The pathogenesis of PWS and SWS is unknown, but there are at least two major competing hypotheses: the neural (nerve degeneration) theory, and the vascular (genetic mutation theory).³³ However, recent confirmatory evidence favors the genetic mutation theory. A deficiency of nerve innervation in PWS led to speculation that this could be a cause of these abnormal hypervascular skin lesions.²³,³⁴,³⁵ Smoller and Rosen³⁶ reported that S-100-positive nerve fibers were found in only 17% of PWS blood vessels, while 89% of normal dermal vasculature had S-100-positive nerve fibers. Rydh et al³⁴ showed that defective nerve innervations were found only in pathologically dilated PWS vessels, but not in other normal skin structures. Selim et al³⁵ found that there is a significant decrease in nerve density in all PWS sites compared to normal skin. The absence of nerve innervation to blood vessels may cause a decrease in the basal tone of the vessels and/or a loss of neuronal trophic factors, which contribute to the development of PWS.³³

However, whole-genome sequencing of DNA from patients with PWS and SWS has suggested a somatic activating mutation in GNAQ as a possible underlying cause. A nonsynonymous single-nucleotide GNAQ variant (c.548G→A, p.Arg183Gln) was identified in 88% of 26 patients with SWS (OMIM #185300, 9q21) and from 92% of 13 patients with apparently nonsyndromic PWSs (OMIM #16300, 9q21).³⁷,³⁸,³⁹ This is a somatic activating mutation in the GNAQ gene, which increases cell proliferation and inhibits apoptosis due to increased downstream signaling through the RAS effector pathways. The cell of origin affected by the mutation is not known, but it may be that the mutation occurs earlier during embryonic development in SWS than in isolated PWS, thus affecting a more primitive progenitor with wider potential effects.⁴⁰ These mutations may lead to dysregulation of vascular MAPK and/or PI3K signaling pathways during embryonic development causing the pathogenesis and progression of PWS/SWS.³³ Interestingly, the GNAQ mutation is found significantly more frequently in lesions located on the forehead, eyebrow, and upper eyelid than in those located in other facial regions, and PWS in these regions are more likely to be associated with SWS.

Waelchli et al⁴⁰ examined 192 children with PWS and divided the face into several areas on each side that were involved with PWS, including the forehead, upper eyelid, lower eyelid, maxillary area, mandibular area, ear, and chin, and correlated these with clinical complications such as seizures and glaucoma and abnormal head magnetic resonance imaging findings. They considered the adult arterial supply and venous drainage, and the embryological origin of the face and its vasculature. Based on their results, they proposed that the distribution of facial PWS appears to follow the embryological vasculature of the developing face rather than the trigeminal nerve distribution.

Dutkiewicz et al⁴¹ evaluated the distribution patterns of facial lesions in children with PWS and those with SWS. They identified six phenotypes: linear, frontotemporal, cheek and canthus, combined linear and cheek, hemifacial, and median. These phenotypes support the idea that PWS lesions may not strictly correspond to dermatomes of trigeminal innervation.

PWSs are capillary malformations that occur in up to 0.5% of newborns. They initially present as painless, well-demarcated flat pink macules and patches that may be mistaken for a superficial bruise (Figure 95.1).⁴² Over time, these lesions thicken and darken, with some developing significant nodularity (Figure 95.2).