Discovery, Diagnosis, and Etiology of Craniofacial Ciliopathies

Abstract

Seventy-five percent of congenital disorders present with some form of craniofacial malformation. The frequency and severity of these malformations makes understanding the etiological basis crucial for diagnosis and treatment. A significant link between craniofacial malformations and primary cilia arose several years ago with the determination that ∼30% of ciliopathies could be primarily defined by their craniofacial phenotype. The link between the cilium and the face has proven significant, as several new "craniofacial ciliopathies" have recently been diagnosed. Herein, we reevaluate public disease databases, report several new craniofacial ciliopathies, and propose several "predicted" craniofacial ciliopathies. Furthermore, we discuss why the craniofacial complex is so sensitive to ciliopathic dysfunction, addressing tissue-specific functions of the cilium as well as its role in signal transduction relevant to craniofacial development. As a whole, these analyses suggest a characteristic facial phenotype associated with craniofacial ciliopathies that can perhaps be used for rapid discovery and diagnosis of similar disorders in the future.

Figure 1.

Common features of craniofacial ciliopathies. (A) Frequency of the five craniofacial phenotypes common to craniofacial ciliopathies. (B) Frontal diagram of cleft lip/palate phenotypes. (C) Frontal diagram of the midline defects hypotelorism and hypertelorism. (D) Sagittal diagram of micrognathia. (E) Dorsal view of skulls with multiple types of craniosynostosis. (F) Frequency of core ciliopathic phenotypes among known craniofacial ciliopathies. a, anterior; p, posterior.

Figure 2.

Human craniofacial development. Diagram showing progression of human craniofacial development beginning at 5 weeks of gestation and ending at 11 weeks of gestation. fnp, Frontonasal prominence; mxp, maxillary prominence; mnp, mandibular prominence; np, nasal pits; e, eye.