Thromboembolism and congenital malformations: from Duane syndrome to thalidomide embryopathy.

Cameron Parsa // Publications // Apr 01 2013

PubMed ID: 23710497

Author(s): Parsa CF, Robert MP. Thromboembolism and congenital malformations: from Duane syndrome to thalidomide embryopathy. JAMA Ophthalmol. 2013 Apr;131(4):439-47. PMID 23710497

Journal: Jama Ophthalmology, Volume 131, Issue 4, Apr 2013

OBJECTIVE To propose a pathophysiologic mechanism to unify a variety of disparate sporadic congenital malformations.

METHODS Inductive and deductive analyses to correlate malformation laterality with asymmetries in thoracic anatomy, critical analysis of malformations with female predominance, and concepts of hydrodynamic pressure gradients in vascular growth were applied to the ensuing development of guiding tissue scaffolds for cellular proliferation, differentiation, and apoptosis.

RESULTS Duane syndrome may develop following a focal vascular insult to the sixth nerve trunk with axonal degeneration, allowing for substitutive innervation from third nerve axons to the lateral rectus muscle. Causative fibrin clots may originate from the venous system and paradoxically migrate through physiological right-to left shunts, or they may arise directly from the heart. Hence, the unilateral, left-sided, and female predominance of Duane syndrome results from the asymmetry in the thoracic anatomy and from thrombosis risk factors. Embolic occlusions may also alter local hemodynamic pressure gradients, leading to the compensatory enlargement and persistence of the fetal vasculature and may dysregulate tissue growth. Within the eye, this results in forms of Peters anomaly, unilateral congenital cataracts, and the morning glory disc anomaly, all in the vascular territory of the carotid arteries that also share a propensity for left-sided involvement in girls. Most aberrant misinnervation phenomena (eg, jaw-winking syndrome, crocodile tear syndrome, Brown syndrome, and congenital fibrosis syndrome) and, by extrapolation, the hypoplasia or dysgenesis of noncephalic anatomical structures (including limbs) may be similarly explained. Such malformations will occur more frequently under thrombogenic conditions, such as those induced by thalidomide.

CONCLUSIONS Fibrin emboli and focal hypoperfusion may explain the development of many sporadic congenital malformations.