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Ultrasound in Obstetrics & Gynecology :... Jul 2014It has recently been reported that fetuses with achondroplasia have a wider than expected femoral proximal diaphysis-metaphysis angle (femoral angle). The aim of this...
OBJECTIVES
It has recently been reported that fetuses with achondroplasia have a wider than expected femoral proximal diaphysis-metaphysis angle (femoral angle). The aim of this case-control study was to investigate this finding.
METHODS
Cases with confirmed achondroplasia (n = 6), small-for-gestational-age fetuses (n = 70) and a group of normal fetuses (n = 377) were included in this study. The ultrasound image of the femur was examined by two independent experienced observers blinded to the diagnosis, who measured the femoral angle. These values were converted into multiples of the expected median (MoM), after adjustment for gestational age and femur length. Prevalence of various prenatal ultrasound signs of achondroplasia was determined in affected fetuses. Intra- and interobserver agreement of measurement of femoral angle was assessed using 95% limits of agreement and kappa statistics.
RESULTS
The femoral angle can be measured accurately by ultrasound, and increases with both increasing gestational age and increasing femur length. The femoral angle-MoM was significantly higher in fetuses with achondroplasia than in the control group (1.36 vs 1.00 MoM, P < 0.001) and in the SGA group (1.36 vs 1.04 MoM, P < 0.001). It measured more than 130° in five of the six cases with achondroplasia (83.3%), which was the most consistent finding other than shortening of the long bones.
CONCLUSIONS
The femoral angle is wider in fetuses with achondroplasia. This new ultrasound sign appears promising as an additional discriminatory marker when clinicians are faced with a case of short long bones in the third trimester.
Topics: Achondroplasia; Adult; Case-Control Studies; Diaphyses; Female; Femur; Humans; Infant, Small for Gestational Age; Observer Variation; Pregnancy; Pregnancy Trimester, Third; ROC Curve; Regression Analysis; Single-Blind Method; Ultrasonography, Prenatal
PubMed: 24623391
DOI: 10.1002/uog.13339 -
Oman Medical Journal Nov 2013Metatropic dysplasia is a rare but severe spondyloepimetaphyseal dysplasia characterized by long trunk and short extremities. The exact incidence is not known; however,...
Metatropic dysplasia is a rare but severe spondyloepimetaphyseal dysplasia characterized by long trunk and short extremities. The exact incidence is not known; however, 81 cases have been reported in the literature till now. Due to progressive kyphoscoliosis, there is a reversal of proportions in childhood (shortening of trunk with relative long extremities). The diagnostic radiographic findings include marked platyspondyly (wafer-thin vertebral bodies), widened metaphyses (dumbbell-shaped tubular bones) and small epiphysis and a specific pelvic shape. The severe kyphoscoliosis is relentless and resistant to conservative treatment with bracing. Operative treatment is controversial due to the recurrence of deformity despite aggressive correction. We, herein report a case of this rare dysplasia and its follow-up after corrective surgery for spine and limb deformity. The excellent correction and good functional pulmonary status at 6-year follow-up has never been previously reported.
PubMed: 24223250
DOI: 10.5001/omj.2013.123 -
PloS One 2014Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their α2β1 integrin as well as via...
Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their α2β1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3-6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the α1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth.
Topics: Animals; Biomechanical Phenomena; Bone and Bones; Cartilage; Epiphyses; Extracellular Matrix Proteins; Femur; Gene Silencing; Growth Plate; Integrin-Binding Sialoprotein; Mice; Osteopontin; Phenotype; Proteome; RNA, Messenger; X-Ray Microtomography
PubMed: 23755099
DOI: 10.1371/journal.pone.0063080 -
Cuadernos de Bioetica : Revista Oficial... 2013Personalism not only provides a valuable contribution to those interested in bioethics by allowing contrasts with other schools and currents of thought, but its ethical...
Personalism not only provides a valuable contribution to those interested in bioethics by allowing contrasts with other schools and currents of thought, but its ethical and anthropological features can serve to widen the horizon of reason. Bioethics today needs to expand the horizon of rationality in which it is animated through: 1) An ontologically ground personalism thanks to which the personal being emerges with all its evidence as being in the most proper sense of being. 2) The overcoming of subjectivism-objectivism antinomy through the claim that human subjectivity is an objective fact. 3) The recognition of the personalistic norm of action as a fundamental precept of natural law. When bioethics is built with openness to the objective datum of subjectivity it becomes easy to appreciate the human person as a real aim that should not be used as mere means. 4) The discovery of the normative basis of the moral life, because determining the ultimate end of human action is not the same as obtaining an ultimate justification of the norms of human action. When this distinction is deeply assimilated, it can show that the precepts of natural law must be respected regardless the acceptance of God's existence.
Topics: Bioethics; Metaphysics; Personhood
PubMed: 23745817
DOI: No ID Found -
Journal of Orthopaedic Research :... Apr 2013Individuals with multiple osteochondromas (MO) demonstrate shortened long bones. Ext1 or Ext2 haploinsufficiency cannot recapitulate the phenotype in mice. Loss of...
Individuals with multiple osteochondromas (MO) demonstrate shortened long bones. Ext1 or Ext2 haploinsufficiency cannot recapitulate the phenotype in mice. Loss of heterozygosity for Ext1 may induce shortening by steal of longitudinal growth into osteochondromas or by a general derangement of physeal signaling. We induced osteochondromagenesis at different time points during skeletal growth in a mouse genetic model, then analyzed femora and tibiae at 12 weeks using micro-CT and a point-distribution-based shape analysis. Bone lengths and volumes were compared. Metaphyseal volume deviations from normal, as a measure of phenotypic widening, were tested for correlation with length deviations. Mice with osteochondromas had shorter femora and tibiae than controls, more consistently when osteochondromagenesis was induced earlier during skeletal growth. Volumetric metaphyseal widening did not correlate with longitudinal shortening, although some of the most severe shortening was in bones with abundant osteochondromas. Loss of heterozygosity for Ext1 was sufficient to drive bone shortening in a mouse model of MO, but shortening did not correlate with osteochondroma volumetric growth. While a steal phenomenon seems apparent in individual cases, some other mechanism must also be capable of contributing to the short bone phenotype, independent of osteochondroma formation. Clones of chondrocytes lacking functional heparan sulfate must blunt physeal signaling generally, rather than stealing growth potential focally.
Topics: Animals; Disease Models, Animal; Doxycycline; Exostoses, Multiple Hereditary; Femur; Growth Plate; Haploinsufficiency; Loss of Heterozygosity; Male; Mice; N-Acetylglucosaminyltransferases; Phenotype; Tibia
PubMed: 23192691
DOI: 10.1002/jor.22280 -
Journal of Bone and Mineral Research :... Feb 2013Generalized arterial calcification (AC) of infancy (GACI) is an autosomal recessive disorder that features hydroxyapatite deposition within arterial elastic fibers....
Generalized arterial calcification (AC) of infancy (GACI) is an autosomal recessive disorder that features hydroxyapatite deposition within arterial elastic fibers. Untreated, approximately 85% of GACI patients die by 6 months of age from cardiac ischemia and congestive heart failure. The first-generation bisphosphonate etidronate (EHDP; ethane-1-hydroxy-1,1-diphosphonic acid, also known as 1-hydroxyethylidene-bisphosphonate) inhibits bone resorption and can mimic endogenous inorganic pyrophosphate by blocking mineralization. With EHDP therapy for GACI, AC may resolve without recurrence upon treatment cessation. Skeletal disease is not an early characteristic of GACI, but rickets can appear from acquired hypophosphatemia or prolonged EHDP therapy. We report a 7-year-old boy with GACI referred for profound, acquired, skeletal disease. AC was gone after 5 months of EHDP therapy during infancy, but GACI-related joint calcifications progressed. He was receiving EHDP, 200 mg/day orally, and had odynodysphagia, diffuse opioid-controlled pain, plagiocephaly, facial dysmorphism, joint calcifications, contractures, and was wheelchair bound. Biochemical parameters of mineral homeostasis were essentially normal. Serum osteocalcin was low and the brain isoform of creatine kinase and tartrate-resistant acid phosphatase 5b (TRAP-5b) were elevated as in osteopetrosis. Skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, long-bone bowing, widened physes, as well as metaphyseal osteosclerosis, cupping and fraying, and "tongues" of radiolucency. Radiographic features of osteopetrosis included osteosclerosis and femoral Erlenmeyer flask deformity. After stopping EHDP, he improved rapidly, including remarkable skeletal healing and decreased joint calcifications. Profound, but rapidly reversible, inhibition of skeletal mineralization with paradoxical calcifications near joints can occur in GACI from protracted EHDP therapy. Although EHDP treatment is lifesaving in GACI, surveillance for toxicity is crucial.
Topics: Adult; Bone Diseases; Child; Child, Preschool; Etidronic Acid; Female; Humans; Infant; Infant, Newborn; Male; Radiography; Vascular Calcification
PubMed: 22972716
DOI: 10.1002/jbmr.1752 -
Human Molecular Genetics Nov 2012Dysosteosclerosis (DSS) is the form of osteopetrosis distinguished by the presence of skin findings such as red-violet macular atrophy, platyspondyly and metaphyseal...
Dysosteosclerosis (DSS) is the form of osteopetrosis distinguished by the presence of skin findings such as red-violet macular atrophy, platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses. At the histopathological level, there is a paucity of osteoclasts when the disease presents. In two patients with DSS, we identified homozygous or compound heterozygous missense mutations in SLC29A3 by whole-exome sequencing. This gene encodes a nucleoside transporter, mutations in which cause histiocytosis-lymphadenopathy plus syndrome, a group of conditions with little or no skeletal involvement. This transporter is essential for lysosomal function in mice. We demonstrate the expression of Slc29a3 in mouse osteoclasts in vivo. In monocytes from patients with DSS, we observed reduced osteoclast differentiation and function (demineralization of calcium surface). Our report highlights the pleomorphic consequences of dysfunction of this nucleoside transporter, and importantly suggests a new mechanism for the control of osteoclast differentiation and function.
Topics: Amino Acid Sequence; Animals; Child, Preschool; Consanguinity; Exome; Female; Humans; Infant; Mice; Molecular Sequence Data; Mutation; Nucleoside Transport Proteins; Osteopetrosis; Osteosclerosis; Radiography; Sequence Alignment
PubMed: 22875837
DOI: 10.1093/hmg/dds326 -
Taiwanese Journal of Obstetrics &... Jun 2012To demonstrate perinatal imaging findings and to investigate the mutation in the NEK1 gene in a fetus with type III short rib-polydactyly syndrome (SRPS) (Verma-Naumoff).
Prenatal diagnosis and molecular genetic analysis of short rib-polydactyly syndrome type III (Verma-Naumoff) in a second-trimester fetus with a homozygous splice site mutation in intron 4 in the NEK1 gene.
OBJECTIVE
To demonstrate perinatal imaging findings and to investigate the mutation in the NEK1 gene in a fetus with type III short rib-polydactyly syndrome (SRPS) (Verma-Naumoff).
CASE REPORT
A 34-year-old woman with no past history of fetal SRPS was referred to the hospital at 21 weeks of gestation because of sonographic diagnosis of short limbs in the fetus. Fetal ultrasound revealed a narrow thorax, short ribs, short limbs with marginal spurs, and postaxial hexadactyly in both the hands and feet. A diagnosis of SRPS III (Verma-Naumoff) was made. Amniocentesis was performed. The karyotype was 46,XY. Molecular genetic analysis of the amniotic fluid cells identified a homozygous splice site mutation in intron 4 (c.331-1 A > G) or IVS4-1 A > G in the NEK1 gene. The parents were heterozygous for the mutation. The pregnancy was subsequently terminated and a malformed fetus was delivered with prominent forehead, a flattened nasal bridge, a narrow and short trunk, a protuberant abdomen, bilateral postaxial polydactyly and syndactyly of the hands and feet, and micromelic limbs. No facial cleft or genital abnormality was noted. The radiograph was consistent with SRPS III.
CONCLUSION
Polydactyly, micromelia, metaphyseal spurs, widened humeral metaphyses, and shortened ribs can be prominent prenatal ultrasound findings of SRPS III. The present case provides evidence for a correlation of a mutation in the NEK1 gene with SRPS III.
Topics: Abortion, Induced; Adult; Amniocentesis; Cell Cycle Proteins; Female; Humans; Introns; Karyotype; Male; Middle Aged; Mutation; NIMA-Related Kinase 1; Pregnancy; Pregnancy Trimester, Second; Protein Serine-Threonine Kinases; Short Rib-Polydactyly Syndrome; Ultrasonography, Prenatal
PubMed: 22795106
DOI: 10.1016/j.tjog.2012.04.018 -
FASEB Journal : Official Publication of... Sep 2011Jansen metaphyseal chondrodysplasia (JMC) is caused by a constitutively activating mutation of the parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PTHR1)...
Jansen metaphyseal chondrodysplasia (JMC) is caused by a constitutively activating mutation of the parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PTHR1) and is characterized by widening of the metaphyses, reduction of long bone length, and short stature. A transgenic mouse expressing this mutation under the collagen α1(II) promoter has been generated to investigate the mechanisms responsible for this chondrodysplasia. We recently identified zinc finger protein 521 (Zfp521) as a downstream target gene of PTHrP signaling. Interestingly, loss of Zfp521 from chondrocytes leads to reduced cell proliferation and increased differentiation in the growth plate. Thus, we hypothesized that specifically ablating Zfp521 from Jansen chondrocytes could sufficiently rescue the chondrodysplasia phenotype. Our results show that Zfp521 expression is up-regulated in Jansen mouse growth plate chondrocytes and that PTHR1 is required for Zfp521 expression. Its ablation from Jansen chondrocytes restored normal cell differentiation, thus initiating chondrocyte apoptosis at the chondro-osseous junction, leading to partial rescue of endochondral bone formation shown by proper bone length. This study provides the first genetic evidence that Zfp521 is required downstream of PTHR1 signaling to act on chondrocyte proliferation, differentiation, and cell death.
Topics: Animals; Bone Development; Cells, Cultured; Chondrocytes; Disease Models, Animal; Gene Deletion; Gene Expression Regulation; Genotype; Growth Plate; Mice; Mice, Knockout; Osteochondrodysplasias; Phenotype; Transcription Factors; Up-Regulation
PubMed: 21642473
DOI: 10.1096/fj.11-183277 -
Chang Gung Medical Journal 2011Reports of the efficacy of Salter's osteotomy have often been based on groups of patients with complex disease conditions and treatment. The purposes of this study were...
BACKGROUND
Reports of the efficacy of Salter's osteotomy have often been based on groups of patients with complex disease conditions and treatment. The purposes of this study were to document the results of patients with well-defined conditions, focusing on the onset and sequelae of osteonecrosis.
METHODS
The study participants consisted of 63 patients with unilateral hip dislocation who had undergone one-stage open reduction and Salter's innominate osteotomy between the ages of 1 and 3 years. The results were evaluated clinically by McKay's classification and radiologically by the modified Severin's classification. Early signs of osteonecrosis were identified by neck widening, epiphysis fragmentation, and presence of a metaphyseal growth disturbance line in the first year after the operation.
RESULTS
After a follow-up of 10 years on average, good clinical and radiographic results were noted in 89% and 92% of the patients, respectively. Osteonecrosis occurred in 30 hips, of which 14 subsequently developed femoral head deformity. Residual dysplasia was noted in 5 hips, mostly resulting from late-onset coxa valga. Eighty-five percent of the hips without osteonecrosis and 53% of the hips with osteonecrosis (p < 0.05) were classified as Severin class 1. No pre-operative factors were found to be associated with the occurrence of osteonecrosis.
CONCLUSION
One-stage open reduction and Salter's osteotomy was an effective treatment for developmental dysplasia of the hip after walking age. However, parents must be informed of the two major complications, osteonecrosis and residual dysplasia, that can lead to long-term morbidity.
Topics: Adolescent; Child; Child, Preschool; Female; Hip Dislocation, Congenital; Humans; Infant; Male; Osteonecrosis; Osteotomy
PubMed: 21392478
DOI: No ID Found