a number of questions which are relevant for a more general multicultural approach to concepts of health, illness and disease. The article argues that notions of rlung/pneuma/wind/ qi constitute a particularly interesting area for an exploration of culture-bound syndromes, as they reside in the meeting point between material and non-material, physical and mental, as well as the psychological, spiritual and religious. They are hence fundamental for a more cross-cultural approach to the mind-body problem. The article also deals with the significance of history of medicine, particularly histories of medicine, which attempt to widen the scope of the traditional Eurocentric narrative of the history of medicine, in dealing with questions such as concepts of health and illness. Allowing alternative narratives-whether narratives of patients, other cultures or historical ones-can enhance our understanding of what health, illness and disease are. Discussing perceptions of the body as culturally defined is not only important from a philosophical or historical point of view, but also has important practical ramifications, which are particularly crucial in our global age.
Topics: Cross-Cultural Comparison; Culture; Disease; History of Medicine; History, Ancient; Humans; Medicine, Traditional; Mind-Body Relations, Metaphysical; Qi; Syndrome; Tibet; Wind
PubMed: 21112005
DOI: 10.1016/j.shpsc.2010.10.005 -
Journal of Bone and Mineral Research :... Nov 2010Dysosteosclerosis (DSS), an extremely rare dense bone disease, features short stature and fractures and sometimes optic atrophy, cranial nerve palsy, developmental... (Review)
Review
Dysosteosclerosis (DSS), an extremely rare dense bone disease, features short stature and fractures and sometimes optic atrophy, cranial nerve palsy, developmental delay, and failure of tooth eruption in infancy or early childhood consistent with osteopetrosis (OPT). Bone histology during childhood shows unresorbed primary spongiosa from deficient osteoclast action. Additionally, there is remarkable progressive flattening of all vertebrae and, by adolescence, paradoxical metaphyseal osteopenia with thin cortical bone. Reports of consanguinity indicate autosomal recessive inheritance, yet more affected males than females suggest X-linked recessive inheritance. We investigated a nonconsanguineous girl with DSS. Osteosclerosis was discovered at age 7 months. Our studies, spanning ages 11 to 44 months, showed weight at approximately 50th percentile, and length diminishing from approximately 30th percentile to -2.3 SD. Head circumference was +4 SD. The patient had frontal bossing, blue sclera, normal teeth, genu valgum, and unremarkable joints. Radiographs showed orbital and facial sclerosis, basilar thickening, bone-in-bone appearance of the pelvis, sclerotic long bone ends, and fractures of ribs and extremities. Progressive metaphyseal widening occurred as vertebrae changed from ovoid to flattened and became beaked anteriorly. A hemogram was normal. Consistent with OPT, serum parathyroid hormone (PTH) concentrations reflected dietary calcium levels. Serum bone alkaline phosphatase, osteocalcin, and TRACP-5b were subnormal. The iliac crest contained excessive primary spongiosa and no osteoclasts. No mutations were identified in the splice sites or exons for the genes encoding chloride channel 7, T-cell immune regulator 1, OPT-associated transmembrane protein 1, and monocyte colony-stimulating factor (M-CSF) and its receptor C-FMS, ANKH, OPG, RANK, and RANKL. Genomic copy-number microarray was unrevealing. Hence, DSS is a distinctive OPT of unknown etiology featuring osteoclast deficiency during early childhood. How osteopenia follows is an enigma of human skeletal pathobiology.
Topics: Adult; Bone and Bones; Child, Preschool; DNA Mutational Analysis; Diagnosis, Differential; Family; Female; Humans; Infant; Infant, Newborn; Osteoclasts; Osteopetrosis; Osteosclerosis; Pregnancy; Radiography, Thoracic; Tomography, X-Ray Computed
PubMed: 20499338
DOI: 10.1002/jbmr.131 -
Orthopaedics & Traumatology, Surgery &... Apr 2010Five-year following total hip implantation femur adaptive morphology was compared between two groups differing only in their femoral stem design.
INTRODUCTION
Five-year following total hip implantation femur adaptive morphology was compared between two groups differing only in their femoral stem design.
MATERIAL AND METHODS
Group 1, recruited prospectively, included 51 Dédicace stems(Stryker-Howmedica) and group 2, retrospectively matched to group 1, comprised 51 Kerboull MK3 stems (Stryker-Howmedica). While MK3 prosthetic system increases in size homogeneously (widening along the whole length as the implant dimension increases), the Dédicace prosthetic system provides various metaphyseal widths for a given diaphyseal size. We opted for primary fixation (press fit according to the "French paradox") prior to cementing in both cases, despite the risk of discontinuity in the cement mantle. The homogeneous dimensioning of the MK3 stem enables distal primary fixation, whereas the Dédicace range allows differentiated adaptation to diaphyseal length and metaphyseal caliber. The following parameters were measured and calculated: Noble index, femoral cortical thickness score of Barnett and Nordindiaphyseal filling and stress-shielding at three levels around the stem.
RESULTS
Bone-remodeling, assessed on X-ray, was without clinical impact, whether it took the form of spongialization or stress-shielding. The sole factor tending to induce stress-shielding was a high degree of canal filling by the distal third of the stem, more frequently encountered with the MK3 model. Metaphyseal filling was equivalent with all stems. In the matched series on the contralateral healthy side, femoral spongialization was comparable.
LEVEL OF PROOF
Level III; case/control study.
Topics: Adaptation, Physiological; Aged; Bone Remodeling; Cementation; Female; Femur; Hip Prosthesis; Humans; Male; Middle Aged; Osteoarthritis, Hip; Prosthesis Design
PubMed: 20417907
DOI: 10.1016/j.rcot.2010.02.006 -
Pediatric Rheumatology Online Journal Mar 2010CINCA/NOMID is an autoinflammatory disorder characterized by the triad of neonatal onset of cutaneous symptoms, chronic meningitis, and recurrent fever and it presents...
CINCA/NOMID is an autoinflammatory disorder characterized by the triad of neonatal onset of cutaneous symptoms, chronic meningitis, and recurrent fever and it presents with distinctive osteoarthropathy, synovitis mainly of the large joints and overgrowth of epimetaphyseal cartilage, particularly of the long bones. The cartilage overgrowth eventually causes osseous overgrowth and deformity that persists beyond skeletal maturity and leads to limb length discrepancy, joint contracture, and early degenerative arthropathy. Autoinflammation in CAPS/NOMID has been proven to derive from excessive release of interleukin-1 (IL-1). It has been well documented that the IL-1 receptor antagonist anakinra (Kineret(R)) helps mitigate systemic inflammation in the disorder. However, a general consensus has not been reached on its beneficial effect on osteoarthropathy. The case of a girl with CINCA/NOMID syndrome who showed dramatic improvement of osteoarthropathy after anakinra treatment is reported. A 4-year-old girl suffered at the age of 10 months from a generalized urticarial skin lesion with recurrent episodes of fever and growth disorder. Blood examination revealed persistent massive neutrophilia, anemia and intense acute phase response. She manifested knee joint swelling with limited ROM when she was 20 months old and was diagnosed as being CINCA/NOMID based on characteristic findings of radiograph despite negative CIAS1 mutation. Radiological examination demonstrated metaphyseal fraying and cupping and widening of the growth plate in the distal femur. MR imaging showed mottled gadolinium enhancement at the chondrosseous junction. Neither significant joint effusion nor synovitis was identified. At 2 years and 7 months of age, anakinra, 2 mg/kg/day given by regular daily subcutaneous injections, was started. A few days after the initiation of the treatment, her clinical symptoms and laboratory findings of active inflammation were promptly alleviated. She was not able to walk unaided prior to the treatment, but she walked independently 1 month after the treatment. Follow-up radiographs and MR imaging showed that growth plate widening and gadolinium enhancement at the chondrosseous junction were less conspicuous. Furthermore, longitudinal growth of the femur and tibia was identified during 20 months of observation.
PubMed: 20230645
DOI: 10.1186/1546-0096-8-9 -
Journal of Bone and Mineral Research :... Nov 2009Runx2 controls the commitment of mesenchymal cells to the osteoblastic lineage. Distinct promoters, designated P1 and P2, give rise to functionally similar Runx2-II and...
Runx2 controls the commitment of mesenchymal cells to the osteoblastic lineage. Distinct promoters, designated P1 and P2, give rise to functionally similar Runx2-II and Runx2-I isoforms. We postulate that this dual promoter gene structure permits temporal and spatial adjustments in the amount of Runx2 isoforms necessary for optimal bone development. To evaluate the gene dose-dependent effect of Runx2 isoforms on bone development, we intercrossed selective Runx2-II(+/-) with nonselective Runx2-II(+/-)/Runx2-I(+/-) mice to create compound mutant mice: Runx2-II(+/-), Runx2-II(+/-)/Runx2-I(+/-), Runx2-II(-/-), Runx2-II(-/-)/Runx2-I(+/-), Runx2-II(-/-)/Runx2-I(-/-). Analysis of the different Runx2-deficient genotypes showed gene dose-dependent differences in the level of expression of the Runx2 isoforms. In addition, we found that Runx2-I is predominately expressed in the perichondrium and proliferating chondrocytes, whereas Runx2-II is expressed in hypertrophic chondrocytes and metaphyseal osteoblasts. Newborn mice showed impaired development of a mineralized skeleton, bone length, and widening of the hypertrophic zone that were proportionate to the reduction in total Runx2 protein expression. Osteoblast differentiation ex vivo was also proportionate to total amount of Runx2 expression that correlated with reduced Runx2 binding to the osteocalcin promoter by quantitative chromatin immunoprecipitation analysis. Functional analysis of P1 and P2 promoters showed differential regulation of the two promoters in osteoblastic cell lines. These findings support the possibility that the total amount of Runx2 derived from two isoforms and the P1 and P2 promoters, by regulating the time, place, and amount of Runx2 in response to changing environmental cues, impacts on bone development.
Topics: Alkaline Phosphatase; Animals; Body Weight; Bone Development; Bone and Bones; Calcium; Chromatin Immunoprecipitation; Core Binding Factor Alpha 1 Subunit; Embryo, Mammalian; Gene Dosage; Gene Expression Profiling; Gene Expression Regulation, Developmental; Homeostasis; Mice; Osteoblasts; Osteocalcin; Promoter Regions, Genetic; Protein Binding; Protein Isoforms; Time Factors; X-Ray Microtomography
PubMed: 19419310
DOI: 10.1359/jbmr.090502 -
Cases Journal Nov 2008Enchondromatosis represent a heterogenous group of disorders. Spranger et al attempted a classification into 6 types: Ollier disease, Maffuci syndrome,...
Acroform type of enchondromatosis associated with severe vertebral involvement and facial dysmorphism in a boy with a new variant of enchondromatosis type I1 of Spranger: case report and a review of the literature.
BACKGROUND
Enchondromatosis represent a heterogenous group of disorders. Spranger et al attempted a classification into 6 types: Ollier disease, Maffuci syndrome, metachondromatosis, spondyloenchondrodysplasia, enchondromatosis with irregular vertebral lesions, and generalized enchondromatosis. Halal and Azouz added 3 tentative categories to the 6 in the classification of Spranger et al.
CASE PRESENTATION
We report on a 15-year-old boy with acrofrom upper limbs and mixed appearance of radiolucency, cysts and striae of fibro-chondromatosis. Lower limbs (femoral, tibial and fibular dysplasia showed enlarged metaphyses near the knees bilaterally) were present. Additional features of short stature, macrocephaly, facial dysmorphism, and generalised platyspondyly have been encountered. These bone shortenings were associated with bone bending, curving and rhizomelia of the upper limbs with significant macrodactyly. Limitations in articular movements were present. The forearm deformities were similar to those observed in hereditary multiple exostosis.
CONCLUSION
The acrofrom upper limbs with mixed appearances of radiolucencies, cysts and striae of fibro-chondromatosis are the basic features of type I1Spranger. The constellation of facial dysmorphic features and significant vertebral abnormalities in our present patient were not compatible with the above-mentioned type of enchondromatosis. Our report widens the knowledge of disorders characterised by enchondromatosis. Ascertainment of the mode of inheritance in our present patient was difficult because of insufficient family history and parents declined clinical/radiographic documentation.
PubMed: 19017386
DOI: 10.1186/1757-1626-1-324 -
American Journal of Human Genetics Jun 2008We present clinical, radiological, biochemical, and genetic findings on six patients from two consanguineous families that show EDS-like features and radiological...
We present clinical, radiological, biochemical, and genetic findings on six patients from two consanguineous families that show EDS-like features and radiological findings of a mild skeletal dysplasia. The EDS-like findings comprise hyperelastic, thin, and bruisable skin, hypermobility of the small joints with a tendency to contractures, protuberant eyes with bluish sclerae, hands with finely wrinkled palms, atrophy of the thenar muscles, and tapering fingers. The skeletal dysplasia comprises platyspondyly with moderate short stature, osteopenia, and widened metaphyses. Patients have an increased ratio of total urinary pyridinolines, lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP), of approximately 1 as opposed to approximately 6 in EDS VI or approximately 0.2 in controls. Lysyl and prolyl residues of collagens were underhydroxylated despite normal lysyl hydroxylase and prolyl 4-hydroxylase activities; underhydroxylation was a generalized process as shown by mass spectrometry of the alpha1(I)- and alpha2(I)-chain-derived peptides of collagen type I and involved at least collagen types I and II. A genome-wide SNP scan and sequence analyses identified in all patients a homozygous c.483_491 del9 SLC39A13 mutation that encodes for a membrane-bound zinc transporter SLC39A13. We hypothesize that an increased Zn(2+) content inside the endoplasmic reticulum competes with Fe(2+), a cofactor that is necessary for hydroxylation of lysyl and prolyl residues, and thus explains the biochemical findings. These data suggest an entity that we have designated "spondylocheiro dysplastic form of EDS (SCD-EDS)" to indicate a generalized skeletal dysplasia involving mainly the spine (spondylo) and striking clinical abnormalities of the hands (cheiro) in addition to the EDS-like features.
Topics: Adult; Amino Acid Sequence; Amino Acids; Base Sequence; Cation Transport Proteins; Child; Child, Preschool; Collagen; Consanguinity; DNA; Ehlers-Danlos Syndrome; Female; Genes, Recessive; Haplotypes; Humans; Male; Molecular Sequence Data; Mutation; Pedigree; Phenotype; Sequence Deletion; Sequence Homology, Amino Acid
PubMed: 18513683
DOI: 10.1016/j.ajhg.2008.05.001 -
The Journal of Biological Chemistry May 2004Runx2 (runt-related transcription factor 2) is a master regulator of skeletogenesis. Distinct promoters in the Runx2 gene transcribe the "bone-related" Runx2-II and...
Runx2 (runt-related transcription factor 2) is a master regulator of skeletogenesis. Distinct promoters in the Runx2 gene transcribe the "bone-related" Runx2-II and non-osseous Runx2-I isoforms that differ only in their respective N termini. Existing mutant mouse models with both isoforms deleted exhibit an arrest of osteoblast and chondrocyte maturation and the complete absence of mineralized bone, but they do not distinguish the separate functions of the two N-terminal isoforms. To elucidate the function of the bone-related isoform, we generated selective Runx2-II-deficient mice by the targeted deletion of the distal promoter and exon 1. Homozygous Runx2-II-deficient (Runx2-II(-/-)) mice unexpectedly formed axial, appendicular, and craniofacial bones derived from either intramembranous ossification or mesenchymal cells of the bone collar, but they failed to form the posterior cranium and other bones derived from endochondral ossification. Heterozygous Runx2-II-deficient mice had grossly normal skeletons, but were osteopenic. The commitment of mesenchymal cells ex vivo to the osteoblast lineage occurred in Runx2-II(-/-) mice, but osteoblastic gene expression was impaired. Chondrocyte maturation appeared normal, but the zone of hypertrophic chondrocytes was not transformed into metaphyseal bone, leading to widened growth plates in Runx2-II(-/-) mice. Compensatory increments in Runx2-I expression occurred in Runx2-II(-/-) mice but were not sufficient to normalize osteoblastic maturation or transcriptional activity. Our findings support distinct functions of Runx2-II and -I in the control of skeletogenesis. Runx2-I is sufficient for early osteoblastogenesis and intramembranous bone formation, whereas Runx2-II is necessary for complete osteoblastic maturation and endochondral bone formation.
Topics: Alkaline Phosphatase; Animals; Bone and Bones; Chondrocytes; Core Binding Factor Alpha 1 Subunit; Exons; Genes, Reporter; Heterozygote; Homozygote; Mice; Mice, Mutant Strains; Models, Genetic; Neoplasm Proteins; Osteoblasts; Phenotype; Promoter Regions, Genetic; Protein Isoforms; Protein Structure, Tertiary; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tomography, X-Ray Computed; Transcription Factors; Transcription, Genetic
PubMed: 15007057
DOI: 10.1074/jbc.M401109200 -
International Orthopaedics 2003We used Magnetic resonance imaging (MRI) in five patients (six knees), mean age 13.2 (12-15) years, with late-onset tibia vara (Blount's disease), to study the growth...
We used Magnetic resonance imaging (MRI) in five patients (six knees), mean age 13.2 (12-15) years, with late-onset tibia vara (Blount's disease), to study the growth plate and its abnormalities. The MRI study was classified for severity of disease and compared with a radiographic classification. In severely involved knees, MRI indicated severe growth-plate changes on both sides of the knee joint. Widening in the entire proximal tibial growth plate, involvement of the distal femoral growth plate, as well as cartilage invaginations into the metaphyses, were constant findings. Three knees were treated operatively with oblique tibial osteotomy and three with lateral hemiepiphysiodesis. Two severely involved patients treated initially with hemiepiphysiodesis required additional surgery. The three patients with mild disease treated with tibial osteotomy had good clinical and functional results. This study suggests that extensive growth-plate changes in severe, late-onset tibia vara preclude successful treatment by tibial hemiepiphysiodesis. In addition, oblique osteotomy, which was successful in mild cases, was problematic in severe cases.
Topics: Adolescent; Bone Diseases, Developmental; Child; Growth Plate; Humans; Knee; Magnetic Resonance Imaging; Male; Obesity; Severity of Illness Index; Tibia; Treatment Outcome
PubMed: 12748828
DOI: 10.1007/s00264-003-0467-4