Congenital melanocytic naevi (CMN) have an abnormally high concentration of melanocytes, the pigment cells of the skin, in sharply defined regions. Large and giant CMN can have increased hair density and growth, various levels of pigmentation, proliferative nodules and deficient skin annexes such as sweat and oil glands.
The disfiguring aspect of the malformation is coupled with a currently unmeasurable risk of severe neurological associations and pediatric malignant melanoma (MM), with very poor prognosis. No environmental or genetic risk factors for these life-threatening additional conditions are currently known.
Malformations of neural crest cell derivatives:
Constitutional activation of molecular signaling pathways transducing growth factor stimuli can lead to both vascular and pigment cell anomalies. Vascular smooth muscle of the aortic arch arteries and the forebrain meninges is derived from embryonic neural crest cells (NCC). Mammalian hearts and meninges are also invested by NCC-derived, apparently non-functional pigment cells. Our group has shown that retinoic acid signaling is needed for the correct functional shape of the cardiac outflow tract and separation of the great vessels by an indirect effect on NCC organization. In addition, Wnt signaling affects the specification of NCC-derived cells to either vascular smooth muscle or pigment cells, affecting the vital closure of an embryonic shunt between pulmonary and aortic circulations immediately after birth.
Animal and human induced pluripotent stem cell models are used to study the effects of the activation of convergent signaling pathways on NCC specification to, and behavior in, pigment cell or vascular smooth muscle lineages. For example, constitutive activation of an effector named Nras in NCC leads to homing of pigment cells to multiple vascular beds and the development of symptoms of the rare disease, congenital melanocytic nevus syndrome. Similar activating Braf or Pik3ca mutations in NCC derivatives also induce multiple malformations relevant to human pathologies affecting the skin and cardiovascular system. We use transcriptomics and protein-based outcomes to designate and study the effects of pharmacological inhibitors on these model systems, with the goal of developing novel therapeutic approaches to treating a wide class of individually rare diseases of NCC.