Cleft Palate in Apert Syndrome

Abstract

Apert syndrome is a rare genetic disorder characterized by craniosynostosis, midface retrusion, and limb anomalies. Cleft palate occurs in a subset of Apert syndrome patients. Although the genetic causes underlying Apert syndrome have been identified, the downstream signaling pathways and cellular mechanisms responsible for cleft palate are still elusive. To find clues for the pathogenic mechanisms of palatal defects in Apert syndrome, we review the clinical characteristics of the palate in cases of Apert syndrome, the palatal phenotypes in mouse models, and the potential signaling mechanisms involved in palatal defects. In Apert syndrome patients, cleft of the soft palate is more frequent than of the hard palate. The length of the hard palate is decreased. Cleft palate is associated most commonly with the S252W variant of FGFR2. In addition to cleft palate, high-arched palate, lateral palatal swelling, or bifid uvula are common in Apert syndrome patients. Mouse models of Apert syndrome display palatal defects, providing valuable tools to understand the underlying mechanisms. The mutations in FGFR2 causing Apert syndrome may change a signaling network in epithelial-mesenchymal interactions during palatogenesis. Understanding the pathogenic mechanisms of palatal defects in Apert syndrome may shed light on potential novel therapeutic solutions.

Keywords: Apert syndrome; FGF; FGFR2; cleft palate; high-arched palate; palatogenesis; pseudo-cleft palate; uvula.

Figure 1

Cleft palate and high-arched palate in Apert syndrome. (A) Cleft palate in a patient with Apert syndrome (adapted from [48] and used with permission from Dermatology Online Journal: https://escholarship.org/uc/doj). (B) High-arched palate and gingival enlargement in a patient with Apert syndrome (adapted from [70]).

Figure 2

The palatal phenotypes of FGFR2 S252W and P253R Apert mouse models. (A,B) Incomplete closure of the anterior Fgfr2^+/2S252W secondary palate at P1 (B) compared to WT (A) (adapted from [84] and used with permission from Development: dev.biologists.org). (C,D) Incomplete closure of the anterior Fgfr2^+/P253R secondary palate at P0 (D) compared to WT (C) (adapted from [85]). ns, nasal septum; sp, secondary palate. Arrows indicate incomplete fusion.

Figure 3

Potential signaling regulations involved in palatal defects in Apert syndrome during palatal shelf growth.