Metopic craniosynostosis due to mutations inGLI3: A novel association

Abstract

We report on the novel association of trigonocephaly and polysyndactyly in two unrelated patients due to mutations within the last third (exon 14) and first third (exon 6) of the GLI3 gene, respectively. GLI3 acts as a downstream mediator of the Sonic hedgehog signal-transduction pathway which is essential for early development; and plays a role in cell growth, specialization, and patterning of structures such as the brain and limbs. GLI3 mutations have been identified in patients with Pallister-Hall, Grieg cephalopolysyndactyly syndrome (GCPS), postaxial polydactyly type A1, preaxial polydactyly type IV, and in one patient with acrocallosal syndrome (ACLS). Furthermore, deletions including the GLI3 gene have been reported in patients with features of GCPS and ACLS. To date, trigonocephaly has not been associated with abnormalities of GLI3 and craniosynostosis is not a feature of GCPS. However, Hootnick and Holmes reported on a father with polysyndactyly and son with trigonocephaly, polysyndactyly, and agenesis of the corpus callosum, considered GCPS thereafter. Guzzetta et al. subsequently described a patient with trigonocephaly, polysyndactyly, and agenesis of the corpus callosum postulating a diagnosis of GCPS, later considered ACLS. In retrospect, these two patients, evaluated prior to mutational analysis, and our patients, with confirmed mutations, likely fall within the GLI3 morphopathy spectrum and may provide a bridge to better understanding those patients with overlapping features of GCPS and ACLS. Based on this observation, we suggest GLI3 studies in patients presenting with this constellation of findings, specifically metopic craniosynostosis with polysyndactyly, in order to provide appropriate medical management and genetic counseling.

Prevention of Premature Fusion of Calvarial Suture in GLI-Kruppel Family Member 3 (Gli3)-deficient Mice by Removing One Allele of Runt-related Transcription Factor 2 (Runx2)

“…Craniosynostosis is an infrequent but important feature of Grieg cephalopolysyndactyly syndrome caused by mutations in GLI3 (2,3). Most forms of craniosynostosis, including those in Grieg cephalopolysyndactyly syndrome, occur prior to birth and are not detected until birth.…”

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…GLI3 is implicated in a craniofacial syndrome involving cognitive impairment both in humans (Greig cephalopolisyndactily, OMIM #175700) and in mice [Veis tinen et al, 2012;Tabler et al, 2016;Lattanzi et al, 2017] with cognitive impairment, which entails language delay [McDonald-McGinn et al, 2010;Lattanzi, 2016]. Indeed, it regulates skull development acting on the DLX5/RUNX2 cascade , and hence it is expected to have played a role in the physiological events leading to globularization, in which these genes were seemingly involved [Boeckx and Benítez-Burraco, 2014a]; nearly 98% of Altaic Neanderthals and Denisovans gained a nonsynonymous change in GLI3 that is described as mildly disruptive [Castellano et al, 2014].…”

Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas

“…Also, some pathogenic variants cause overlapping phenotypes of GCPS and PHS [19]. Therefore, the concept of GLI3 morphopathies has been postulated to designate these mutually overlapped syndromes [5].…”

“…The pathogenic variants of GLI3 gene cause various malformations including Greig cephalopolysyndactyly (GCPS) syndrome [2] and Pallister-Hall syndrome (PHS) [4] in an autosomal dominant pattern. Although GCPS and PHS have some distinct clinical presentations (GCPS is characterized by polysyndactyly, macrocephaly, hypertelorism, and PHS is characterized by hypothalamic hamartoma, bifid epiglottis, and insertional polydactyly), the apparent lack of GLI3 genotype-phenotype correlation occasionally precludes clear phenotypic classification [5]. Described here is a case of an overlapped GCPS and PHS phenotype with agenesis of the gallbladder and the pancreas, bearing a novel likely pathogenic GLI3 variant by point mutation.…”