In this review, we will discuss the role of PDE4D in acrodysostosis and the contrasting mechanisms that have been proposed to explain how mutations in PDE4D reduce cAMP signalling and lead to acrodysostosis.27 As PDE4 has been directly implicated in other neurological diseases, the lessons learned here will also be relevant in other contexts. The gene discussed is PDE4A; the disease is acrodysostosis.