Systematic review of hormonal and genetic factors involved in the nonsyndromic disorders of the lower jaw

Abstract

Mandibular disorders are among the most common birth defects in humans, yet the etiological factors are largely unknown. Most of the neonates affected by mandibular abnormalities have a sequence of secondary anomalies, including airway obstruction and feeding problems, that reduce the quality of life. In the event of lacking corrective surgeries, patients with mandibular congenital disorders suffer from additional lifelong problems such as sleep apnea and temporomandibular disorders, among others. The goal of this systematic review is to gather evidence on hormonal and genetic factors that are involved in signaling pathways and interactions that are potentially associated with the nonsyndromic mandibular disorders. We found that members of FGF and BMP pathways, including FGF8/10, FGFR2/3, BMP2/4/7, BMPR1A, ACVR1, and ACVR2A/B, have a prominent number of gene‐gene interactions among all identified genes in this review. Gene ontology of the 154 genes showed that the functional gene sets are involved in all aspects of cellular processes and organogenesis. Some of the genes identified by the genome‐wide association studies of common mandibular disorders are involved in skeletal formation and growth retardation based on animal models, suggesting a potential direct role as genetic risk factors in the common complex jaw disorders. Developmental Dynamics 248:162‐172, 2019. © 2018 Wiley Periodicals, Inc.

Diverse Fate of an Enigmatic Structure: 200 Years of Meckel’s Cartilage

“…Similar to the mouse, defects in MC result in the formation of a smaller, malformed dentary bone, resulting in agnathia, micrognathia, or mandibular hypoplasia. Such mandibular defects are fairly common birth defects, with small jaws leading to additional problems associated with airway obstruction and feeding difficulties ( Manocha et al, 2019 ). Mandible defects can be observed in various syndromes including hemifacial microsomia, campomelic dysplasia, Pierre Robin syndrome/sequence, Treacher Collins syndrome, DiGeorge syndrome, and Goldenhar syndrome ( Mckenzie, 1958 ; Bi et al, 2001 ; Ricks et al, 2002 ; Wiszniak et al, 2015 ; Duplan et al, 2016 ), or be nonsyndromic (see Manocha et al, 2019 for a systematic review).…”

“…Such mandibular defects are fairly common birth defects, with small jaws leading to additional problems associated with airway obstruction and feeding difficulties ( Manocha et al, 2019 ). Mandible defects can be observed in various syndromes including hemifacial microsomia, campomelic dysplasia, Pierre Robin syndrome/sequence, Treacher Collins syndrome, DiGeorge syndrome, and Goldenhar syndrome ( Mckenzie, 1958 ; Bi et al, 2001 ; Ricks et al, 2002 ; Wiszniak et al, 2015 ; Duplan et al, 2016 ), or be nonsyndromic (see Manocha et al, 2019 for a systematic review). In the case of campomelic dysplasia, causative mutations have been identified in SOX9 , the master cartilage gene, again highlighing that the microagnathia observed in these patients is due to a defect in MC rather than the later developing dentary ( Mansour et al, 2002 ).…”

“…In the mouse model, the timing of the appearance of MC and its propagation and degradation (see Table 1 ) has been described, the temporospatial pattern of a number genes connected to MC development has been established (see Table 2 ), and genetic manipulations have pointed to several factors essential for its formation (Sox9, Dlx5/6, Fgf8 or Shh), growth (Alk2, Snail1/2, VegfA) and patterning (Fuz, Noggin, Setdb1) (see Table 3 ). Both Fgf and Bmp signalling, for example, have been highlighted as involved in non-syndromic lower jaw defects ( Manocha et al, 2019 ).…”

A cleft lip and palate gene, Irf6, is involved in osteoblast differentiation of craniofacial bone

“…Similarly, a complete loss of Irf6 in mice leads to skeletal abnormalities, including xiphoid and digit malformation (Ingraham et al, 2006;Fakhouri et al, 2017), while exogenous overexpression of IRF6 in basal epithelium partly rescued the craniofacial phenotype in Irf6 null embryos . Despite all these findings, no studies have reported IRF6 expression in osteogenic cells during bone formation (Fakhouri et al, 2017;Manocha et al, 2018). Our recently published study showed that IRF6 is not expressed in migratory cranial neural crest cells; however, it regulates the expression of endothelin 1 (Edn1) ligand in the mandibular epithelium, which binds at Edn1 receptors expressed in adjacent mesenchymal cells to stimulate the cell differentiation (Fakhouri et al, 2017).…”

Identification of Disease Risk DNA Variations is Shaping the Future of Precision Health

“…DNA variations in regulatory elements can disrupt gene expression and alter epigenome modifications, whereas coding mutations can alter protein function, stability, or localization [2,3]. Notably, molecular and genetic studies using animal models have shown that DNA variations play a critical role in increasing fitness to environmental conditions [4]. In contrast, certain DNA variations increase the risk for Mendelian and complex diseases [5,6,7,8].…”