Differential proliferation of fibroblasts cultured from hereditary gingival fibromatosis and normal gingiva

Hereditary gingival fibromatosis (HGF) is an oral condition characterized by the enlargement of the gingiva of both the maxilla and mandible. To study the cell proliferation index of fibroblasts from HGF and normal gingiva (NG), cell cultures from 4 members of the same family with HGF and from 4 healthy patients were established. Our results obtained from 6 different cell proliferation assays clearly showed that the cell proliferation rate was significantly higher in fibroblasts from HGF than from normal gingiva. HGF and control fibroblasts in subconfluent culture densities were typically spindle, but in saturation density HGF cells were shorter than control cells. These data suggest that the higher proliferative index of HGF fibroblasts possibly has a role in the pathogenesis of gingival outgrowth in HGF patients.     

Proliferation of fibroblasts cultured from normal gingiva and hereditary gingival fibromatosis is dependent on fatty acid synthase activity

BACKGROUND: Fatty acid synthase (FAS) is the enzyme that synthesizes palmitate from malonyl-CoA and acetyl-CoA. Recent studies have shown that FAS is overexpressed in human cancers and that its activity is necessary for cell proliferation. Hereditary gingival fibromatosis (HGF) is a genetic disease manifested as a progressive enlargement of the gingiva. The pathogenesis of this condition is not understood; however, a proliferative advantage of HGF fibroblasts in comparison with cells from normal gingiva (NG) has been described. The aim of this study was to investigate the role of FAS in NG and HGF fibroblast proliferation. METHODS: NG and HGF fibroblasts had their proliferative potential assessed by automated cell counting and immunocytochemistry against Ki-67 or proliferating cell nuclear antigen (PCNA). The production of FAS, androgen receptor (AR), and ErbB2 was analyzed by Western blot and the pattern of FAS expression studied by immunocytochemistry. FAS activity was blocked by the specific inhibitor cerulenin. RESULTS: Higher proliferation rates were found in fibroblasts isolated from HGF than from NG. HGF fibroblasts with greater proliferative potential produced more FAS and AR than the cell lines with lower growth rates, and all studied cell lines produced similar amounts of the ErbB2 protein. In addition, the FAS inhibitor cerulenin was able to significantly reduce the proliferation of both NG and HGF cells. CONCLUSIONS: These results show that FAS is expressed by gingival fibroblasts and that highly proliferative HGF cells produced more FAS and AR than the other fibroblast cell lines. Moreover, FAS inhibition significantly reduced both NG and HGF fibroblast growth, suggesting a role for the androgen-driven fatty acid biosynthesis in their proliferation.     

Hereditary gingival fibromatosis: Clinical and ultrastructural features of a new family

Objective: This article describes the diagnosis, clinical and microscopic (histopathology and ultrastructural) features and treatment of a new family with hereditary gingival fibromatosis (HGF) and highlights the importance of this genetic condition. Study Design: To characterize the pattern of inheritance and the clinical features, members of a new family with HGF were examined. The pedigree was reliably constructed including the four latest generations of family. Hematoxylin and eosin staining and ultrastructural analysis were performed with the gingival tissue. Results: Examination of the family pedigree revealed that the patient III-2 represent the index patient of this family (initial patient with a mutation), which was transmitted to her daughter through an autosomal dominant mode of inheritance. The affected patients showed a generalized gingival overgrowth. The patient was treated with surgical procedures of gingivectomy and gingivoplasty. The diagnosis was confirmed by histopathology examination that showed a well-structured epithelium with elongated and thin papillae inserted in fibrous connective tissue with increased amount of collagen. The ultrastructural aspects of the tissue show collagen fibrils exhibiting their typically repeating banding pattern with some fibrils displaying loops at their end. Moreover, it was possible to seen in some regions fibrillar component presenting tortuous aspects and loss of the alignment among them. Conclusions: This HGF frequently resulted in both esthetic and functional problems. The genetic pattern of this Brazilian family suggested a new mutation, which was later transmitted by an autosomal dominant trait. Key words:Gingival fibromatosis, genetic disease, pedigree, ultrastructure.     

Hereditary gingival fibromatosis--a review

Hereditary gingival fibromatosis (HGF) is a rare gingival lesion that presents as localized or generalized enlargement of the attached gingiva. The gingiva is characterized as pink, firm, and very fibrous, with little tendency to bleed. HGF can present as an isolated feature or as part of a syndrome. Recent findings report a defect in the Son of sevenless-1 gene on chromosome 2p21-p22 (HGF1) as a possible cause of this clinical presentation. HGF inheritance is transmitted through both autosomal dominant and recessive modes. While clinicians disagree on the modalities and timing of treatment for HGF, the clinical condition generally requires repeated resective periodontal surgical procedures over the patient's lifetime. This article reviews differential diagnosis, etiology, complications, and treatment of HGF.     

Gingival overgrowth in children: epidemiology, pathogenesis, and complications. A literature review

Gingival overgrowth is the enlargement of the attached gingiva due to an increased number of cells. The most prevalent types of gingival overgrowth in children are drug-induced gingival overgrowth, hereditary gingival fibromatosis (HGF), and neurofibromatosis I (von Recklinghausen disease). Gingival overgrowth induced by drugs such as phenytoin, nifedipine, and cyclosporin develops due to an increase in the connective tissue extracellular matrix. According to epidemiologic studies, it is more prevalent in male children and adolescents. There is an additive effect of those drugs on the degree of gingival overgrowth. Genetic heterogeneity seems to play an important role in the development of the disease. Functional difficulties, disfigurement, increased caries, and delayed eruption of permanent teeth are the main complications of drug-induced gingival overgrowth. HGF is the most common syndromic gingival enlargement in children. This autosomal dominant disease usually appears at the time of eruption of permanent dentition. Histologically, it is characterized by highly collagenized connective tissue. The most important complications are drifting of teeth, prolonged retention of primary dentition, diastemata, and poor plaque control. Neurofibromatosis I is an autosomal dominant disease more common in mentally handicapped individuals. Gingival overgrowth is caused by the formation of plexiform neurofibromas in the connective tissue of the gingiva. Plexiform neurofibromas are pathognomonic of the disease and consist of hypertrophic nerves arranged as lobules in the connective tissue. Complications of the disease are multiple and severe due to neurofibromas and their occasional malignant transformation.     

Hereditary fibrous hyperplasia of the gingiva with varying penetrance and expressivity

abstract — A kindred affected with hereditary fibrous hyperplasia of the gingiva with varying penetrance and expressivity is described. Most of the affected members were short in stature. The pedigree strongly suggested an autosomal dominant mode of inheritance. The penetrance of the trait varied, and three unaffected persons had transmitted the disease to their offspring. There were two modes of expression. The mild form showed only bilateral rugose thickening of the palate, whereas the severe form showed gingival hyperplasia in addition to changes in the palatal mucosa. The changes were already present at birth. Histological examination showed large amounts of alcian blue-positive extracellular material in the subepithelial connective tissue of the hyperplastic mucosa. Loose collagen-poor connective tissue with alcian blue-positive extracellular material and dense collagen-rich connective tissue in the rugose projections of the palatal mucosa were often segregated.     

Hereditary fibrous hyperplasia of the gingiva with varying penetrance and expressivity.

A kindred affected with hereditary fibrous hyperplasia of the gingiva with varying penetrance and expressivity is described. Most of the affected members were short in stature. The pedigree strongly suggested an autosomal dominant mode of inheritance. The penetrance of the trait varied, and three unaffected persons had transmitted the disease to their offspring. There were two modes of expression. The mild form showed only bilateral rugose thickening of the palate, whereas the severe form showed gingival hyperplasia in addition to changes in the palatal mucosa. The changes were already present at birth. Histological examination showed large amounts of alcian blue-positive extracellular material in the subepithelial connective tissue of the hyperplastic mucosa. Loose collagen-poor connective tissue with alcian blue-positive extracellular material and dense collagen-rich connective tissue in the rugose projections of the palatal mucosa were often segregated.     

Histomorphometric characteristics and expression of epidermal growth factor and its receptor by epithelial cells of normal gingiva and hereditary gingival fibromatosis

OBJECTIVE: The objective of this study was to examine the histomorphometric features and evaluate the expression of epidermal growth factor (EGF) and transmembranic receptor (EGFr) and the proliferative potential of epithelial cells from normal and hereditary gingival fibromatosis (HGF) gingival tissues. BACKGROUND: EGF is a multifunctional cytokine with a variety of biological effects including stimulation of cell proliferation by binding to its specific EGFr. METHODS: Immunohistochemistry was performed to measure EGF and EGFr expression and the epithelial cell proliferation was determined by measuring proliferating cell nuclear antigen (PCNA). RESULTS: Histomorphometric evaluation indicated that in HGF the mean height of the epithelial papillae was higher compared to the normal gingiva (NG), whereas mean epithelial area and number of epithelial papillae were quite similar in both groups. The EGF and EGFr positive cells were observed in the basal, spinous and granular cell layers of both normal and HGF tissues, with a gradual reduction from the basal layer. Although the expressions of EGF and EGFr in the control group were significantly higher than those from HGF, in HGF the epithelial papilla tips showed increased number of proliferating cells and elevated expression of EGF and EGFr. There was a correlation between the proliferative potential of epithelial cells and the expression of EGF or EGFr only in the epithelial papilla tips of HGF gingiva. CONCLUSION: Our data suggest that EGF and EGFr in the oral epithelium of HGF gingiva may stimulate epithelial cell proliferation, with the resultant apical migration of the oral epithelium and formation of the slender deep epithelial papillae; however, without hyperplastic alterations.     

Hereditary gingival fibromatosis: a systematic review

Generalized gingival enlargement can be caused by a variety of etiological factors. It can be inherited (hereditary gingival fibromatosis [HGF]); associated with other diseases characterizing a syndrome; or induced as a side effect of systemic drugs, such as phenytoin, cyclosporin, or nifedipine. HGF, previously known as elephantiasis gingivae, hereditary gingival hyperplasia, and hypertrophic gingiva, is a genetic disorder characterized by a progressive enlargement of the gingiva. This review will focus on diagnosis, treatment, and control of HGF. The pattern of inheritance, the histopathologic characteristics, and the known biologic and genetic features associated with HGF are also emphasized.     

Ultrastructural aspects of connective tissue in hereditary gingival fibromatosis.

OBJECTIVE: The purpose of this study was to analyze the ultrastructure of gingival connective tissue from patients in one family affected by hereditary gingival fibromatosis (HGF). STUDY DESIGN: Electron microscopic examination was performed with gingival tissue from 10 patients from a Brazilian family with 132 members. Fifty of 96 persons at risk for this disorder were affected, which is consistent with an autosomal dominant pattern of inheritance. RESULTS: The extracellular matrix showed flocculent material and collagen fibrils with structural abnormalities and variation in diameter. Increased numbers of oxytalan fibers were identified; however, elastic fibers were rare in the analyzed areas. CONCLUSIONS: The structural alterations found in HGF appear similar to those described in certain other heritable collagen disorders, suggesting that HGF should be included in the group of hereditary diseases in which connective tissue alterations have a distinct pattern, in contrast to reactive fibrotic gingival enlargements with no genetic component.     

Nonsyndromic hereditary gingival fibromatosis: Characterization of a family and review of genetic etiology

Our aim is to describe a family with a nonsyndromic form of hereditary gingival fibromatosis (HGF) and discuss genetic characteristics of this rare disease by reviewing reported cases. A mother and three descendants were diagnosed with HGF. There was marked variable expressivity: from severe generalized gingival overgrowth in a 16-year-old boy (the proband) to minimal manifestations in the mother. The proband was submitted to gingivectomy and gingivoplasty. In younger siblings, the disease remained stable for 5 years, suggesting that clinical surveillance is a good option. The diagnosis was supported by histopathological examination. Analysis of this family and literature-reported cases supports that HGF most frequently shows an autosomal dominant inheritance with high penetrance and variable expressivity. Neomutations and gonadal mosaicism do not seem to be a rare event. Although five loci have been mapped by linkage analysis, only two genes, SOS1 and REST, were identified in four families.     

Case reports of a new syndrome associating gingival fibromatosis and dental abnormalities in a consanguineous family

BACKGROUND: Gingival fibromatosis (GF) is characterized by fibrotic enlargement of the gingiva that can be inherited as an isolated trait (named hereditary gingival fibromatosis) or as a component of a syndrome. This article reports one kindred affected by a syndrome characterized by GF associated with dental abnormalities (DA) including generalized thin hypoplastic amelogenesis imperfecta (AI). METHODS: To characterize the pattern of inheritance and the clinical features, 70 family members were examined. Hematoxylin and eosin staining, immunohistochemistry, and scanning electronic microscopy (SEM) were performed to identify the alterations on gingiva, teeth, and dental follicles. RESULTS: Examination of the family pedigree demonstrated multiple consanguineous first-cousin marriages and an autosomal recessive trait of inheritance. Four members demonstrated mild GF in association with DA, including generalized thin hypoplastic AI, intrapulpal calcifications, delay of tooth eruption, and pericoronal radiolucencies involving unerupted teeth. One of those four patients also had mental retardation (MR). MR as an isolated feature was observed in six members, whereas isolated GF was found in one individual. A combination of gingivectomy and gingivoplasty followed by regular dental procedures were performed in these patients. Histologic examination of the gingival enlargement revealed a dense connective tissue containing myofibroblasts, islands of odontogenic epithelium, and calcified psammomatous deposits, which resembled cementicle-like structures by SEM. Pericoronal lesions also showed calcified psammomatous deposits in association with islands of odontogenic epithelium. Enamel ultrastructure analysis revealed normal surface alternating with irregular and porous areas. CONCLUSION: To the best of our knowledge, these cases represent a new syndrome within the spectrum of those including GF.     

Hereditary gingival fibromatosis and expression of Ki-67 antigen: a case report

BACKGROUND: Hereditary gingival fibromatosis (HGF) is a fibrotic enlargement of the gingiva. The mechanism that leads to the accumulation of abnormal amounts of gingival tissue in HGF is still unknown. The aim of this report was to present the clinical and histopathologic characteristics of a patient with gingival fibromatosis and to evaluate the proliferation of HGF fibroblasts. METHODS: We examined the proliferation rate of fibroblasts in this case by using Ki-67 immunohistochemical staining and compared the rate to fibroblasts of non-fibromatosis gingival tissues from 5 healthy patients serving as controls. RESULTS: There were no Ki-67-positive cells in the lesional tissue, and the control gingiva revealed no immunostaining. The number of Ki-67 antigen-positive epithelial cell nuclei was observed to be low in the basal cell layers of hyperplastic gingival epithelia, similar to the control group. CONCLUSIONS: In the present case, there was no increase in the proliferation rate of lesional fibroblasts observed by Ki-67 immunohistochemical staining as a proliferation marker; only the epithelium was stained. It seems likely that the underlying mechanism of HGF may be an increase in the biosynthesis of collagen and glycosaminoglycans rather than cell proliferation.     

Diagnosis and treatment of a hereditary gingival fibromatosis case

Hereditary gingival fibromatosis (HGF) is a rare condition characterised by severe gingival hyperplasia, which could result in serious aesthetic and emotional problems and functional impairment. Here the present authors report a case of a 28-year-old female patient with generalised severe gingival enlargement covering almost all of the teeth and diagnosed as HGF. Her family history was of significance, since her father and 3-year-old daughter suffered from the same symptoms. Many studies have agreed that surgical removal should be used in the treatment of HGF, and gingivectomy is the most common method. This study tried both external and internal bevel incisions. The results suggest that the former is better for shaping gingival contour, if the attached gingiva is adequate. Correct physiological contour of the marginal gingiva, good oral hygiene and periodic recall can decrease recurrence risk. Post-surgical follow-up after 26 months demonstrated no recurrence and the patient was satisfied with her appearance.     

环孢菌素A导致牙龈过度生长机理的研究近况

牙龈过度生长是环孢菌素A的重要的不良反应之一,其病理特征是牙龈组织上皮层的增厚和胞外基质的蓄积,但其确切的病理机制仍不清楚。该文就环孢菌素A导致的牙龈过度生长的病因及病理机制的研究现状做一综述。     

Treatment of gingival overgrowth in a child with Bardet-Biedl syndrome

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare, heterogeneous, autosomal recessive condition, primarily characterized by polydactyly, obesity, mental retardation, hypogonadism, retinopathy, and renal failure. Dental anomalies, regarded as secondary manifestations, include hypodontia, microdontia, short roots, and deep palate. Few reports in the literature have described the oral manifestations of BBS. This article reports a case of BBS in a boy who presented some typical oral manifestations added to a generalized gingival overgrowth, an anomaly that had not been reported previously in patients with this syndrome. METHODS: A 12-year-old white male presented with a diagnosis of BBS and chief complaint of gingival enlargement in the anterior segment of both arcades. The treatment plan included surgical removal of the overgrown gingiva followed by orthodontic therapy. The excised tissues were submitted to histologic analysis. RESULTS: There was no sign of recurrence 1 year after gingivectomy. Histopathology revealed a dense connective tissue with a mild inflammatory infiltrate, irregularly arranged fiber bundles, and epithelial acanthosis, which is characteristic of gingival overgrowth. CONCLUSIONS: The gingival overgrowth was treated successfully by gingivectomy. The periodontal surgery minimized the functional, social, and emotional consequences of the oral manifestation associated with the syndrome.