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Cleft Palate in Apert Syndrome
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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. 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. 

Apert syndrome cleft palate FGF FGFR2 birth defect rare disease palatogenesis
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Table of Contents

    1. Introduction

    Orofacial clefts (OFCs) are the most common craniofacial birth defects [1]. OFCs cause health issues and complications early in life such as feeding problems and ear infections, increasing morbidity and mortality risks [2]. Treatments including surgery, speech therapy, and dental management usually are required. In addition, OFCs cause significant psychological and socioeconomic difficulties for both the patient and the family, and the effects may extend through adulthood [3].
    OFCs can be classified as cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) [1]. The prevalence is 3.1 per 10,000 live births for cleft lip only, 5.6 per 10,000 for cleft lip with cleft palate, and 5.9 per 10,000 for cleft palate only [4]. CPO is a multifactorial disorder caused by both genetic and environmental factors [5][6]. CPO can be categorized into non-syndromic (isolated) and syndromic CPO [5]: non-syndromic CPO is an isolated condition unassociated with any other recognizable anomalies; syndromic CPO is associated with abnormalities in addition to the cleft or with a syndrome with a known genetic etiology [7].
    Apert syndrome (MIM #101200) is a congenital disorder characterized by clinical features including multisuture craniosynostosis, midface retrusion, and syndactyly of the hands and feet [8]. It occurs in about 1:80,000 to 1:160,000 live births [9][10][11]. The genetic causes of Apert syndrome are variants affecting the fibroblast growth factor receptor 2 (FGFR2) gene. The human FGFR2 gene is located on chromosome 10q26 and encodes a receptor tyrosine kinase. FGFR2 consists of an extracellular portion composed of three immunoglobulin-like domains (IgI, IgII, and IgIII) responsible for extracellular ligand binding, a transmembrane region, and an intracellular tyrosine kinase domain [12][13][14]. More than 98% of Apert syndrome cases are caused by two amino acid substitutions, Ser252Trp (S252W) and Pro253Arg (P253R), in the linker region between the second and third extracellular Ig domains [15][16]. Approximately 67% of Apert syndrome cases have the S252W variant, while P253R accounts for 32% of cases [15][16][17]. Other rare variants include Ser252Phe (S252F) [17][18][19][20], Ser137Trp (S137W) [21], Alu-element insertions in FGFR2 [22], and a deletion between FGFR2 exons IIIb and IIIc creating a chimeric IIIb/IIIc exon [23]. These are all gain-of-function FGFR2 mutations [24][25].

    2. Clinical Characteristics of the Palate in Apert Syndrome

    Apert syndrome patients present with anomalies of the palate, which may or may not include cleft palate (Table 1 and Table 2). Cleft palate is present in a subset of affected individuals with Apert syndrome [8] and the frequency is higher than control subjects [26]. However, the incidence of cleft palate in patients with Apert syndrome varies between different studies. Kreiborg and Cohen reported that in a study of 119 patients with Apert syndrome, 75% of the patients had a cleft of the soft palate or bifid uvula [27]. In a group of seven Japanese patients with Apert syndrome, Kobayashi et al. reported two patients with a cleft of the soft palate (28.6%) and one with a cleft of the hard palate (14.3%) [28]. In 17 cases of Apert syndrome reported by Arroyo Carrera et al., cleft palate was identified in 23.5% of patients [29]. In a retrospective study in Brazil, only 1 of 23 (4%) Apert syndrome patients presented with a true cleft palate [30].
    Table 1. Palatal phenotypes in cohort studies of Apert syndrome.
    Table 2. Palatal phenotypes in case reports of Apert syndrome.
    Cohort studies have shown that a high-arched palate (also described as “high palate”, “pseudo-cleft”, “vaulted palate”, or “Byzantine arch-shaped palate”) with lateral palatal swelling is the most common palatal anomaly in patients with Apert syndrome (Table 1), usually present in more than 90% of the patients [28][30][31][32][34][38]. It also is present frequently in case reports of Apert syndrome (Table 2). Patients with narrow, high-arched palates and/or gingival swellings [28][30][32][34], may lead to a misdiagnosis of cleft palate in early studies [32].
    Apert syndrome has a high frequency of soft palate cleft or bifid uvula [27]. Clefts of the soft palate are more frequent than of the hard palate in patients with Apert syndrome [28][30]. Bifid uvula, which is a split uvula, is often considered as a marker for submucous cleft palate (SMCP) [68][69]. SMCP is a subgroup of cleft palate resulting from insufficient medial fusion of the muscles of the soft palate during palatogenesis [69]. A submucous cleft palate may appear to be structurally intact, but other defects may be present, including a bony notch in the hard palate, a bluish line at the midline of the soft palate (zona pellucida), and a bifid uvula [70][71].
    In addition to the clefts, decreased length of the hard palate has been observed in patients with Apert syndrome [33][72]. This may indicate defects in palatal bone formation caused by the pathogenic FGFR2 variant, or it could be secondary to midface hypoplasia, which is one of the features of Apert syndrome.
    Genotype–phenotype correlations in Apert syndrome have been studied. Although these correlations are variable, cleft palate is associated more commonly with the S252W variant than P253R in multiple studies comparing subgroups defined by these two variants in FGFR2 [16][17][73][74][75][76]. Cleft palate is present in approximately 60% of patients with the S252W variant and 15% of patients with the P253R variant (Table 3), suggesting this genotype–phenotype correlation in Apert syndrome.
    Table 3. Genotype–phenotype correlations of cleft palate with the FGFR2 S252W and P253R variants.

    3. Open Questions and Future Directions

    In patients with Apert syndrome, high-arched palate with lateral palatal swelling is the most common palatal anomaly (70–100%, Table 1). Approximately 50% of patients presented with cleft palate (Table 1 and Table 3), and 30% of patients presented with bifid uvula [32][77]. The incidence of cleft palate and other palatal defects in patients with Apert syndrome varies between different studies. This may be caused by factors such as genetic background, environmental effects, variability of phenotypes, and diagnostic criteria across studies.
    Craniosynostosis is a diagnostic feature of Apert syndrome. Almost all Apert patients have coronal craniosynostosis, and a majority have sagittal and lambdoid craniosynostosis [8][34]. A subset of affected individuals have cleft palate. A wide array of other abnormalities is seen in Apert syndrome patients, including craniofacial malformations, syndactyly, feeding problems, cognitive disorders, hearing loss, and speech and language difficulties. Thus, a multidisciplinary team is essential to provide treatment and care. For cleft palate, various treatments including surgery, dental management, speech therapy, and psychological support are required [2]. Palate repair surgery is typically performed prior to development of pressure consonants to improve speech production and intelligibility [8]. However, patients may experience lifelong psychosocial effects from the malformation of the facial appearance even after surgeries [2]. Future studies can be performed to determine if there is a correlation between the palatal phenotype and other phenotypes and management issues in Apert syndrome.
    Various potential therapies are emerging to remedy cleft palate. One potential therapeutic avenue applicable to Apert syndrome is targeting of FGFR activity and downstream signaling pathways. For example, coronal suture fusion in calvarial explants was decreased by exposure to the MEK1 inhibitor PD98059 in the FGFR2 P253R model [78]. Both pre- and postnatal administrations of the MEK1/2 inhibitor U0126 alleviated symptoms in the FGFR2 S252W model, as did a gene therapy strategy of expressing a short hairpin RNA against the Fgfr2S252W allele [79]. FGFR2-related signaling network analysis may help to find targets for novel drugs to treat or alleviate symptoms. In addition, innovative cellular therapeutics such as stem cell transplantation have been applied in cleft palate treatment [80][81]. Mazzetti et al. reported results from patients with cleft lip and palate who had stem cells from umbilical cord blood and placental blood injected into the bone and soft tissue during the primary surgical repair procedure. Compared to controls, the group with stem cell injection showed improvement in the inflammatory response, fewer postoperative complications and less fibrosis. Tomography showed an improved maxillary alignment, and the alveolar cleft became smaller [81].
    High-arched palate has been reported in ciliopathy-related syndromes [82][83]. Ciliopathies are disorders that arise from the dysfunction of motile and/or non-motile cilia [84], with craniofacial dysmorphology as a common feature [83]. An etiological link between ciliopathies and FGF hyperactivation syndromes has been identified [83]. The primary cilium is the central organelle for the transduction of the hedgehog signaling pathway in vertebrates and is also a signaling center for other signaling pathways, such as WNT, Notch, Hippo, GPCR, PDGF, and other RTKs including FGF, mTOR, and TGF-β [85][86]. Considering that FGF signaling regulates the formation of primary cilia [86], it would be interesting to investigate the roles of cilia and associated signaling pathways in the palatal defects in Apert syndrome, especially the high-arched palate.

    4. Conclusion

    Apert syndrome is a rare genetic disorder caused by pathogenic variants of the FGFR2 gene. Cleft palate is a common phenotype in Apert syndrome cases, and high arched palate, lateral palatal swelling, and bifid uvula also occur with high frequency. Palatal defects in Apert syndrome inform the critical role of FGFR2 in the regulatory network for palatogenesis. Mouse models of Apert syndrome have been established and display many phenotypes of Apert syndrome. In mouse models of FGFR2 S252W and FGFR2 P253R, incomplete closure of the anterior end of the secondary palate occurs in newborn mice. These models provide opportunities for in vivo investigation of the role of FGF signaling in palatal defects in Apert syndrome.

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      Willie, D.; Holmes, G.; Jabs, E.W.; Wu, M. Cleft Palate in Apert Syndrome. Encyclopedia. Available online: https://encyclopedia.pub/entry/26554 (accessed on 07 February 2023).
      Willie D, Holmes G, Jabs EW, Wu M. Cleft Palate in Apert Syndrome. Encyclopedia. Available at: https://encyclopedia.pub/entry/26554. Accessed February 07, 2023.
      Willie, Delayna, Greg Holmes, Ethylin Wang Jabs, Meng Wu. "Cleft Palate in Apert Syndrome," Encyclopedia, https://encyclopedia.pub/entry/26554 (accessed February 07, 2023).
      Willie, D., Holmes, G., Jabs, E.W., & Wu, M. (2022, August 26). Cleft Palate in Apert Syndrome. In Encyclopedia. https://encyclopedia.pub/entry/26554
      Willie, Delayna, et al. ''Cleft Palate in Apert Syndrome.'' Encyclopedia. Web. 26 August, 2022.
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