Clinics and genetic background of hereditary gingival fibromatosis

Abstract

Background: Hereditary gingival fibromatosis (HGF) is a rare condition characterized by slowly progressive overgrowth of the gingiva. The severity of overgrowth may differ from mild causing phonetic and masticatory issues, to severe resulting in diastemas or malposition of teeth. Both, autosomal-dominant and autosomal-recessive forms of HGF are described. The aim of this review is a clinical overview, as well as a summary and discussion of the involvement of candidate chromosomal regions, pathogenic variants of genes, and candidate genes in the pathogenesis of HGF. The loci related to non-syndromic HGF have been identified on chromosome 2 (GINGF, GINGF3), chromosome 5 (GINGF2), chromosome 11 (GINGF4), and 4 (GINGF5). Of these loci, pathogenic variants of the SOS-1 and REST genes inducing HGF have been identified in the GINGF and the GINGF5, respectively. Furthermore, among the top 10 clusters of genes ranked by enrichment score, ATP binding, and fibronectin encoding genes were proposed as related to HGF.

Conclusion: The analysis of clinical reports as well as translational genetic studies published since the late'90s indicate the clinical and genetic heterogeneity of non-syndromic HGF and point out the importance of genetic studies and bioinformatics of more numerous unrelated families to identify novel pathogenic variants potentially inducing HGF. This strategy will help to unravel the molecular mechanisms as well as uncover specific targets for novel and less invasive therapies of this rare, orphan condition.

Keywords: Chromosome; Gene; Hereditary gingival fibromatosis; Linkage analysis; Pathogenic variant; Whole-exome sequencing.

Fig. 1

Phenotypic heterogeneity of hereditary gingival fibromatosis. A. the photography shows the gingiva from a 10-year-old Caucasian male patient diagnosed with HGF. Both mother of the patient and her sister are also affected. The surface of the gingiva is almost homogeneous, smooth and with a normal stippling of the attached gingiva. An unusually wide zone of the keratinized gingiva is equally distributed along teeth in both dental arches in the maxilla and in the mandible. The margin of gingiva obscures half of the crowns’ height, which makes teeth appearing not completely erupted; B.  a 15-year-old Caucasian female diagnosed with asymmetric gingival overgrowth of hereditary origin in the maxilla and in the mandible. Hypertrophy of gingiva caused spacing between teeth. It also makes clinical crowns appearing to be shorter than their anatomical length. Gingiva around some teeth looks almost normal while in other locations it presents a significant amount of keratinized tissue, which covers the teeth surface. The surface of the gingiva is heterogeneous at different sites of oral cavity. Some areas are smooth with a normal stippling of the gingiva, whereas other resemble multiple verrucous lesions. Some interdental papillae are overgrown, inflamed, and bleed easily during tooth brushing

Fig. 2

Schematic representation of the loci and affected genes associated with a non-syndromic variant of HGF. Two loci are present on chromosome 2 (GINGF, 2p21-p22 and GINGF3, 2p22.3-p23.3), one on chromosome 4 (GINGF5, 4q12), chromosome 5 (GINGF2, 5q13-q22) and one on chromosome 11 (GINGF4, 11p15). Pathogenic variants  of the SOS-1 (Son-of-Sevenless-1) and REST (RE1-silencing transcription factor) genes were associated with GINGF and GINGF5, respectively