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Limb Defects (limb + defect)
Selected AbstractsFrontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteinsDEVELOPMENTAL DYNAMICS, Issue 5 2006Amy L. Donner Abstract The AP-2 transcription factor family is linked with development of the head and limbs in both vertebrate and invertebrate species. Recent evidence has also implicated this gene family in the evolution of the neural crest in chordates, a critical step that allowed the development and elaboration of the vertebrate craniofacial skeleton. In mice, the inappropriate embryonic expression of one particular AP-2 gene, Tcfap2a, encoding AP-2,, results in multiple developmental abnormalities, including craniofacial and limb defects. Thus, Tcfap2a provides a valuable genetic resource to analyze the regulatory hierarchy responsible for the evolution and development of the face and limbs. Previous studies have identified a 2-kilobase intronic region of both the mouse and human AP-2, locus that directs expression of a linked LacZ transgene to the facial processes and the distal mesenchyme of the limb bud in transgenic mice. Further analysis identified two highly conserved regions of ,200,400 bp within this tissue-specific enhancer. We have now initiated a transgenic and biochemical analysis of the most important of these highly conserved regions. Our analysis indicates that although the sequences regulating face and limb expression have been integrated into a single enhancer, different cis -acting sequences ultimately control these two expression domains. Moreover, these studies demonstrate that a conserved STAT binding site provides a major contribution to the expression of Tcfap2a in the facial prominences. Developmental Dynamics 235:1358,1370, 2006. © 2006 Wiley-Liss, Inc. [source] Loss of the Tg737 protein results in skeletal patterning defectsDEVELOPMENTAL DYNAMICS, Issue 1 2003Qihong Zhang Abstract Tg737 mutant mice exhibit pathologic conditions in numerous tissues along with skeletal patterning defects. Herein, we characterize the skeletal pathologic conditions and confirm a role for Tg737 in skeletal patterning through transgenic rescue. Analyses were conducted in both the hypomorphic Tg737orpk allele that results in duplication of digit one and in the null Tg737,2-3,Gal allele that is an embryonic lethal mutation exhibiting eight digits per limb. In early limb buds, Tg737 expression is detected throughout the mesenchyme becoming concentrated in precartilage condensations at later stages. In situ analyses indicate that the Tg737orpk mutant limb defects are not associated with changes in expression of Shh, Ihh, HoxD11,13, Patched, BMPs, or Glis. Likewise, in Tg737,2-3,Gal mutant embryos, there was no change in Shh expression. However, in both alleles, Fgf4 was ectopically expressed on the anterior apical ectodermal ridge. Collectively, the data argue for a dosage effect of Tg737 on the limb phenotypes and that the polydactyly is independent of Shh misexpression. Developmental Dynamics 227:78,90, 2003. © 2003 Wiley-Liss, Inc. [source] Mutational analysis of HOXD13 and HOXA13 genes in the triphalangeal thumb,brachyectrodactyly syndromeJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2002A. Pérez-Cabrera Abstract The triphalangeal thumb-brachyectrodactyly syndrome is a very rare autosomal dominant disorder of unknown etiology characterized by an unusual pattern of limb malformations: triphalangeal thumbs and brachyectrodactyly in the hands, and ectrodactyly in the feet. In a previous report, we described the clinical and radiographical features of three related subjects with the disease and suggest that due to the unusual combination of limb defects and to its phenotypic similarity with the limb malformative pattern induced by disrupting the Hoxd13 gene in mouse, the triphalangeal thumb-brachyectrodactyly syndrome might be caused by mutations in a HOX gene. After sequencing the entire coding region of HOXD13 and the highly conserved homeodomain encoding region of HOXA13, we do not detect any deleterious mutation in any of the patients excluding that alterations at these sequences are responsible for the disease. Mutations in regulatory regions of these genes or in other genes involved in limb development might be responsible for the disease. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] Postoperative monitoring of lower limb free flaps with the Cook,Swartz implantable Doppler probe: A clinical trialMICROSURGERY, Issue 5 2010B.Med.Sc., P.G.Dip.Surg.Anat., Ph.D., Warren M. Rozen M.B.B.S. Background: Free flaps to the lower limb have inherently high venous pressures, potentially impairing flap viability, which may lead to limb amputation if flap failure ensues. Adequate monitoring of flap perfusion is thus essential, with timely detection of flap compromise able to potentiate flap salvage. While clinical monitoring has been popularized, recent use of the implantable Doppler probe has been used with success in other free flap settings. Methods: A comparative study of 40 consecutive patients undergoing microvascular free flap reconstruction of lower limb defects was undertaken, with postoperative monitoring achieved with either clinical monitoring alone or the use of the Cook-Swartz implantable Doppler probe. Results: The use of the implantable Doppler probe was associated with salvage of 2/2 compromised flaps compared to salvage of 2/5 compromised flaps in the group undergoing clinical monitoring alone (salvage rate 100% vs. 40%, P = 0.28). While not statistically significant, this was a strong trend toward an improved flap salvage rate with the use of the implantable Doppler probe. There were no false positives or negatives in either group. One flap loss in the clinically monitored group resulted in limb amputation (the only amputation in the cohort). Conclusion: A trend toward early detection and salvage of flaps with anastomotic insufficiency was seen with the use of the Cook,Swartz implantable Doppler probe. These findings suggest a possible benefit of this technique as a stand-alone or adjunctive tool in the clinical monitoring of free flaps, with further investigation warranted into the broader application of these devices. © 2009 Wiley-Liss, Inc. Microsurgery 30:354,360, 2010. [source] Trends in elective terminations of pregnancy between 1989 and 2000 in a French county (the Isère)PRENATAL DIAGNOSIS, Issue 11 2003P. Guillem Abstract Objectives This study was performed in order to provide a description of indications for induced elective terminations of pregnancy (ETOP), their characteristics (e.g. gestational age), and their evolution over time. Design of the Study This is an epidemiological study. The geographic area covered is the French county of ,Isère', which represents a mean of 14 000 births per year over the study period. Materials and Methods Data on ETOPs were collected actively from medical records by a register of childhood deficiencies and adverse perinatal events in this county. Between 1989 and 2000, 996 ETOPs were notified. Results Four main grounds for ETOPs were identified: (1) morphological anomalies with normal karyotype (39%), (2) chromosomal anomalies (35%), (3) other fetal grounds (16%), and (4) maternal indications (10%). Prevalence rates for the first two grounds increased significantly over the study period respectively from 2.0 to 2.9 and from 1.4 to 2.7 per 1000. Among the ETOPs carried out because of fetal indications, the percentage of late ETOPs (from 24 weeks of gestation) was 34.6%, and remained stable over the studied period. In some cases, a medical consensus was not reached with respect to indications for termination (sex chromosome anomalies, limb defects). We estimated the percentage of these cases as being 2.7% of the figure for fetal indications, without any variation in prevalence over the whole period (p = 0.59). The increasing number of ETOPs that occurred in the chromosomal aberrations group during the study period is thought to be due to an increase in diagnostic sensitivity. The increase that occurred in the morphological anomalies group is thought to be due both to an increase in sensitivity and to a widening of the field with respect to indications, some of which have an uncertain prognosis (e.g. agenesis of the corpus callosum). Conclusion This study provides useful data for monitoring medical practice consistency within the field of prenatal diagnosis, and for the drive to keep medical practice within ethically acceptable limits. Copyright © 2003 John Wiley & Sons, Ltd. [source] A twisted hand: bHLH protein phosphorylation and dimerization regulate limb developmentBIOESSAYS, Issue 11 2005Juanliang Cai Saethre-Chotzen syndrome (SCS), a human autosomal dominant condition with limb defects and craniosynostosis, is caused by haploinsufficiency of TWIST1, a basic helix,loop,helix (bHLH) transcription factor. Until recently, the molecular pathogenesis of the limb defects in SCS has not been well understood. Now, Firulli et al.1 show in mouse and chick that ectopic expression of a related bHLH protein, Hand2, results in phenocopies of the limb defects caused by Twist1 loss-of-function mutations. These two proteins interact in a dosage-dependent antagonistic manner, and both can be regulated through phosphorylation at conserved helix I amino acid residues. These findings provide an important link between the misregulation of Twist1 dimerization and the limb phenotypes observed in SCS. BioEssays 27:1102,1106, 2005. © 2005 Wiley Periodicals, Inc. [source] Are birth defects among Hispanics related to maternal nativity or number of years lived in the United States?,,BIRTH DEFECTS RESEARCH, Issue 9 2009Tunu Ramadhani Abstract BACKGROUND: Literature on the risk of birth defects among foreign- versus U.S.,born Hispanics is limited or inconsistent. We examined the association between country of birth, immigration patterns, and birth defects among Hispanic mothers. METHODS: We used data from the National Birth Defects Prevention Study and calculated odds ratios (ORs) and 95% confidence intervals and assessed the relationship between mothers' country of birth, years lived in the United States, and birth defects among 575 foreign-born compared to 539 U.S.,born Hispanic mothers. RESULTS: Hispanic mothers born in Mexico/Central America were more likely to deliver babies with spina bifida (OR = 1.53) than their U.S.,born counterparts. Also, mothers born in Mexico/Central America or who were recent United States immigrants (,5 years) were less likely to deliver babies with all atrial septal defects combined, all septal defects combined, or atrial septal defect, secundum type. However, Hispanic foreign-born mothers who lived in the United States for >5 years were more likely to deliver babies with all neural tube defects combined (OR = 1.42), spina bifida (OR = 1.89), and longitudinal limb defects (OR = 2.34). Foreign-born mothers, regardless of their number of years lived in the United States, were more likely to deliver babies with anotia or microtia. CONCLUSIONS: Depending on the type of birth defect, foreign-born Hispanic mothers might be at higher or lower risk of delivering babies with the defects. The differences might reflect variations in predisposition, cultural norms, behavioral characteristics, and/or ascertainment of the birth defects. Birth Defects Research (Part A), 2009. © 2009 Wiley-Liss, Inc. [source] Tetramethylcyclopropyl analogue of the leading antiepileptic drug, valproic acid: Evaluation of the teratogenic effects of its amide derivatives in NMRI mice,BIRTH DEFECTS RESEARCH, Issue 9 2008Akinobu Okada Abstract BACKGROUND: Although valproic acid (VPA) is used extensively for treating various kinds of epilepsy, it causes hepatotoxicity and teratogenicity. In an attempt to develop a more potent and safer second generation to VPA drug, the amide derivatives of the tetramethylcyclopropyl VPA analogue, 2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD), N -methyl-TMCD (MTMCD), 4-(2,2,3,3-tetramethylcyclopropanecarboxamide)-benzenesulfonamide (TMCD-benzenesulfonamide), and 5-(TMCD)-1,3,4-thiadiazole-2-sulfonamide (TMCD-thiadiazolesulfonamide) were synthesized and shown to have more potent anticonvulsant activity than VPA. Teratogenic effects of these CNS-active compounds were evaluated in Naval Medical Research Institute (NMRI) mice susceptible to VPA-induced teratogenicity by comparing them to those of VPA. METHODS: Pregnant NMRI mice were given a single sc injection of either VPA or TMC-amide derivatives on gestation day 8.5, and then the live fetuses were examined to detect any external malformations on gestation day 18. After double-staining for bone and cartilage, their skeletons were examined. RESULTS: In contrast to VPA, which induced NTDs in a high number of fetuses at 2.4,4.8 mmol/kg, TMCD, TMCD-benzenesulfonamide, and TMCD-thiadiazolesulfonamide at 4.8 mmol/kg and MTMCD at 3.6 mmol/kg did not induce a significant number of NTDs. TMCD-thiadiazolesulfonamide exhibited a potential to induce limb defects in fetuses. Skeletal examination also revealed that fetuses exposed to all four of the tetramethylcyclopropanecarboxamide derivatives developed vertebral and rib abnormalities less frequently than those exposed to VPA. Our results established that TMCD, MTMCD, and TMCD-benzenesulfonamide are distinctly less teratogenic than VPA in NMRI mice. CONCLUSIONS: The CNS-active amides containing a tetramethylcyclopropanecarbonyl moiety demonstrated better anticonvulsant potency compared to VPA and a lack of teratogenicity, which makes these compounds good second-generation VPA antiepileptic drug candidates. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc. [source] Perturbation of retinoic acid (RA)-mediated limb development suggests a role for diminished RA signaling in the teratogenesis of ethanol,,§BIRTH DEFECTS RESEARCH, Issue 9 2007Corey S. Johnson Abstract BACKGROUND: A proposed mechanism for ethanol teratogenicity entails ethanol-mediated reductions in retinoic acid (RA). This premise was investigated utilizing a mouse model, with limb reduction defects as the teratogenic end point. METHODS: Ethanol, Disulfiram, or BMS-189453 was administered to C57BL/6J mice on the 9th day of pregnancy. Forelimb morphology was assessed on gestation day 18 using Alcian blue and Alizarin red staining. Nile blue sulfate or LysoTracker Red (LTR) vital staining identified cell death in the limb bud. The ability of RA to prevent ethanol-induced cell death was assessed by coadministration followed by laser scanning confocal microscopic examination of LTR-staining. In situ hybridization and qPCR were used to examine gene expression in treated limb buds. RESULTS: Ethanol, Disulfiram, and BMS-189453 resulted in postaxial ectrodactyly, intermediate ectrodactyly, and other digital defects. Excessive Nile blue sulfate staining was evident in the presumptive AER following each of the three exposures. Ethanol-induced LTR staining was prevented by RA supplementation. Both in situ hybridization and qPCR illustrated decreases in Shh and Tbx5 in ethanol-exposed embryos as compared to control. CONCLUSIONS: Contrary to studies of prolonged RA deficiency, acute exposure to functional antagonists of RA results in limb defects that are morphologically similar to those caused by ethanol. The rescue of ethanol-induced cell death by RA and similar changes in Shh transcription further suggest that RA contributes to ethanol-induced limb dysmorphology. Moreover, the repression of key mediators of limb development soon after ethanol exposure adds to the existing knowledge of the pathogenic effects of ethanol. Birth Defects Research (Part A), 2007. © 2007 Wiley-Liss, Inc. [source] Patterns of severe abdominal wall defects: Insights into pathogenesis, delineation, and nomenclatureBIRTH DEFECTS RESEARCH, Issue 3 2007Liliana Vauthay Abstract BACKGROUND: During the last decade, descriptions of malformation complexes involving an abdominal wall defect (AWD) have repeatedly appeared in the literature, and there has been frequent confusion regarding nomenclature, definitions, and delineations. The aims of this work were to evaluate possible embryological relationships among AWD cases, review the related nomenclature, identify patterns involving AWDs, and stress the importance of complete clinical descriptions. METHODS Cases diagnosed as AWD complexes were selected from live- and stillborn infants of the Hospital Materno Infantil Sardá, Buenos Aires, and from the Laboratory of Perinatal Pathology, Buenos Aires, Argentina. They were sorted by the location of the AWD, the umbilical cord length, and the presence or absence of a persistent cloaca. The findings in 26 cases were described, according to proposed definitions. RESULTS: Three patterns could be identified: 1) the AWD involving the umbilical ring, a persistent or exstrophic cloaca, and a spinal cord anomaly; 2) the AWD extending laterally to the umbilical ring, severe unilateral limb defects, and same-sided agenesis of abdominal organs; and 3) the AWD not involving the umbilical ring, clefts, exencephaly, and amputations. Furthermore, overlapping among these patterns was observed, and possible involved mechanisms are discussed. CONCLUSIONS: The observed overlapping among patterns suggested that malformation complexes involving AWDs might not be independent conditions but rather belong to a common and broader spectrum of anomalies. Complete clinical descriptions, the avoidance of synonyms and generalizations, and strictly defined inclusion criteria are proposed for a better understanding of pathogenetic pathways in, and relationships among, AWD complexes. Birth Defects Research (Part A), 2007. © 2006 Wiley-Liss, Inc. [source] Molecular basis of EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome: five new mutations in the DNA-binding domain of the TP63 gene and genotype,phenotype correlationBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2010S.E. Clements Summary EEC (ectrodactyly, ectodermal dysplasia, clefting; OMIM 604292) syndrome is an autosomal dominant developmental disorder. Characteristic clinical features comprise abnormalities in several ectodermal structures including skin, hair, teeth, nails and sweat glands as well as orofacial clefting and limb defects. Pathogenic mutations in the TP63 transcription factor have been identified as the molecular basis of EEC syndrome and to date 34 mutations have been reported. The majority of mutations involve heterozygous missense mutations in the DNA-binding domain of TP63, a region critical for direct interactions with DNA target sequences. In this report, we present an overview of EEC syndrome, discuss the role of TP63 in embryonic development and skin homeostasis, and report five new TP63 gene mutations. We highlight the significant intra- and interfamilial phenotypic variability in affected individuals and outline the emerging paradigm for genotype,phenotype correlation in this inherited ectodermal dysplasia syndrome. [source] Cornelia de Lange syndrome, cohesin, and beyondCLINICAL GENETICS, Issue 4 2009J Liu Cornelia de Lange syndrome (CdLS) (OMIM #122470, #300590 and #610759) is a dominant genetic disorder with multiple organ system abnormalities which is classically characterized by typical facial features, growth and mental retardation, upper limb defects, hirsutism, gastrointestinal and other visceral system involvement. Mutations in three cohesin proteins, a key regulator of cohesin, NIPBL, and two structural components of the cohesin ring SMC1A and SMC3, etiologically account for about 65% of individuals with CdLS. Cohesin controls faithful chromosome segregation during the mitotic and meiotic cell cycles. Multiple proteins in the cohesin pathway are also involved in additional fundamental biological events such as double-strand DNA break repair and long-range regulation of transcription. Moreover, chromosome instability was recently associated with defective sister chromatid cohesion in several cancer studies, and an increasing number of human developmental disorders is being reported to result from disruption of this pathway. Here, we will discuss the human disorders caused by alterations of cohesin function (termed ,cohesinopathies'), with an emphasis on the clinical manifestations of CdLS and mechanistic studies of the CdLS-related proteins. [source] | |||||||||||||