[1][2] These disorders affect tissues that arise from the ectodermal germ layer, such as skin, hair, and nails.

Hay–Wells syndrome is autosomal dominant,[3] caused by a missense mutation in the Sterile alpha motif (SAM) of the TP73L (p63) gene which encodes for a protein-protein interaction domain.

[4] The syndrome is thought to arise from a missense mutation in a gene pivotal for the proper development of craniofacial structures and extremities, as well as skin differentiation.

[6] Residing on the long-arm of chromosome 3, the Tumor Protein 63 (TP63) gene is critical for proper development and homeostasis of stratified epithelia.

[7] In Hay–Wells syndrome, and other ectodermal dysplasia disorders, a missense, nonsense, or insertion mutation has occurred in the TP63 gene.

[11] Reported mutations that have resulted in Hay–Wells syndrome have occurred within the sterile alpha motif (SAM) and the transactivation inhibitory (TI) domains of the p63-coding region.

[12][13] Recent work has shown that mutations within these domains lead to repression of other known transcriptional activators of epidermal differentiation.

In particular, the hypopigmentation observed in several Hay-Wells patients is believed to be the result of improperly developed keratinocytes not being able to properly interact with melanocytes.