Genetic Regulation of Embryological Limb Development with Relation to Congenital Limb Deformity in Humans

Barham, Guy; Clarke, Nicholas

doi:10.1007/s11832-008-0076-2

Cited by 37 publications

(35 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Associations emerged for additional genes in race/ethnic group-specific analyses ( CYP26B1, WNT7A, FGF8, TBX3 , GDF5, SALL4 ) and in analyses by LD phenotype ( WNT7A, FGF4, TBX3, GREM1, SALL4 ). The importance of each of these genes in limb development has been demonstrated in experimental studies using vertebrate limb models [Barham and Clarke, 2008; Johnson and Tabin, 1997]. …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Although mechanical disruption (chorionic villus sampling) and teratogens (thalidomide, misoprostol) have been linked to LDs, genetic factors, including chromosomal abnormalities and single gene defects are thought to be common causes [Barham and Clarke, 2008; Gold et al, 2011]. In particular, genes in a number of signaling pathways regulate different aspects of limb bud growth and patterns of development in three axes: dorsal-ventral, anterior-posterior, and proximal-distal [Barham and Clarke, 2008; Johnson and Tabin, 1997]. Disruptions in such genes or those important in vascularization or coagulation have been associated with LDs [Barham and Clarke, 2008; Carmichael et al, 2006a; Carmichael et al, 2006b; Fantel et al, 1997; Gregg et al, 1998; Hunter, 2000; Johnson and Tabin, 1997].…”

Section: Introductionmentioning

confidence: 99%

“…Based on experimental studies using vertebrate limbs, the following genes are recognized as being involved in normal human limb development: fibroblast growth factors (FGFs) FGF4, FGF8 , and FGF10 ; sonic hedgehog ( SHH ); gremlin 1 ( GREM1 ); WNT7A ; engrailed-1 ( EN1 ); LIM homeobox transcription factor 1-beta ( LMBX1 ); Beta-catenin ( CTNNB1 ); bone morphogenetic protein ( BMP ) genes including GDF5 ; HOX genes HOX9 - HOX13 ; T-box ( TBX ) genes TBX2 - TBX5 ; Sal-like protein 4 ( SALL4 ); and cytochrome P450 genes CYP26B1 and CYP26A1 (through control of retinoic acid levels) [Barham and Clarke, 2008; Johnson and Tabin, 1997]. In humans, pathogenic mutations in many of these genes may cause syndromes that commonly include LDs.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies

Browne

Carter

Kay

et al. 2012

American J of Med Genetics Pt A

View full text Add to dashboard Cite

We conducted a population-based case-control study of single nucleotide polymorphisms (SNPs) in selected genes to find common variants that play a role in the etiology of limb deficiencies (LD)s. Included in the study were 389 infants with LDs of unknown cause and 980 unaffected controls selected from all births in New York State (NYS) for the years 1998 to 2005. We used cases identified from the NYS Department of Health (DOH) Congenital Malformations Registry. Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation (F2, F5, MTHFR). Genotype call rates were >97% and SNPs were tested for departure from Hardy-Weinberg expectations by race/ethnic subgroups. For each SNP, odds ratios (OR)s and confidence intervals (CI)s were estimated and corrected for multiple comparisons for all LDs combined and for LD subtypes. Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR=1.99; 95% CI=1.43-2.77; uncorrected p=0.000043 for rs10805683 heterozygous genotype, and OR=2.37; 95% CI=1.48-3.78; uncorrected p=0.00032 for rs13170645 homozygous minor genotype). We also observed suggestive evidence for associations with SNPs in other genes including CYP26B1 and WNT7A. Animal studies have shown that FGF10 induces formation of the apical ectodermal ridge and is necessary for limb development. Our data suggest that common variants in FGF10 increase the risk for a wide range of non-syndromic limb deficiencies.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies

Browne

Carter

Kay

et al. 2012

American J of Med Genetics Pt A

View full text Add to dashboard Cite

show abstract

“…When multiple limbs are affected by a limb deficiency, one can often assume that this was either an autosomal-dominant gene disorder (inherited or new mutation) or related to a teratologic agent (drug, radiation, virus, etc.). FH has been reproduced in a mouse model [4], suggesting that in most cases it may be a somatic gene mutation, although this theory has not been confirmed.…”

Section: Introductionmentioning

confidence: 99%

Surgical reconstruction for fibular hemimelia

Paley¹

2016

Journal of Children's Orthopaedics

View full text Add to dashboard Cite

Fibular hemimelia presents with foot deformity and leg length discrepancy. Previous classifications have focused on the degree of fibular deficiency rather than the type of foot deformity. Published methods of surgical reconstruction have often failed due to residual or recurrent foot deformity. The purpose of this report is to introduce new classification and reconstruction methods. The Paley SHORDT procedure is used to stabilize the ankle when there is a hypoplastic distal fibula with a dynamic valgus deformity. It involves shortening and realignment of the distal tibia relative to the fibula. In contrast, the Paley SUPERankle procedure is used when there is a fixed equinovalgus foot deformity. The SUPERankle uses a supramalleolar shortening-realignment osteotomy and/or subtalar osteotomies with anlage resection. Due to the bony instead of soft tissue correction of deformity, residual or recurrent deformity is prevented. Weakening of gastro-soleus and peroneal muscles is avoided by shortening of the tibia instead of tendon lengthening. The limitation of ankle motion is related to ankle dysplasia rather than surgery or lengthening. A plantigrade-stable foot and ankle leads to an excellent functional result comparable or better than a Syme’s amputation with prosthetic fitting. Serial lengthening procedures combined with the SHORDT or SUPERankle reconstruction lead to limb length equalization with a plantigrade, painless, functional foot.

show abstract

Amelia: A multi‐center descriptive epidemiologic study in a large dataset from the International Clearinghouse for Birth Defects Surveillance and Research, and overview of the literature

Bermejo‐Sánchez

Cuevas

Amar³

et al. 2011

American J of Med Genetics Pt C

View full text Add to dashboard Cite

This study describes the epidemiology of congenital amelia (absence of limb/s), using the largest series of cases known to date. Data were gathered by 20 surveillance programs on congenital anomalies, all International Clearinghouse for Birth Defects Surveillance and Research members, from all continents but Africa, from 1968 to 2006, depending on the program. Reported clinical information on cases was thoroughly reviewed to identify those strictly meeting the definition of amelia. Those with amniotic bands or limb-body wall complex were excluded. The primary epidemiological analyses focused on isolated cases and those with multiple congenital anomalies (MCA). A total of 326 amelia cases were ascertained among 23,110,591 live births, stillbirths and (for some programs) elective terminations of pregnancy for fetal anomalies. The overall total prevalence was 1.41 per 100,000 (95% confidence interval: 1.26-1.57). Only China Beijing and Mexico RYVEMCE had total prevalences, which were significantly higher than this overall total prevalence. Some under-registration could influence the total prevalence in some programs. Liveborn cases represented 54.6% of total. Among monomelic cases (representing 65.2% of nonsyndromic amelia cases), both sides were equally involved, and the upper limbs (53.9%) were slightly more frequently affected. One of the most interesting findings was a higher prevalence of amelia among offspring of mothers younger than 20 years. Sixty-nine percent of the cases had MCA or syndromes. The most frequent defects associated with amelia were other types of musculoskeletal defects, intestinal, some renal and genital defects, oral clefts, defects of cardiac septa, and anencephaly.

show abstract

Genetic Regulation of Embryological Limb Development with Relation to Congenital Limb Deformity in Humans

Cited by 37 publications

References 33 publications

Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies

Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies

Surgical reconstruction for fibular hemimelia

Amelia: A multi‐center descriptive epidemiologic study in a large dataset from the International Clearinghouse for Birth Defects Surveillance and Research, and overview of the literature

Contact Info

Product

Resources

About