# Non-Plaque Induced Diffuse Gingival Overgrowth: An Overview
## 5 Genetically Determined Gingival Enlargement  
_Hereditary Gingival Fibromatosisosis (HGF)_  
Hereditary gingival fibromatosisis (HGF), also known as \"gingival elephantiasis\", hereditary gingival hyperplasia or gingival hypertrophy is a rare benign disease characterized by a progressive increase in gingival tissue [3,37,38]. The gingival enlargement is due to an increase in submucosal connective tissue and occurs in different forms and severities [3,39,30]. It rarely appears at birth, more often with the eruption of deciduous or permanent teeth, and then worsen during adolescence and into adulthood [2,30,40,41,42]. Men and women are equally affected with an incidence of one case in 175,000 people [2, 3, 43,31,32,34,35,43]. Clinically, the lesions occur with a slow but progressive gingival overgrowth that can be localized or diffuse, with a preference for the tuber area, and the vestibular area of the molars [2, 3,11,32]. However, involvement of the anterior jaw has been reported too [3]. The lesions are particularly thick and fibrous, very hard in consistency and in some cases extended beyond the surface of the teeth [2, 11,31,32,44]. The inflammatory alterations tend to be negligible except for localized gingivitis and secondary to the accumulation of plaque [30,31,37,45]. Therefore, most of the lesions are neither hemorrhagic nor erythematous [3,30,31,35,37,38]. Tissues are light pink and nodular in appearance, with some documented exceptions [3,30,31,32,35,37,38,30]. The gum's enlargement causes both aesthetic and functional problems [3, 30,31,34,35,37,30]. The most common effects are diastema, malposition of the teeth, prolonged retention of teeth, delays in eruption, cross and open bite, prominent lips, and a tendency to keep the mouth open at rest [3, 30,31,34,37,30]. Although HGF does not directly affect the alveolar bone, gingival growth can cause the formation and accumulation of plaque, leading to a greater risk of developing periodontal disease, bone resorption and halitosis [3, 30,34,37,46]. Traumatic chewing injuries, due to the bulk of enlarged gingiva, are also frequent [11]. A mutation in the Son of Sevenless-1 (SOS-1) gene has been identified on chromosome two as an etiological agent [4, 11,38,47,48]. A deletion mutation introduces a premature stop codon into the encoding of the SOS-1 sequence. This mutation creates a modified SOS-1 protein that is more active than wild type SOS-1. SOS-1 is functionally important in signal transduction, in the cellular growth, differentiation and division control [40]. SOS-1 is expressed by many cells in different tissues, but it is particularly highly expressed in gingival tissue [40]. Studies on the gums of individuals affected by HGF showed an increase in the amount of collagen, number of fibroblasts and tissue proliferation rates. They also showed that there are modifications in the signal transduction of fibroblasts associated with the SOS-1 mutation in patients with HGF [40]. Mutated SOS-1 can move towards the plasma membrane without stimulation of the growth factor, leading to prolonged activation of RAS/MAPK signaling [40]. The consequent rise of the amplitude and duration of ERK signaling and the enhancement of phosphorylation of some proteins in the nucleus are associated with the upregulation of cell cycle regulators and the transcription factors that promote cell cycle progression from G to S phase [40]. However, several studies indicate genetic heterogeneity as the cause of HGF. In fact, while the SOS-1 gene mutation is etiological for some cases of gingival fibromatosisis, other cases are caused by other types of genetic alterations such as chromosomal abnormalities [40]. HGF can be an isolated form or be part of a more complex multiorgan syndromic picture [2; 3; 41]. The syndromic traits accompanying HGF are usually autosomal recessive, while isolated HGF generally have autosomal dominant modes of inheritance [2; 3; 32; 35].