Premature bone fusion, craniosynostosis, is one of the key features playing role in the narrowing and easier collapse of the airways. It is often diagnosed together with midface hypoplasia, i.e., a combination of the underdevelopment of the maxilla, cheekbones, and eye sockets (although both these features may occur also independently). Even though these features are well-recognized factors in POSA development, the etiology is usually multifactorial and many children suffer from multilevel airway obstruction (24). Underdevelopment of the upper jaw, i.e., maxillary hypoplasia or, in the case of more pronounced narrowing, maxillary constriction, which are often associated also with narrow and/or high arched palate and lateral crossbite, are other characteristics often present in children suffering from POSA (19, 23, 24, 26). Severe reduction of the naso- and oro-pharyngeal airway space may be present in children with craniosynostosis, in patients with clefts originating from prenatal incomplete tissue fusion (20, 21, 27), or in those with anomalies of the mandible, especially if the mandible is undersized, (i.e., micrognathia; (19, 23, 24, 26). However, the underdevelopment of the maxillo-mandibular complex is not the only factor decreasing the airway patency. According to cephalometric studies, sagittal and vertical maxillo-mandibular complex discrepancies, such as mandibular retrognathia, often diagnosed as skeletal class II malocclusion, and increased overjet or open bite, which may appear due to increased mandibular plane angle, are overrepresented in children diagnosed with POSA (22, 26, 28, 29). This hyperdivergent skeletal pattern may lead to the development of the long-face syndrome, which is another facial appearance typical of patients with SRBD (28, 30, 31). Negative anterior overjet and skeletal class III malocclusion are not as often associated with POSA; still, the association is possible, especially if they are caused by severe maxillary deficiency (32). The lower position of the hyoid bone is another skeletal risk factor that can be diagnosed in a cephalogram. As some lingual muscles insert on that bone, their pull in a downward direction can also cause the narrowing of the airway space and, in effect, apnea (14, 33–35).

The morphology of soft tissues plays an important role, too. Adeno-tonsillar hypertrophy is a well-described etiological factor of POSA. The deviation or deformity of the nasal septum, hypertrophy of nasal turbinates, or nasal polyps may also increase nasal resistance (36–38) and contribute towards mouth breathing, often accompanied by unphysiological head posture, insufficient lip seal or open bite, all of which are characteristics often present in patients with POSA (16). The lack of nasal breathing accompanied by an imbalance in muscle activity, often associated with the hypotony of orofacial muscles, have a huge impact on the development and growth of the maxillo-mandibular complex and may contribute to its abnormal shape and size (16, 39, 40).

The tongue is another factor playing a key role in the narrowing and collapse of the upper airway. The short sublingual frenulum (or ankyloglossia) in its most severe form leads to a low tongue position and disrupted tongue movement and has been already associated with the POSA phenotype (16, 41–43). An insufficient stimulation of the palatal suture, caused by this unphysiological tongue position, may result in the formation of a narrow palate and decreased volume of nasal cavities, which, again, contributes to the preference for mouth breathing and airway narrowing (16, 33). POSA has also a high prevalence in patients with glossoptosis, which is a down- and backward position of the base of the tongue (44). The combination of glossoptosis with micrognathia or retrognathia leads to a high risk of tongue-based airway obstruction (24, 45). In addition, macroglossia and/or an elongated soft palate could reduce airway volume and contribute to airway obstruction (14, 34).

These craniofacial characteristics are associated with several syndromes; however, they could be also found in non-syndromic children (14, 15, 19). Even though they are usually present in less severe forms, they could still contribute to airway obstruction. Craniofacial features associated with POSA could be easily diagnosed and their heritability is estimated to be high. This is especially true for the size of the maxillo-mandibular complex and the timing of its growth (11, 13, 46).

The etiology of craniosynostosis may involve genetic, epigenetic, and/or environmental factors (88). Craniosynostosis is associated with a high prevalence of POSA. It is a common feature in patients with Antley-Bixler, Apert, Beare-Stevenson, Crouzon, Pfeiffer, Muenke, Jackson-Weiss, Craniofrontonasal, and Saethre-Chotzen syndromes (89–92). SRDB was present also in 50% of children suffering from non-syndromic craniosynostosis (NSC) (89).

Deviations in the development of the craniofacial area are also associated with a variability in the fibroblast growth factor receptor (FGFR) genes, which are important for cell specialization as well as for bone growth and modeling, especially in the process of ossification and bone fusion (48, 93, 94). Severe mutations in FGFR genes are associated with premature cranial bone fusion and craniosynostosis. These mutations were found in several craniofacial syndromes with a high prevalence of SRBD in children, such as achondroplasia, Antley-Bixler, Beare-Stevenson, Jackson-Weiss, Apert, Crouzon, Pfeiffer, and Saethre-Chotzen syndromes (21, 51, 92, 95–99). These FGFR-related craniosynostosis syndromes are autosomal-dominantly inherited.

Moreover, variants in FGFR genes could also lead to NSC (95, 100, 101). Genes most commonly mutated in familial craniosynostosis include, besides FGFR2 and FGFR3, the twist family bHLH transcription factor 1 (TWIST1) and ephrin-B1 (EFNB1) (102). More than 100 mutations in the EFNB1 gene have been found to cause the craniofrontonasal syndrome, which was confirmed in a study with knockout mice models (103). This rare x-linked disorder shows paradoxically greater severity in heterozygous females than in hemizygous males. TWIST1 acts through Eph–ephrin interactions to regulate the development of the boundary that forms the coronal suture (104). The TWIST1 gene associated with the Saethre-Chotzen syndrome is believed to regulate bone formation through other genes, such as FGFR and RUNX2 (63, 64). Genetic testing of FGFR1, FGFR2, FGFR3, and TWIST1 was even suggested as a first-line test for patients with NSC (101).

Interestingly, not only rare mutations of these genes but also SNPs of these genes are associated with craniofacial dysmorphia. For example, Da Fontoura et al. found an association between SNPs rs11200014 and rs2162540 in FGFR2 and sagittal maxilla-mandibular discrepancy, so-called skeletal malocclusion (both skeletal class II and III). They also found an association between the SNP rs2189000 in TWIST1 and a larger body and shorter ramus of the mandible (62). Although FGFR3 gene variants are associated with Muenke and Crouzon syndromes manifested by craniosynostosis, this feature, surprisingly, was not exhibited in the FGFR3 ^A385E/+ mice model (105–107). Thus, FGFR2 seems to be more important for craniosynostosis development than FGFR3. On the other hand, a mutation in FGFR3 causes achondroplasia, which, according to a recent study by Legare et al., has craniosynostosis as a co-occurring feature (108).

A missense mutation in the Protein Tyrosine Phosphatase Non-Receptor Type 11 (PTPN11) gene was found in almost 50% of patients diagnosed with Noonan syndrome (109). This gene encodes tyrosine phosphatase Shp-2, an enzyme involved in multiple signal transduction cascades including receptors for growth factors involved in the developmental processes, such as FGFR (110). The Noonan syndrome is manifested by micrognathia, maxillomandibular discrepancy, narrow and/or high-arched palate, and long face syndrome (hyperdivergence) (111, 112). Also, craniosynostosis was described in some patients suffering from this syndrome. Mutations in the PTPN11, KRAS, or Leucine-Rich Repeat Scaffold Protein (SHOC2) gene are causally involved in craniosynostosis (113–115). In patients with the Antley-Bixler syndrome, characterized by craniosynostosis, brachycephaly, midface hypoplasia, and choanal atresia and/or stenosis, variants have been found not only in FGFR2, but also in the gene encoding cytochrome p450 oxidoreductase (POR) (116–119). This enzyme transfers electrons from NADPH to all microsomal cytochrome P450 enzymes. While individuals with an ABS-like phenotype and normal steroidogenesis are carriers of FGFR2 mutations, those with genital anomalies and disordered steroidogenesis should be recognized as having a POR deficiency (116).

The SRY-box 9 transcription factor (SOX9) gene plays an important regulatory role during craniofacial development (120). In a rat model with upper airway obstruction, SOX9 level was found to be downregulated, which explains the bone architecture abnormalities (121). This gene is also associated with the Pierre Robin sequence (122). Repressed SOX9 expression leads to changes in the expression of genes essential for normal development of the mandible, causing micrognathia, and, consequently, glossoptosis, airway obstruction, and often, cleft palate (123). The expression of SOX9 is influenced, among others, by FGFR3. Therefore, dysregulation of SOX9 levels, a major regulator of chondrogenesis, is an important underlying mechanism in skeletal diseases caused by mutations in FGFR3 (124–126). Interestingly, the SNP rs12941170 of SOX9 was associated with non-syndromic orofacial clefting. However, its role in these non-syndromic clefts remains unclear (124).

Similarly to SOX9, variants in endothelin 1 (EDN1), the Splicing factor 3B subunit (SF3B2), and Treacle ribosome biogenesis factor 1 (TCOF1) were associated with syndromes manifesting in children by both micrognathia and glossoptosis. EDN1 encodes a vasoactive peptide belonging to the family of endothelins and is associated with the auriculocondylar syndrome (127), a rare syndrome that usually affects facial features. It is characterized by micrognathia, microstomia, and anomalies in the temporomandibular joint and the condyle (127). Also, studies using mice models with the EDN1 gene knocked out or deficient have shown several craniofacial dysmorphisms, mandibular dysfunction, and severe retrognathism (62, 127). SF3B2 may be, according to a study by Timberlake et al., an important factor in the development of craniofacial microsomia, which was also confirmed by a recent review covering this congenital facial anomaly (128, 129). TCOF1 presents an important factor for the undisrupted formation and development of the craniofacial area, cartilage, and skeleton (55, 130, 131). Mutations in these genes were found in patients with Treacher-Collins syndrome (130, 131).

Ehlers-Danlos syndrome, manifesting through retrognathia, micrognathia, and maxillary constriction, has been previously proposed as a genetic model for pediatric OSA (60, 61, 132). Variants in genes encoding and/or influencing the expression of collagens (COL gene family) and others (see Supplementary Table S1 in the Supplement) were associated with this rare connective tissue disorder (60, 133). The minor allele of SNP rs2249492 in the Collagen type I alpha 1 chain (COL1A1) has been previously associated with the increased risk of a sagittal maxilla-mandibular discrepancy (skeletal class III malocclusion) in non-syndromic children (62). The results of the study by Topârcean et al. showed a tendency towards a class II skeletal malocclusion pattern determined by mandibular retrognathism rather than maxillary prognathism among the individuals possessing the mutant allele of this SNP (134).

Other genes for collagens, COL2A1 and COL11A1, are associated with Marshall-Stickler syndrome (86). Collagens II and XI are present throughout the Meckel's cartilage, which provides mechanical support for the developing mandible. The characteristic craniofacial features of Marshall-Stickler syndrome are midface hypoplasia, micrognathia, cleft palate, and Pierre Robin anomaly (50). Variants in COL2A1 and COL11A1 were also associated with the Robin sequence in nonsyndromic patients (135).

Besides collagens, fibrillin and elastin are also present in the architectural scaffolds that impart specific mechanical properties to tissues and organs. The FBN1 gene is essential for the production of fibrillin, and its mutation could cause Marfan syndrome (57, 136).

Fibrillin is crucial for bone and muscle rigidity; hence, its disruption can increase the laxity of airway connective tissues and predispose them to easier collapsibility (56). At the same time, patients often have their maxillo-mandibular complex in a retrognathic position, with a narrow maxilla and palate, and a “long face” appearance (56–58, 137).

Besides FBN1, mutations in the transforming growth factor-β receptor 1 (TGFBR1) and transforming growth factor-β receptor 2 (TGFBR2) may also be found in Marfan syndrome (138). TGFBR2 protein forms a complex with TGFBR1, and both are involved in a signaling pathway responsible for the proliferation, differentiation, and apoptosis of cells throughout the body (139). They are extremely important for bone growth and extracellular matrix formation; moreover, they play a role in the fusion of craniofacial sutures (140). The development of micrognathia and retrognathism was observed in mice with an impaired TGFB2 gene, giving evidence to its importance in craniofacial morphology (141).

The gene for vacuolar protein sorting-associated protein 13B (VPS13B), also called the COH1 gene, encodes a protein forming a part of the Golgi apparatus membrane. Its disruption may be involved through various cellular mechanisms, in several clinical features of Cohen syndrome (142, 143), including micrognathia, constricted hard palate, insufficient lip seal, and truncal obesity. All of these issues increase the risk of the collapse of the upper airway and the development of POSA (65, 66, 142, 143).

Mutations in necidin (NDN) and the melanoma antigen family member L2 (MAGEL2), both localized on chromosome 15, were found in the Prader-Willi syndrome, a complex genetic disorder characterized by several features, such as midface hypoplasia and micrognathia (144). The phenotype of this syndrome includes hypoplastic midface area, hypotonia, and a changed viscosity in secretions. All these factors facilitate the collapse of upper airways and apnea (52, 53, 144). Some polymorphisms in NDN were determined in extremely obese German children and adolescents as well as in neonates examined by polysomnography. However, there was a lack of association with juvenile-onset human obesity or sleep and respiratory parameters (145, 146).

Midface or maxillary hypoplasia are typical features of several syndromes, including mucopolysaccharidosis, Ellis-van Creveld, or congenital central hypoventilation syndrome, the genetic backgrounds of which are described below.

Mucopolysaccharidosis (MPS) is a metabolic disorder characterized by the deficiency or total absence of enzymes responsible for the degradation of glycosaminoglycans. It can be classified into 7 types based on the specific malfunctioning enzyme and clinical manifestations (147). The Morquio syndrome (MPS IV) can be caused by a mutation either in the N-acetylgalactosamine-6-sulfatase (GALNS) gene (MPS type IVA), or in the gene for galactosidase beta 1 (GLB1; MPS type IVB). Among other clinical manifestations, the Morquio syndrome includes also craniofacial dysmorphisms such as mid-facial hypoplasia, condylar deformities, open bite, macroglossia, or abnormal teeth (148, 149).

The mutated gene for arylsulfatase B (ARSB) leads to the reduced function of the enzyme, causing a lysosomal storage disorder – MPS type VI, also known as Maroteaux-Lamy syndrome (117). This syndrome is associated with orofacial manifestations such as macroglossia, malocclusions, or disrupted dental eruption (150).

In syndromic children, the TWIST gene and the genes of the FGFR family, described in detail above, were associated with maxillary hypoplasia. In addition, the EvC ciliary complex subunit 1 (EVC1) and subunit 2 (EVC2) genes were found to be causative for the formation of the Ellis-van Creveld syndrome manifested also by maxillary hypoplasia and mandibular prognathism (151, 152). They encode proteins, the functions of which are not completely understood yet, but appear to be important in the physiological growth and development of bones and teeth (153).

The paired-like homeobox 2B (PHOX2B) transcription factor plays a crucial role in the autonomic nervous system development. Mutations in the PHOX2B gene are known to cause the congenital central hypoventilation syndrome with a specific craniofacial phenotype – maxillary hypoplasia, box-shaped face, and brachycephaly (68). However, a “silent” mutation in this gene was found in children with class III skeletal malocclusion and a history of sleep apnea (63, 154, 155).