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Philip Leder - One of the best experts on this subject based on the ideXlab platform.
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The Role of a Single Formin Isoform in the Limb and Renal Phenotypes of Limb Deformity
Molecular Medicine, 1997Co-Authors: Anthony Wynshaw-boris, Laurie Jackson-grusby, Gabriella Ryan, Chu-xia Deng, David C. Chan, Denise Larson, Judy H. Dunmore, Philip LederAbstract:Background Mutations of the murine Limb Deformity ( ld ) locus are responsible for a pleiotropic phenotype of completely penetrant Limb malformations and incompletely penetrant renal agenesis and/or dysgenesis. The ld locus encodes a complex family of mRNA and protein isoforms. Materials and Methods To examine the role of one of the more prominent of these isoforms, isoform IV, we specifically eliminated it by gene targeting. Results Unlike other mutant ld mice, homozygous mice bearing this isoform IV disruption display incompletely penetrant renal agenesis, but have perfectly normal Limbs. Whole mount in situ hybridization demonstrated that this targeted disruption was specific for isoform IV and did not interfere with the expression of other ld isoforms. The isoform IV-disrupted allele of ld does not complement the renal agenesis phenotype of other ld alleles, in a manner consistent with its penetrance, and like the isoform IV-deficient mice, these compound heterozygotes have normal Limbs. Sequence analysis of formin isoform IV in other ld mutant alleles did not detect any amino acid changes relative to the strain of origin of the mutant allele. Conclusions Thus, the disruption of isoform IV is sufficient for the renal agenesis phenotype, but not the Limb phenotype of ld mutant mice. Structural mutations in this isoform are only one of several genetic mechanisms leading to the renal phenotype, since amino acid changes in this isoform were not detected. These results demonstrate that this gene is Limb Deformity , and that variable isoform expression may play a role in generating the pleiotropic ld phenotype.
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The role of a single formin isoform in the Limb and renal phenotypes of Limb Deformity
Molecular Medicine, 1997Co-Authors: Anthony Wynshaw-boris, Laurie Jackson-grusby, Gabriella Ryan, Chu-xia Deng, David C. Chan, Judy H. Dunmore, Denise M. Larson, Philip LederAbstract:Mutations of the murine Limb Deformity (ld) locus are responsible for a pleiotropic phenotype of completely penetrant Limb malformations and incompletely penetrant renal agenesis and/or dysgenesis. The ld locus encodes a complex family of mRNA and protein isoforms. To examine the role of one of the more prominent of these isoforms, isoform IV, we specifically eliminated it by gene targeting. Unlike other mutant ld mice, homozygous mice bearing this isoform IV disruption display incompletely penetrant renal agenesis, but have perfectly normal Limbs. Whole mount in situ hybridization demonstrated that this targeted disruption was specific for isoform IV and did not interfere with the expression of other ld isoforms. The isoform IV-disrupted allele of ld does not complement the renal agenesis phenotype of other ld alleles, in a manner consistent with its penetrance, and like the isoform IV-deficient mice, these compound heterozygotes have normal Limbs. Sequence analysis of formin isoform IV in other ld mutant alleles did not detect any amino acid changes relative to the strain of origin of the mutant allele. Thus, the disruption of isoform IV is sufficient for the renal agenesis phenotype, but not the Limb phenotype of ld mutant mice. Structural mutations in this isoform are only one of several genetic mechanisms leading to the renal phenotype, since amino acid changes in this isoform were not detected. These results demonstrate that this gene is Limb Deformity, and that variable isoform expression may play a role in generating the pleiotropic ld phenotype.
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polydactyly in the strong s luxoid mouse is suppressed by Limb Deformity alleles
Developmental Genetics, 1996Co-Authors: Thomas F. Vogt, Philip LederAbstract:The study of Limb development has provided insight into pattern formation during vertebrate embryogenesis. Genetic approaches offer powerful ways to identify the critical molecules and their pathways of action required to execute a complex morphogenetic program. We have applied genetic analysis to the process of Limb development by studying two mouse mutants, Limb Deformity (ld) and Strong's luxoid (lst). These mutations confer contrasting phenotypic alterations to the anteroposterior Limb pattern. The six mutant ld alleles are fully recessive and result in oligosyndactyly of all four Limbs. By contrast, the two mutant lst alleles result in a mirror-image polydactylous Limb phenotype inherited in a semidominant fashion. Morphological and molecular analysis of embryonic Limbs has shown that the ld and lst alleles affect the extent and distribution of two key signaling centers differentially: the apical ectodermal ridge and the zone of polarizing activity. Molecular characterization of the ld gene has defined a new family of evolutionarily conserved proteins termed the formins. The underlying molecular defect in the lst mutation has not been identified; however, both loci are tightly linked on mouse chromosome 2, suggesting the possibility that they may be allelic. In this study, we have used genetic analysis to examine the epistatic and allelic relationships of ld and lst. We observed that in + ld/lst + double heterozygotes, a single mutant ld allele is able to suppress the semi-dominant polydactylous lst Limb phenotype. By segregating the lst and ld loci in a backcross, we observed that these loci recombine and are separated by a genetic distance of approximately 6 cM. Therefore, while our observations demonstrate a genetic interaction between ld and lst, it is probable that ld and lst are not allelic. Instead, lst and ld may be operating either in a linear or in a parallel (bypass) genetic pathway to affect the Limb signaling centers.
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Formins: phosphoprotein isoforms encoded by the mouse Limb Deformity locus.
Proceedings of the National Academy of Sciences, 1993Co-Authors: Thomas F. Vogt, Laurie Jackson-grusby, John Rush, Philip LederAbstract:Mutations at the mouse Limb Deformity (ld) locus result in defects of growth and patterning of the Limb and kidney during embryonic development. The gene responsible for this phenotype is large and complex, with the capacity to generate a number of alternatively spliced messenger RNA transcripts encoding nuclear protein isoforms called "formins." We have made polyclonal antibodies to specific formin peptides and have confirmed the authenticity of the antibodies' reactivity, using cell lines derived from mice with molecularly defined mutations at the ld locus. In addition, we have used these antibodies to detect and characterize polypeptides encoded by both wild-type and mutant ld alleles. In so doing, we show that a formin isoform (i) is modified by posttranslational phosphorylation at serine and threonine residues and (ii) when present in a crude nuclear extract, is retained by DNA-cellulose.
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The same genomic region is disrupted in two transgene-induced Limb Deformity alleles
Mammalian Genome, 1992Co-Authors: Thomas F. Vogt, Laurie Jackson-grusby, David C. Chan, Anthony J. Wynshaw-boris, Philip LederAbstract:Mutations of the mouse Limb Deformity locus, ld , map to Chromosome (Chr) 2 and result in defects in the morphogenesis and patterning of the Limb and kidney. Complementation studies have defined the existence of five recessive ld alleles. Remarkably, two of these, ld ^TgHdand ld ^TgBri, are transgene-induced mutations. Recovery of the first transgene insertional allele, ld ^TgHd, facilitated the molecular cloning of a large (>200 kb) candidate gene at the ld locus. This gene is broadly transcribed and encodes a set of novel protein isoforms, termed formins . Here we present characterization of the ld ^TgBrimutation that supports the molecular identification of the ld gene. We show that the ld ^TgBrifails to complement both the ld ^TgHdand the ld ^ORalleles and that it has undergone a genomic deletion that disrupts the cloned ld gene and its transcripts. Curiously, the ld ^TgBrideletion encompasses the same 11-kb interval in which the ld ^TgHdinsertion occurred and in which a chromosomal rearrangement has been identified in a third allele, ld ^In2. These findings suggest that this region of the ld gene is a preferential site for illegitimate recombination.
Rolf Zeller - One of the best experts on this subject based on the ideXlab platform.
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Molecular Interaction between Limb Deformity Proteins (Formins) and Src Family Kinases
Journal of Biological Chemistry, 1996Co-Authors: Peter Uetz, Stefano Fumagalli, Dominic James, Rolf ZellerAbstract:Abstract Ld proteins (formins) are encoded by the Limb Deformity (ld) gene and define a family of related gene products regulating establishment of embryonic polarity. In this study we establish that chicken and murine Ld proteins interact directly with Src family kinases (c-Src and c-Fyn). Specific binding is mediated by the proline-rich domain present in Ld proteins and the ligand binding surface of the Src SH3 domain. Co-immunoprecipitation of Ld and c-Src proteins from transfected cells shows that these proteins associate in vivo. Immunolocalization and biochemical fractionation of fibroblasts confirms the predominant nuclear localization of Ld proteins, but unexpectedly identifies a population of Ld proteins associated to cellular membranes. This population of Ld proteins co-localizes with membrane-associated c-Src proteins at both plasma and perinuclear membranes. These studies indicate that the morphoregulatory Ld proteins interact with signal transduction cascades by association to membrane-bound Src family kinases.
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the Limb Deformity mutation disrupts the shh fgf 4 feedback loop and regulation of 5 hoxd genes during Limb pattern formation
Development, 1995Co-Authors: Anna G Haramis, Jennifer M Brown, Rolf ZellerAbstract:Mutations in the murine Limb Deformity (ld) gene disrupt differentiation of the Apical Ectodermal Ridge (AER) and patterning of distal Limb structures. However, initial outgrowth of the Limb bud is not affected, suggesting that early and late functions of the AER are uncoupled. Similarly, activation of the 5′ members of the HoxD gene cluster (Hoxd-11 to Hoxd-13) is not affected in ld mutant posterior Limb bud mesenchyme, but the subsequent anteriorization of 5′ HoxD domains is delayed by about 12 hours and is associated with reduced levels of polarising activity. These results indicate that the ld gene products act upstream of 5′ HoxD genes during patterning of the autopod. Expression of the signalling molecule Sonic hedgehog (Shh) in the posterior Limb bud mesenchyme is initiated normally, but ceases prematurely indicating a defect in maintenance of Shh by the ld mutant AER. Furthermore, no Fgf-4 transcripts are detected in the ld mutant AER, whereas Fgf-8 transcripts remain expressed. However, Shh expression can be rescued by heterospecific grafting of ld mutant posterior mesenchyme under a wild-type chicken AER. These studies show that the AER defect in ld homozygous Limb buds causes disruption of the FGF-4/SHH feedback loop and support the proposed essential role for FGF-4 in maintaining Shh expression during Limb pattern formation.
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the chicken Limb Deformity gene encodes nuclear proteins expressed in specific cell types during morphogenesis
Genes & Development, 1992Co-Authors: Andreas Trumpp, P A Blundell, J L De La Pompa, Rolf ZellerAbstract:The chicken Limb Deformity (ld) mutation affects morphogenesis of both Limbs and kidneys and is one of few murine mutations for which the affected gene has been isolated. Analysis of the chicken homolog reveals evolutionary conservation of large parts of the encoded ld gene products. This is the first study of these proteins, their intracellular localization, and their temporal and spatial distribution during embryogenesis. A major 180-kD protein is expressed in chicken embryos and certain adult tissues. The proteins are localized in the nuclei of different embryonic cell types in a characteristic punctate pattern. In the developing chicken Limb bud, they are expressed in the newly differentiated apical ectodermal ridge and the mesenchymal compartment, where an unequal distribution along the anteroposterior and, subsequently, the dorsoventral axes, is observed. During kidney morphogenesis, expression is initially restricted to the epithelial compartment of the pronephros and mesonephros. These results correlate well with the previous analysis of the murine ld phenotype and imply determinative roles for ld gene products during the morphogenesis of Limbs and kidneys. Unexpected expression in the notochord, floor plate, and ventral horns suggests an involvement of the ld gene products in establishment of the dorsoventral polarity of the neural tube.
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disruption of formin encoding transcripts in two mutant Limb Deformity alleles
Nature, 1990Co-Authors: Richard P Woychik, Thomas F. Vogt, Richard L Maas, Rolf Zeller, Philip LederAbstract:THE recent identification of a gene residing at the mouse Limb Deformity (Id) locus1–5 permits us to test the hypothesis that disruption of this gene is responsible for an inherited anomaly affecting embryonic pattern formation. The gene gives rise to alternatively processed messenger RNAs that can be translated as a family of related protein products, termed the formins1. We have now analysed transcripts from this gene in four independently isolated mutant alleles. In two of these, the ldHd allele (created by insertion of a transgene2) and the ldln2 allele (created by a translocation–inversion involving mouse chromosomes 2 and 17, ref. 6), a common subset of ld transcripts is abolished, but others are apparently unaltered. The correlation of altered transcripts in two independent ld mutants strongly supports the notion that one or more altered formins is responsible for the observed phenotype. That the defect is limited to the Limb and kidney, despite expression of ld mRNA in other unaffected organs, suggests that these mutant alleles represent only partial loss of Id function.
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formins proteins deduced from the alternative transcripts of the Limb Deformity gene
Nature, 1990Co-Authors: Richard P Woychik, Thomas F. Vogt, Richard L Maas, Rolf Zeller, Philip LederAbstract:VERTEBRATE Limb formation is an evolutionarily conserved process programmed by an array of morphogenetic genes1–5. As a result of transgene insertion, we previously identified a mutation at the mouse Limb Deformity (Id) locus that disrupts embryonic pattern formation, resulting in a reduction and fusion of the distal bones and digits of all Limbs as well as variable incidence of renal aplasia2,6–9. We have now characterized the Id locus at the molecular level. It contains evolutionarily conserved coding sequences that are transcribed in adult and embryonic tissues as a complex group of low abundance messenger RNAs created by alternative splicing and differential polyadenylation. The association of these transcripts with the gene responsible for the mutant phenotype was established by demonstrating that they are disrupted in two independently arising Id alleles8. We have now deduced the structure of several novel proteins (termed formins) from the long open reading frames encoded by the various Id transcripts. The observation of these different RNA transcripts in different tissues suggests that the formins play a part in the formation of several organ systems.
Richard L Maas - One of the best experts on this subject based on the ideXlab platform.
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deficient outgrowth of the ureteric bud underlies the renal agenesis phenotype in mice manifesting the Limb Deformity ld mutation
Developmental Dynamics, 1994Co-Authors: Richard L Maas, Sandra L Elfering, Thomas M Glaser, Lisa JepealAbstract:Mice which are homozygous for the Limb Deformity (ld) mutation also manifest an incompletely penetrant unilateral or bilateral renal agenesis phenotype. Intercross experiments suggest that the differences in penetrance of the renal agenesis phenotype between homozygous mice with different ld alleles are due to intrinsic differences in the strength of the mutant alleles or to one or more closely linked modifying loci, and not to generalized differences in genetic background. Analysis of ld/ld embryos between embryonic days 11–13 reveals delayed outgrowth or complete absence of the ureteric bud, the inducer of metanephric mesenchyme. Since explants of ld/ld metanephric mesenchyme differentiate in culture when apposed to embryonic spinal cord, we conclude that deficient ureteric bud outgrowth is the morphologic basis for renal agenesis in ld/ld mice. However, since ld transcripts can be detected in both metanephric mesenchyme and ureteric bud, the molecular basis for the deficiency in ureteric bud outgrowth could reside in either component. © 1994 Wiley-Liss, Inc.
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a human gene homologous to the formin gene residing at the murine Limb Deformity locus chromosomal location and rflps
American Journal of Human Genetics, 1991Co-Authors: Richard L Maas, Lisa Jepeal, Sandra L Elfering, R F Holcombe, Cynthia C Morton, Roger L Eddy, M G Byers, Thomas B Shows, Philip LederAbstract:Abstract The murine Limb Deformity (ld) locus resides on mouse chromosome 2 and gives rise to a recessively inherited, characteristic Limb Deformity/renal aplasia phenotype. In this locus in the mouse, a gene, termed the "formin" gene, has been identified which encodes an array of differentially processed transcripts in both adult and embryonic tissues. A set of these transcripts are disrupted in independent mutant mouse ld alleles. We wish to report the isolation of a human genomic clone which is homologous to the mouse formin gene by virtue of sequence comparison and expression of conserved exons. Among human fetal tissues analyzed, the kidney appears to be a major site of expression. This human gene, LD, maps to chromosome 15q11----qter in mouse human somatic cell hybrids and, specifically, to 15q13----q14 by chromosomal in situ hybridization. This localization establishes both LD and beta 2-microglobulin as syntenic genes on mouse chromosome 2 and human chromosome 15 and implies the interspecies conservation of the region between them. In addition, we identify in the human locus two frequently occurring DNA polymorphisms which can be used to test the linkage of LD to known human dysmorphoses.
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disruption of formin encoding transcripts in two mutant Limb Deformity alleles
Nature, 1990Co-Authors: Richard P Woychik, Thomas F. Vogt, Richard L Maas, Rolf Zeller, Philip LederAbstract:THE recent identification of a gene residing at the mouse Limb Deformity (Id) locus1–5 permits us to test the hypothesis that disruption of this gene is responsible for an inherited anomaly affecting embryonic pattern formation. The gene gives rise to alternatively processed messenger RNAs that can be translated as a family of related protein products, termed the formins1. We have now analysed transcripts from this gene in four independently isolated mutant alleles. In two of these, the ldHd allele (created by insertion of a transgene2) and the ldln2 allele (created by a translocation–inversion involving mouse chromosomes 2 and 17, ref. 6), a common subset of ld transcripts is abolished, but others are apparently unaltered. The correlation of altered transcripts in two independent ld mutants strongly supports the notion that one or more altered formins is responsible for the observed phenotype. That the defect is limited to the Limb and kidney, despite expression of ld mRNA in other unaffected organs, suggests that these mutant alleles represent only partial loss of Id function.
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formins proteins deduced from the alternative transcripts of the Limb Deformity gene
Nature, 1990Co-Authors: Richard P Woychik, Thomas F. Vogt, Richard L Maas, Rolf Zeller, Philip LederAbstract:VERTEBRATE Limb formation is an evolutionarily conserved process programmed by an array of morphogenetic genes1–5. As a result of transgene insertion, we previously identified a mutation at the mouse Limb Deformity (Id) locus that disrupts embryonic pattern formation, resulting in a reduction and fusion of the distal bones and digits of all Limbs as well as variable incidence of renal aplasia2,6–9. We have now characterized the Id locus at the molecular level. It contains evolutionarily conserved coding sequences that are transcribed in adult and embryonic tissues as a complex group of low abundance messenger RNAs created by alternative splicing and differential polyadenylation. The association of these transcripts with the gene responsible for the mutant phenotype was established by demonstrating that they are disrupted in two independently arising Id alleles8. We have now deduced the structure of several novel proteins (termed formins) from the long open reading frames encoded by the various Id transcripts. The observation of these different RNA transcripts in different tissues suggests that the formins play a part in the formation of several organ systems.
Richard P Woychik - One of the best experts on this subject based on the ideXlab platform.
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disruption of formin encoding transcripts in two mutant Limb Deformity alleles
Nature, 1990Co-Authors: Richard P Woychik, Thomas F. Vogt, Richard L Maas, Rolf Zeller, Philip LederAbstract:THE recent identification of a gene residing at the mouse Limb Deformity (Id) locus1–5 permits us to test the hypothesis that disruption of this gene is responsible for an inherited anomaly affecting embryonic pattern formation. The gene gives rise to alternatively processed messenger RNAs that can be translated as a family of related protein products, termed the formins1. We have now analysed transcripts from this gene in four independently isolated mutant alleles. In two of these, the ldHd allele (created by insertion of a transgene2) and the ldln2 allele (created by a translocation–inversion involving mouse chromosomes 2 and 17, ref. 6), a common subset of ld transcripts is abolished, but others are apparently unaltered. The correlation of altered transcripts in two independent ld mutants strongly supports the notion that one or more altered formins is responsible for the observed phenotype. That the defect is limited to the Limb and kidney, despite expression of ld mRNA in other unaffected organs, suggests that these mutant alleles represent only partial loss of Id function.
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formins proteins deduced from the alternative transcripts of the Limb Deformity gene
Nature, 1990Co-Authors: Richard P Woychik, Thomas F. Vogt, Richard L Maas, Rolf Zeller, Philip LederAbstract:VERTEBRATE Limb formation is an evolutionarily conserved process programmed by an array of morphogenetic genes1–5. As a result of transgene insertion, we previously identified a mutation at the mouse Limb Deformity (Id) locus that disrupts embryonic pattern formation, resulting in a reduction and fusion of the distal bones and digits of all Limbs as well as variable incidence of renal aplasia2,6–9. We have now characterized the Id locus at the molecular level. It contains evolutionarily conserved coding sequences that are transcribed in adult and embryonic tissues as a complex group of low abundance messenger RNAs created by alternative splicing and differential polyadenylation. The association of these transcripts with the gene responsible for the mutant phenotype was established by demonstrating that they are disrupted in two independently arising Id alleles8. We have now deduced the structure of several novel proteins (termed formins) from the long open reading frames encoded by the various Id transcripts. The observation of these different RNA transcripts in different tissues suggests that the formins play a part in the formation of several organ systems.
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molecular and genetic characterization of a radiation induced structural rearrangement in mouse chromosome 2 causing mutations at the Limb Deformity and agouti loci
Proceedings of the National Academy of Sciences of the United States of America, 1990Co-Authors: Richard P Woychik, W M Generoso, Liane B Russell, K T Cain, N L A Cacheiro, Scott J Bultman, P B Selby, Mary E Dickinson, Brigid L M Hogan, Joe C RutledgeAbstract:Abstract Molecular characterization of mutations in the mouse, particularly those involving agent-induced major structural alterations, is proving to be useful for correlating the structure and expression of individual genes with their function in the whole organism. Here we present the characterization of a radiation-induced mutation that simultaneously generated distinct alleles of both the Limb Deformity (ld) and agouti (a) loci, two developmentally important regions of chromosome 2 normally separated by 20 centimorgans. Cytogenetic analysis revealed that an interstitial segment of chromosome 17 (17B- 17C; or, possibly, 17A2-17B) had been translocated into the distal end of chromosome 2, resulting in a smaller-than-normal chromosome 17 (designated 17del) and a larger form of chromosome 2 (designated 2(17). Additionally, a large interstitial segment of the 2(17) chromosome, immediately adjacent and proximal to the insertion site, did not match bands 2E4-2H1 at corresponding positions on a normal chromosome 2. Molecular analysis detected a DNA rearrangement in which a portion of the ld locus was joined to sequences normally tightly linked to the a locus. This result, along with the genetic and cytogenetic data, suggests that the alleles of ld and a in this radiation-induced mutation, designated ldIn2 and ajIn2, were associated with DNA breaks caused by an inversion of an interstitial segment in the 2(17) chromosome.
Peter D Fabricant - One of the best experts on this subject based on the ideXlab platform.
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validation of a modified scoliosis research society instrument for patients with Limb Deformity the Limb Deformity scoliosis research society ld srs score
Journal of Limb Lengthening & Reconstruction, 2016Co-Authors: Peter D Fabricant, Eugene W Borst, Stuart A Green, Robert G Marx, Austin T Fragomen, Robert S RozbruchAbstract:Background: Despite the large negative effect of Limb Deformity on health-related quality of life (QoL), there exists no patient-reported instrument to quantify this impact. Rather, Limb Deformity research has been performed using global QoL measurements concurrently with joint-specific and/or arthritis outcome scales, thereby requiring the completion of multiple instruments. Furthermore, joint- and arthritis-specific instruments focus on the impact pain has on function, whereas Limb deformities may be pain-free with greater social and functional impairment. The purpose of this study was to validate a patient-reported instrument to quantify Limb Deformity-related QoL. Materials and Methods: Because of the similarities with regard to pain, function, and body image between Limb Deformity and scoliosis, the Scoliosis Research Society-30 (SRS-30) spine Deformity instrument was modified such that the words back and trunk were replaced with Limb to create a novel instrument: the Limb Deformity-SRS (LD-SRS). Testing for construct validity (both convergent and discriminant), reliability, floor and ceiling effects, and minimal clinically important difference (MCID) was performed in a validation cohort of 62 subjects aged 18 years or older with nonarthritic, unilateral lower extremity Deformity. Results: Scale reliability was excellent (test-retest reliability, intraclass correlation coefficient = 0.977; internal consistency, Cronbach's alpha = 0.906), scores were normally distributed, and there were no floor or ceiling effects. There was also robust construct validity: convergent validity testing revealed positive correlations between the LD-SRS and all short-form-36 domains, the American Academy of Orthopaedic Surgeons-Lower Limb Module, and higher scores in those who were postcorrection. Discriminant validity was demonstrated with no correlations between the LD-SRS and subject age, sex, body mass index, surgeon-scored Limb Lengthening and Reconstruction Society-AIM Index, or surgeon-generated Deformity measurements. MCID was calculated to be 0.3 (on a 4.0-point scale). Conclusions: The LD-SRS score is a reliable and valid instrument to measure Limb Deformity-related QoL in patients with nonarthritic lower extremity Deformity. It is a valuable tool which allows clinicians to quantify patients' Deformity-related QoL with a single instrument, rather than repurposing scales which have been validated for other conditions and have limited applicability to the unique challenges of treating patients with a lower Limb Deformity. Level of Evidence: Diagnostic, Level 2.
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Validation of a modified Scoliosis Research Society instrument for patients with Limb Deformity: The Limb Deformity-Scoliosis Research Society (LD-SRS) score
Journal of Limb Lengthening & Reconstruction, 2016Co-Authors: Peter D Fabricant, Eugene W Borst, Stuart A Green, Robert G Marx, Austin T Fragomen, S. Robert RozbruchAbstract:Background: Despite the large negative effect of Limb Deformity on health-related quality of life (QoL), there exists no patient-reported instrument to quantify this impact. Rather, Limb Deformity research has been performed using global QoL measurements concurrently with joint-specific and/or arthritis outcome scales, thereby requiring the completion of multiple instruments. Furthermore, joint- and arthritis-specific instruments focus on the impact pain has on function, whereas Limb deformities may be pain-free with greater social and functional impairment. The purpose of this study was to validate a patient-reported instrument to quantify Limb Deformity-related QoL. Materials and Methods: Because of the similarities with regard to pain, function, and body image between Limb Deformity and scoliosis, the Scoliosis Research Society-30 (SRS-30) spine Deformity instrument was modified such that the words "back" and "trunk" were replaced with "Limb" to create a novel instrument: the Limb Deformity-SRS (LD-SRS). Testing for construct validity (both convergent and discriminant), reliability, floor and ceiling effects, and minimal clinically important difference (MCID) was performed in a validation cohort of 62 subjects aged 18 years or older with nonarthritic, unilateral lower extremity Deformity. Results: Scale reliability was excellent (test-retest reliability, intraclass correlation coefficient = 0.977; internal consistency, Cronbach's alpha = 0.906), scores were normally distributed, and there were no floor or ceiling effects. There was also robust construct validity: convergent validity testing revealed positive correlations between the LD-SRS and all short-form-36 domains, the American Academy of Orthopaedic Surgeons-Lower Limb Module, and higher scores in those who were postcorrection. Discriminant validity was demonstrated with no correlations between the LD-SRS and subject age, sex, body mass index, surgeon-scored Limb Lengthening and Reconstruction Society-AIM Index, or surgeon-generated Deformity measurements. MCID was calculated to be 0.3 (on a 4.0-point scale). Conclusions: The LD-SRS score is a reliable and valid instrument to measure Limb Deformity-related QoL in patients with nonarthritic lower extremity Deformity. It is a valuable tool which allows clinicians to quantify patients' Deformity-related QoL with a single instrument, rather than repurposing scales which have been validated for other conditions and have limited applicability to the unique challenges of treating patients with a lower Limb Deformity. Level of Evidence: Diagnostic, Level 2.
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management of a rare complication after screw fixation of a pediatric tibial spine avulsion fracture a case report with follow up to skeletal maturity
Journal of Orthopaedic Trauma, 2011Co-Authors: Peter D Fabricant, Daryl C Osbahr, Daniel W GreenAbstract:Avulsion of the tibial spine is functionally equivalent to rupture of the anterior cruciate ligament in an adolescent athlete. It therefore presents to general orthopaedists as well as a wide variety of orthopaedic subspecialty surgeons, including traumatology sports medicine, and pediatrics. Restoration of normal knee kinematics is dependent on anatomic reduction and fixation of the avulsed fragment. Because this injury is typically sustained by the skeletally immature patient, epiphyseal fixation is ideal to avoid physeal injury, which can lead to angular Limb Deformity. We present a case, the first report to our knowledge, of coronal plane Deformity in a lower extremity after open reduction and internal fixation of a tibial spine avulsion fracture. A successful treatment plan using hemiepiphysiodesis and guided growth is used with 20-month follow-up to skeletal maturity.