GLI3‐related polydactyly: a review

Abstract

GLI3 mutations are known to be associated with nine syndromes/conditions in which polydactyly is a feature. In this review, the embryology, pathogenesis, and animal models of GLI3-related polydactyly are discussed first. This is followed by a detailed review of the genotype-phenotype correlations. Based on our review of the literature and our clinical experiences, we recommend viewing GLI3-related syndromes/conditions as four separate entities; each characterized by a specific pattern of polydactyly. These four entities are: the preaxial polydactyly type IV-Greig-acrocallosal spectrum, postaxial polydactyly types A/B, Pallister-Hall syndrome (PHS), and oral-facial-digital overlap syndrome. We also provide illustrative clinical examples from our practice including a family with a novel GLI3 mutation causing PHS. The review also introduces the term 'Forme Fruste' preaxial polydactyly and gives several conclusions/recommendations including the recommendation to revise the current criteria for the clinical diagnosis of PHS.

Human Malformation Syndromes of Defective <b><i>GLI</i></b>: Opposite Phenotypes of 2q14.2 (<b><i>GLI2</i></b>) and 7p14.2 (<b><i>GLI3</i></b>) Microdeletions and a GLIA/R Balance Model

“…Typical polysyndactyly features are bilateral preaxial polysyndactyly (PPD) of the feet, broad thumb, or PPD with simple syndactyly of other digits of the hands. In addition, PAP of the hands may be present [Al-Qattan et al, 2017]. GCPS can appear both by point mutations of GLI3 or by contiguous gene deletion syndrome of 7p13 (GCPS-CGS).…”

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

“…A proper balance between the GLI3 activator and the repressor, organized by hedgehog signaling, elicits proper evolvement of the various organs during development [11][12][13]. Pathogenic variants in different domains of the gene underlie several congenital diseases including GCPS (MIM ID#175700), PHS (MIM ID #146510), preaxial polydactyly type IV (MIM ID #174700), and postaxial polydactyly types A1 and B (MIM ID #174200), Acrocallosal Syndrome (MIM ID #200990), trigonocephaly with craniosynostosis and polydactyly, and some types of oral-facial-digital syndromes [14]. Typical GCPS involves polysyndactyly of hands and feet, and craniofacial abnormality.…”

Targeted exome sequencing reveals a novel GLI3 mutation in a Chinese family with nonsyndromic polydactyly

“…It has been described that polydactyly is mostly inherited in an autosomal dominant model and many polydactyly entities have been mapped . Preaxial polydactyly maps to 7q36, postaxial polydactyly to 13q and 19p, and complex types caused by mutations in GLI3 and ZRS to 7p14 and 7q36, respectively .…”

“…Preaxial polydactyly maps to 7q36, postaxial polydactyly to 13q and 19p, and complex types caused by mutations in GLI3 and ZRS to 7p14 and 7q36, respectively . GLI3 is one of three GLI zinc‐finger transcription factors that mediate the sonic hedgehog (SHH) signaling acting as both a transcriptional activator and repressor during development and tissue patterning . Numerous pathogenic variants of GLI3 gene have been linked to complex clinical phenotypes, including Greig cephalopolysyndactyly syndrome (GCPS), Pallister‐Hall syndrome (PHS), and nonsyndromic polydactyly …”

“…Polydactyly is a phenotypically and genetically heterogeneous limb deformity in clinical genetics and can occur as an isolated event or in association with pleiotropic developmental anomaly syndromes. 1 According to the Temtamy and McKusick scheme, polydactyly can be classified as preaxial in which the extra digit is located outside the great toe or thumb, central in which the extra digit is located among three central digits and postaxial in which the extra digit is located outside the fifth digit. 2 Postaxial polydactyly is far more common than preaxial and central subtypes; moreover, concomitant syndactyly is often seen with some forms of polydactyly.…”