Management of congenital limb deficiency

A broad range of abnormalities can affect the developing human limb. This chapter includes an overview of limb bud development, the mechanisms involved in normal growth, and congenital skeletal deficiencies of the lower limb. The use of ultrasonography in antenatal screening and the clinical and radiological features in childhood are also discussed in addition to management including surgical reconstruction and prosthetic use.

Meta-strategy learning in physical problem-solving: the effect of embodied experience

'Embodied cognition' suggests that our experience in our bodies -- including our motor experiences -- shape our cognitive and perceptual capabilities broadly. Much work has studied how differences in the physical body (either natural or manipulated) can impact peoples' cognitive and perceptual capacities, but often these judgments relate directly to those body differences. Here we focus instead on how natural embodied experience affects what kinds of abstract physical problem-solving strategies people use in a virtual task. We compare how groups with different embodied experience -- children and adults with congenital limb differences versus those born with two hands -- perform on this task, and find that while there is no difference in overall accuracy or time to complete the task, the groups use different meta-strategies to come to solutions. Specifically, both children and adults born with limb differences take a longer time to think before acting, and as a result take fewer overall actions to reach solutions to physical reasoning problems. Conversely, the process of development affects the particular actions children use as they age regardless of how many hands they were born with, as well as their persistence with their current strategy. Taken together, our findings suggest that differences in embodied experience drive the acquisition of different meta-strategies for balancing acting with thinking, deciding what kinds of actions to try, and deciding how persistent to be with a current action plan.

Genome sequencing in families with congenital limb malformations

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.

Models of Distal Arthrogryposis and Lethal Congenital Contracture Syndrome

Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including key effects on peripheral nerve function. While Distal Arthrogryposis and Lethal Congenital Contracture Syndromes display superficial similarities in phenotype, the underlying mechanisms for these conditions are diverse but overlapping. In this review, we discuss the important insights gained into these human genetic diseases resulting from in vitro molecular studies and in vivo models in fruit fly, zebrafish, and mice.

Congenital limb defects in a married female population of the Rahim Yar Khan District in Pakistan

Background Congenital limb defects (CLD) have a range of phenotypes and can be a substantial cause of disability. The prevalence of CLD in the adult population of Pakistan is not well described. Objectives To investigate the prevalence of CLD and their associated factors in a married female population of the Rahim Yar Khan (RYK) District in Pakistan. Methods A cross-sectional population-based study was conducted in 4 tehsils of RYK District, and married women and girls from 22 different localities were enrolled by convenience sampling in public places and through door-to-door visits. Data regarding limb phenotype and demographic variables were obtained from participants. Results We enrolled 2,204 married women and girls. We found 11 participants with CLD suggesting a prevalence of 4.99/1,000 (proportion: 0.005; 95% confidence interval [CI] <0.001–0.01). Polydactyly was the most frequent (n = 5; prevalence: 2.27/1,000), followed by others in the following sequence: brachydactyly (n = 4; prevalence: 1.81/1,000), camptodactyly (n = 1; prevalence: 0.45/1,000), and oligodactyly (n = 1; prevalence: 0.45/1,000). The odds of occurrence of CLD were higher in individuals originating from Khanpur tehsil (odds ratio [OR] 2.05; 95% CI 0.37–11.27), speaking languages other than Punjabi and Saraiki (OR 2.35; 95% CI 0.24–22.80), belonging to Araien caste (OR 2.35; 95% CI: 0.24–22.80), of a nuclear family (OR 3.35; 95% CI 0.79–16.97), or having parental consanguinity (OR 1.87; 95% CI 0.49–7.06). Conclusion Preliminary estimate of CLD prevalence in the married female sample population in RYK appears high compared with estimates from birth defects registries in other countries.

Deletion of CTCF sites in the SHH locus alters enhancer–promoter interactions and leads to acheiropodia

Acheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions lead to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer–promoter interactions.