Arterial dysgenesis and limb defects: Clinical and experimental examples

Abstract

Limb malformations are amongst the most common and visible birth effects. Causes have been purported to include genetic aberrations as well as teratogens, such as thalidomide. Here we review the evidence for vascular disruption in the genesis of limb malformations through abnormal arterial transitioning and from events such as amniocentesis, uterine constriction, and through teratogen exposure. We use several clinical and experimental examples and highlight the need to understand more about the role the vascular system plays in the molecular mechanisms underpinning normal limb development. AbstractLimb malformations are amongst the most common and visible birth effects. Causes have been purported to include genetic aberrations as well as teratogens, such as thalidomide. Here we review the evidence for vascular disruption in the genesis of limb malformations through abnormal arterial transitioning and from events such as amniocentesis, uterine constriction, and through teratogen exposure. We use several clinical and experimental examples and highlight the need to understand more about the role the vascular system plays in the molecular mechanisms underpinning normal limb development.

“The legacy of thalidomide” ‐ A multidisciplinary meeting held at the University of York, United Kingdom, on September 30, 2016

“…The drugs action on blood vessel formation, its ability to induce cell death and interact with Cereblon are widely accepted as mechanisms of the drug's action. Indeed, he described how the drug's actions on blood vessels can result in a range of limb damage (Vargesson, , ; Vargesson and Hootnick, ). He also described the advances his team has made in finding a “safe” form of the drug, retaining the clinical benefits but without the side‐effect of embryonic damage (Beedie et al, ).…”

The syndrome of proximal femur, fibula, and midline metatarsal long bone deficiencies

“…Recognition of this syndrome of deficiencies of the proximal femur, fibula, and midline metatarsals may lead to advances in the taxonomy of lower limb skeletal defects. Coordinated clinical (Maroteaux & Le Merrer, 1997) and molecular (Vargesson & Hootnick, 2017) inquiries of this proposed vascular mediated post-specification mechanism may prove auspicious in achieving the elusive goal of understanding the genesis of such congenital limb dysmorphologies.…”

“…The arterial transitions terminate by the 8th week. There are several periods of very rapid growth (Vargesson & Hootnick, 2017). During those times, while the outgrowth of the lower extremities is rapidly progressing and after specification of the limbs nears termination, embryonic arterial alterations of the lower extremity evolves.…”

Expression analysis of limb element markers during mouse embryonic development

“…Skeletal patterning of the limbs begins with the formation of cartilage condensations, from around E11.5 (Martin, 1990), which are the precursors of bones of the limbs (Martin, 1990;Nowlan et al, 2010). These elements form in a proximal to distal manner: For example, the humerus/femur forms before the radius and ulna/tibia and fibula, which form before the digits (Martin, 1990;Vargesson and Hootnick, 2017). Joint development begins with the formation of the interzone, a region of flat, condensed mesenchymal cells.…”