Gingival fibromatosis-3 (GINGF3) is an autosomal dominant disorder characterized by the development of gingival overgrowth in early childhood, at the time of tooth eruption. Gingival fibromatosis develops slowly in affected individuals, and consists of firm and nodular fibrous tissue (Ye et al., 2005; Pampel et al., 2010).

For phenotypic information and a discussion of genetic heterogeneity of hereditary gingival fibromatosis, see GINGF (135300).

Ye et al. (2005) ascertained a 5-generation Chinese family with autosomal dominant nonsyndromic hereditary gingival fibromatosis, with onset between 2 to 6 years of age, around the time of tooth eruption. The 12 individuals examined all had typical findings, but gingival involvement was variable, ranging from mild to severe.

Pampel et al. (2010) reported a 4-generation German family segregating autosomal dominant gingival fibromatosis mapping to chromosome 2. Of 15 family members examined, 9 were classified as affected. Diagnostic criteria included enlarged gingiva covering at least one third of clinical dental crowns of 5 or more teeth, with no history of exposure to any drugs known to induce gingival overgrowth. The onset of gingival fibromatosis consistently occurred with the eruption of the primary teeth in all affected family members. Gingival fibromatosis was slowly progressive and variably involved localized or generalized enlargement of keratinized gingiva. The overgrowth consisted of dense fibrous tissue that felt firm and nodular on palpation. The excess tissue was associated with periodontal problems, and caused difficulty in daily oral hygiene. Histologic evaluation of patient specimens showed hyperplasia of fibrous tissue characterized by squamous epithelium with elongated rete ridges overlaying markedly increased cell-poor fibrous tissue. Pseudoepitheliomatous hyperplasia of the squamous epithelium with formation of papillae was present in severely affected individuals.

By haplotype construction and analysis in a 5-generation Chinese family segregating autosomal dominant hereditary gingival fibromatosis, Ye et al. (2005) identified a novel locus for this disorder, which they designated GINGF3, in an 11.4-cM interval between markers D2S2221 and D2S1788 on chromosome 2p23.3-p22.3. Maximum 2-point and multipoint lod scores of 3.45 and 5.00, respectively, were achieved for this region. Ye et al. (2005) noted that this locus is distal to and does not overlap with the previously described GINGF locus on 2p22-p21.

By haplotype and lod score analysis in a 4-generation German family segregating autosomal dominant gingival fibromatosis, Pampel et al. (2010) excluded GINGF1 and GINGF2 (605544) loci. Linkage of the disease to the GINGF3 locus was demonstrated with a maximal 2-point lod score of 3.45 with marker D2S171 and a maximal multipoint lod score of 3.91 with marker D2S390 (theta = 0 for both). Recombination events defined markers D2S220 and D2S352 as boundaries of the linked interval. The authors noted that the 6.65-cM, 8.28-Mb region overlapped the previously defined GINGF3 interval and contained 112 known and hypothetical genes.

Associations Pending Confirmation

By exome sequencing in an 8-year-old Brazilian girl and her 27-year-old mother with severe gingival overgrowth, and her mildly affected 64-year-old maternal grandmother (family A), Machado et al. (2023) identified heterozygosity for a c.361C-T transition in the ALK gene (105590), resulting in an arg121-to-trp (R121W) substitution at a nonconserved residue located between functional domains. The variant was not found in the proband's unaffected father or in an unaffected maternal uncle. Limited clinical information was provided, but microscopically affected gingival tissue was reported as showing hyperplastic parakeratinized stratified squamous epithelium, projecting long, thin, and deep epithelial ridges into the connective tissue, which was composed of increased amounts of collagen fiber bundles extending in all directions, with few fibroblasts present.

Exclusion Studies

In an affected member of 4-generation German family segregating autosomal dominant gingival fibromatosis mapping to chromosome 2p23, Pampel et al. (2010) sequenced 2 candidate genes, ALK and C2ORF18 (SLC35F6; 619667) but did not find any mutations. Whole-genome analysis of copy number variation in the patient showed no aberrations at the GINGF3 locus or elsewhere.