Examining the evidence for vascular pathogenesis of selected birth defects

Am J Med Genet A. 2010 Oct;152A(10):2426-36. doi: 10.1002/ajmg.a.33636.


Vascular mechanisms have been proposed to be involved in the pathogenesis of a number of defects, including transverse-limb defects, intestinal atresias, gastroschisis, hydranencephaly, porencephaly, oromandibular-limb hypogenesis sequence, and oculoauriculovertebral spectrum (OAVS). Here, we examine the available clinical, epidemiologic, and experimental evidence for four defects (transverse-limb defects, intestinal atresias, gastroschisis, and OAVS) for which vascular pathogenesis has been hypothesized. Based on our review, transverse-limb defects appear to sometimes be due to vascular events related to placental vascular abnormalities, hypoperfusion, abnormal development of blood vessels, intrauterine compression, hemoglobinopathies, or exposure to vasoactive agents, although epidemiological studies have not consistently demonstrated the latter association. However, transverse-limb defects can also be due to abnormal developmental events, such as aberrant molecular signaling in the apical ectodermal ridge. Some intestinal atresias may have a vascular origin, with the hypothesis supported by experiments in canines. However, evidence is accumulating that a more common mechanism might be related to improper molecular signaling related to gut specification early in development. In contrast, evidence to support vascular pathogenesis for gastroschisis and OAVS is less compelling. Instead, these defects probably arise from interference with basic developmental events [e.g., body wall closure (gastroschisis) and neural crest cell development (OAVS)]. These conclusions are important for counseling parents of children with these defects and for guiding the design of future epidemiological studies and experiments to further characterize the causes of these defects.

MeSH terms

  • Animals
  • Blood Flow Velocity / genetics
  • Blood Vessels / abnormalities*
  • Congenital Abnormalities / genetics*
  • Disease Models, Animal
  • Dogs
  • Female
  • Gastroschisis / etiology
  • Gastroschisis / genetics*
  • Humans
  • Intestinal Atresia / etiology
  • Intestinal Atresia / genetics
  • Leg / abnormalities
  • Limb Deformities, Congenital / complications*
  • Pregnancy
  • Rats
  • Vascular Diseases / genetics*