Signaling Mechanisms Underlying Genetic Pathophysiology of Craniosynostosis

Abstract

Craniosynostosis, is the premature fusion of one or more cranial sutures which is the second most common cranial facial anomalies. The premature cranial sutures leads to deformity of skull shape and restricts the growth of brain, which might elicit severe neurologic damage. Craniosynostosis exhibit close correlations with a varieties of syndromes. During the past two decades, as the appliance of high throughput DNA sequencing techniques, steady progresses has been made in identifying gene mutations in both syndromic and nonsyndromic cases, which allow researchers to better understanding the genetic roles in the development of cranial vault. As the enrichment of known mutations involved in the pathogenic of premature sutures fusion, multiple signaling pathways have been investigated to dissect the underlying mechanisms beneath the disease. In addition to genetic etiology, environment factors, especially mechanics, have also been proposed to have vital roles during the pathophysiological of craniosynostosis. However, the influence of mechanics factors in the cranial development remains largely unknown. In this review, we present a brief overview of the updated genetic mutations and environmental factors identified in both syndromic and nonsyndromic craniosynostosis. Furthermore, potential molecular signaling pathways and its relations have been described.

Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis

“…This contrasts with the pattern typically seen in individuals with syndromic CS, where multiple suture synostosis is the most common finding [5,26], and also with our finding in individuals with the more common CS syndromes (Tables 1 and 3). The most common reported CS syndromes have a high frequency of CS and are caused by genes acting in [27,28]. The difference in affected sutures between the common CS syndromes and the rare or ultrarare syndromes, with a low frequency of CS caused by genes acting in other pathways, might indicate that the synostoses in these two groups have different molecular mechanisms.…”

“…The difference in affected sutures between the common CS syndromes and the rare or ultrarare syndromes, with a low frequency of CS caused by genes acting in other pathways, might indicate that the synostoses in these two groups have different molecular mechanisms. Individuals with rare genetic syndromes which includes macrocephaly (e.g., Malan syndrome) might also be at higher risk of developing CS due to foetal head constraints that are associated with CS, especially regarding coronal premature fusion [27,29]. Notably, in our cohort we detected several Mendelian disorders of chromatin modification (chromatinopathies), including (with the associated gene in parentheses): CHARGE (CHD7), Kleefstra (EHMT1), Floating-Harbor syndrome (SRCAP), KAT6B-related disorders (KAT6B), and 2q37 deletion syndrome (caused by haploinsufficiency of the HDAC4 gene [30]).…”

Personalized Bone Reconstruction and Regeneration in the Treatment of Craniosynostosis

“…Different genes have been recently associated with NCS, suggesting possible genotype/phenotype correlations between the mutated genes and the patterns of suture closure [5,7,[9][10][11][12][13][14][15][16][17][18][19]. On this regard, it is worth noting that the presence of gene mutations may affect the neurodevelopmental prognosis in both syndromic and nonsyndromic CS patients [18,20].…”

The power of zebrafish models for understanding the co‐occurrence of craniofacial and limb disorders

“…Therefore, patients with craniosynostosis have abnormally shaped skulls. Most cases of craniosynostosis are caused by genetic variants in TWIST1 , FGFRs, and EFNB1 among other genes [reviewed in Wu & Gu, 2019]. Twist1 is a transcription factor that is expressed in either the osteogenic front as a homodimer (T/T) or as a heterodimer with E proteins (T/E), such as Tcf12, in the mesenchymal cells of cranial sutures (schematic in Figure 2b).…”