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.     

Hereditary gingival fibromatosis: report of a five-generation family using cellular proliferation analysis

BACKGROUND: Hereditary gingival fibromatosis (HGF) is an uncommon condition characterized by an accumulation of extracellular matrix resulting in a fibrotic enlargement of the gingiva. The goal of this article is to describe one kindred affected with HGF and discuss the diagnosis, treatment, and control of the disease. The pattern of inheritance, histopathologic characteristics, and proliferative potential of epithelial and mesenchymal cells of HGF are also emphasized. METHODS: To characterize the pattern of inheritance and the clinical appearance of gingival overgrowth, 117 family members were examined. The recurrence risk was estimated by the use of a genetic analysis program. Immunohistochemistry against the proliferating cell nuclear antigen (PCNA) and pKi-67 was performed to assess cellular proliferation of normal gingiva (NG) and HGF cells. RESULTS: Examination of the family pedigree demonstrated an autosomal dominant trait of inheritance, and a sibling recurrence risk of 0.085 and an offspring recurrence risk of 0.078, indicating that HGF was a consequence of genetic alteration with low penetrance. Unaffected and affected members transmitted the disease to their offspring. The affected patients showed a generalized but mild gingival overgrowth. Surgical treatment consisted of a combination of gingivectomy and gingivoplasty. Histologic examination showed that the gingival lesions of all patients were quite similar, with increased amounts of collagen fiber bundles in the connective tissue. Immunohistochemistry revealed that the proliferative potential of epithelial cells was significantly higher in the HGF group compared to the NG group, whereas mesenchymal cells from both groups were negative for the proliferative markers. CONCLUSION: Our data demonstrated that, in the studied family, HGF is transmitted by an autosomal dominant pattern with incomplete disease penetrance, and although the gingival enlargement resulted from an excessive accumulation of collagen fibers, HGF is characterized by an increase in the proliferation rate of epithelial cells.     

遗传性牙龈纤维瘤病超微结构及基因定位研究

目的：研究遗传性牙龈纤维瘤病的超微结构特征及染色体基因突变的位点。方法：对1例遗传性牙龈纤维瘤病谱系进行分析;用光镜、透射电镜观察病变龈组织;用微卫星DNA标记诊断遗传病的方法标记基因位点。结果：① 此列遗传性牙龈纤维瘤病是常染色体显性遗传性疾病。②病变牙龈组织有大量的致密纤维结缔组织,其中可见上皮样细胞、平滑肌细胞、成纤维细胞和纤维母细胞等,细胞分化成熟,但排列紊乱。③微卫星定位标记,疾病基因定位于染色体5q13-q22。结论：遗传性牙龈纤维瘤病可能并非仅由单一的纤维细胞成分构成,本例遗传性牙龈纤维瘤病的牙龈组织有类似于“错构瘤”样病理改变;染色体基因定位是确认遗传性牙龈纤维瘤病的遗传学基础。     

遗传性牙龈纤维瘤病（附2例报告）

目的通过探讨遗传性牙龈纤维瘤病（HGF）的临床特点及治疗方法,增进对本病的认识,从而提高诊断治疗水平。方法先证者法收集两个HGF家系全部成员资料,观察不同家系及同一家系不同个体的临床表型和发病特点,绘制系谱图,分析可能的遗传方式。对两名先证者采用手术治疗。结果两家系发病患者均符合非综合征型HGF特征。发病患者不同个体间的表现度不同。两家系均符合常染色体显性遗传特征。经随访,手术患者治疗效果良好。结论 HGF遗传方式以常染色体显性遗传为主,且同一家系的不同受累个体其增生程度轻重不一,极具差异,具有高度遗传异质性。手术是治疗该病的有效的方法。     

Evidence of genetic heterogeneity for hereditary gingival fibromatosis

Hereditary Gingival Fibromatosis (HGF) is the most common genetic form of gingival fibromatosis. The condition is most frequently reported to be transmitted as an autosomal-dominant trait, but autosomal-recessive inheritance has also been reported. The clinical presentation of HGF is variable, both in the distribution (number of teeth involved) and in the degree (severity) of expression. It is unknown if the variable clinical expression of HGF in different families is due to variable expression of a common gene mutation, allelic mutations, or non-allelic mutations. The apparently different modes of Mendelian inheritance of HGF suggest genetic heterogeneity. A gene locus for HGF has been localized to a 37-cM genetic interval on chromosome 2p21-p22 (D2S1352, Zmax = 5.10, theta = 0.00) flanked by D2S1788 and D2S441. To evaluate the generality of this linkage, we tested linkage with 9 markers from this candidate region in another large family, segregating for an autosomal-dominant form of generalized HGF, and found no support for linkage with any of these markers. Furthermore, statistical tests of this apparent heterogeneity were highly significant. Analysis of these data provides direct evidence that at least two genetically distinct loci are responsible for autosomal-dominant hereditary gingival fibromatosis.     

常染色体显性遗传性牙龈纤维瘤病的临床和遗传学特点分析

目的：探讨遗传性牙龈纤维瘤病(HGF)的临床表型和遗传学特点。方法：先证者法收集5个HGF家系并进行问卷和口腔检查，观察不同家系及同一家系不同个体的临床表型和发病特点，分析可能的遗传方式，绘制系谱图。结果：所有家系符合常染色体显性非综合征型HGF特征，发病年龄在牙齿萌出期，患者均有典型的牙龈增生，但不同个体其增生范围和严重程度有明显差异。龈切术可极大地恢复口腔功能和颜面外形，但部分病例在术后有复发倾向。结论：收集的5个家系均为非综合征型常染色体显性遗传HGF，且疾病外显率高，表现度变异大。     

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.     

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.     

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.     

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.     

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.     

Management of idiopathic gingival fibromatosis: report of a case and literature review

Gingival hyperplasia is a rare condition and is of importance for cosmetic and mechanical reasons. Idiopathic gingival fibromatosis, a benign, slow-growing proliferation of the gingival tissues, is genetically heterogeneous. The enlargement is most intense during the eruption of the primary and permanent teeth, and minimal or nondetectable growth is observed in adults. The genetic aspect, clinical feature, histopathology, immunohistochemistry, and treatment aspects are reviewed. The purpose of this paper was to report a case of idiopathic gingival fibromatosis in a 13-year-old female who had a negative family history for a similar type of gingival enlargement. The diagnosis was established through history, clinical examination, and histopathology using both hematoxylin and eosin and Van Giesen stain (a special stain for collagen). Surgical treatment, which included both gingivectomy and gingivoplasty, was carried out. The case showed remarkable esthetic and functional improvement. The patient returned after a year and showed no recurrence.     

遗传性牙龈纤维瘤病的临床特点及致病基因检测

目的检测分析遗传性牙龈纤维瘤病（hereditary gingval fibromatosis，HGF）患者的临床特点及致病基因。方法收集HGF家系1个，采用先证者查证法对其家庭成员进行全身健康状况及口腔专科检查。收集患者及健康牙龈组织作HE和Masson染色进行组织学检查。抽取患者及正常家族成员的静脉血，提取基因组DNA，PCR扩增SOSI基因并测序，同源性比较分析（basiclocalalignmentsearchtool，BLAST）。结果患者牙龈组织HE染色显示典型牙龈纤维瘤病的组织病理表现，Masson染色显示胶原纤维较正常人丰富。SOSl基因突变检测未发现突变点。结论HGF具有高度遗传异质性，目前被成功克隆与鉴定的致病基因SOSl不是唯一的致病基因。     

A case of Zimmermann-Laband syndrome with supernumerary teeth

BACKGROUND: Zimmermann-Laband syndrome is a rare autosomal dominant disorder that is characterized by gingival fibromatosis, ear, nose, bone, and nail defects, and hepatosplenomegaly. METHODS: This case report describes the clinical presentation and periodontal findings in a 13-year-old female patient with previously undiagnosed Zimmermann-Laband syndrome. RESULTS: Clinical and radiographic findings and genetic counseling confirmed the diagnosis of Zimmermann-Laband syndrome. The most striking oral findings were the presence of gingival enlargement involving both the maxillary and mandibular arches, anterior open bite, non-erupted teeth, and two supernumerary teeth. Periodontal treatment consisted of gingivectomy in four quadrants. Histopathologic evaluation of excised tissue supported the diagnosis of gingival fibromatosis. The patient was referred for appropriate orthodontic treatment and genetic counseling, and has been closely followed for the earliest signs of hepatosplenomegaly. CONCLUSIONS: Dental practitioners should be alert for developmental abnormalities that may occur in patients with gingival fibromatosis as this may indicate the presence of a rare disorder like Zimmermann-Laband syndrome. A comprehensive medical history and physical systemic evaluation are essential for correct diagnosis and treatment of these cases.     

遗传性牙龈纤维瘤病一家族三代1例

遗传性牙龈纤维瘤病是一种罕见的家族遗传性疾病,以牙龈组织缓慢、渐进性增生为主要特征。本文对1例遗传性牙龈纤维瘤病家族进行报道及文献回顾。     

遗传性牙龈纤维瘤病致病基因的排除性定位

目的:对我国现有的2例家族遗传性牙龈纤维瘤病进行国外已证实的已知基因突变位点--SOS1基因21号外显子的排除性定位。方法:采用PCR—SSCP-银染的方法对2例遗传性牙龈纤维瘤病家系的致病基因进行排除性定位。结果:两家系中均未发现SOS1基因的缺失。5％的聚丙烯酰胺凝胶电泳结果表明两家系中无典型临床表现者电泳条带无明显的异常，而有典型临床表现者发现家系1有4例患者的电泳条带有明显位移，条带离加样孔较正常对照近，家系2有2例患者的电泳条带有明显位移，但条带离加样孔较正常对照远。结论：两家系无典型临床表现者无SOS1基因的突变，有典型临床表现者存在有SOS1基因21号外显子的突变，但是，是否所有有典型临床症状的患者其基因突变的位置及涉及的碱基片段都相同还需进一步研究。     

Hereditary gingival fibromatosis associated with generalized aggressive periodontitis: a case report

BACKGROUND: Hereditary gingival fibromatosis is a rare, genetically inherited overgrowth condition that is clinically characterized by a benign fibrous enlargement of maxillary and mandibular keratinized gingiva. A syndromic association between gingival fibromatosis and a wide variety of other genetically inherited disorders has been described. However, its coexistence with aggressive periodontitis has not been reported. METHODS: A 24-year-old African-American female, patient (proband X, [Px]) reported with a chief complaint of tooth mobility and gingival enlargement. Clinical examination revealed moderate to severe gingival overgrowth on both mandible and maxilla. Generalized attachment loss and mobility of the teeth were observed. Radiographic evaluation demonstrated severe alveolar bone loss. The patient was diagnosed with gingival fibromatosis and aggressive periodontitis based on the clinical and radiographic findings. Her brother (Bx) and her mother (Mx) were evaluated and diagnosed with gingival fibromatosis suggesting that this is a dominant trait in the family and gingival fibromatosis might be of hereditary origin. In addition, the brother also exhibited localized aggressive periodontitis. Medical history revealed no other systemic or local contributory factors associated with the oral findings in any of the subjects. RESULTS: Surgical therapy included internal bevel gingivectomy combined with open flap debridement procedures for Px and Bx. Only internal bevel gingivectomy was performed for Mx since there was mild bone resorption and no intrabony defects. At the time of surgery, gingival biopsies were obtained and fixed in 4% paraformaldehyde. Multiple serial sections were stained with hematoxylin and eosin. Microscopic evaluation of the gingival specimens revealed large parallel collagen bundles associated with scarce fibroblasts in the connective tissue. The collagen bundles reached into the subepithelial connective tissue where elongated rete-pegs were also observed. Following the completion of the treatment, no signs of recurrence or bone resorption were observed over 2-year follow-up. CONCLUSIONS: This is the first report of hereditary gingival fibromatosis associated with aggressive periodontitis. Combined treatment comprising removal of fibrotic gingival tissue and traditional flap surgery for the elimination of intrabony defects represents a unique treatment approach in periodontal therapy. Two-year follow-up revealed that both the gingival overgrowth and the destructive lesions were successfully treated.     

Further evidence of genetic heterogeneity segregating with hereditary gingival fibromatosis

Aim: To clinically characterize and map the disease-associated locus in a five-generation Chinese family with autosomal dominant early-onset hereditary gingival fibromatosis (HGF).
Material and Methods: A complete oral examination was conducted. Genomic DNA samples were obtained from 14 individuals. Short tandem repeats markers, which encompass four previously known loci related to HGF, were genotyped. Two-point log of the odds (LOD) scores were calculated using MLINK program of the LINKAGE software, multipoint and non-parametric linkage (NPL) analysis were performed using the GENEHUNTER software.
Results: Clinical evaluation and histological examination of this family suggested typical features of HGF. The onset age was early in the generations, ranging between 1 and 2 years. None of the tested markers showed cosegregation among affected individuals. Genotyping data from four putative regions yielded significant negative two-point LOD scores (<−2.0) at θ=0. The maximum multipoint LOD scores and NPL analysis revealed exclusion of these loci as well.
Conclusions: Exclusion of linkage in this family to any of the known HGF loci proved the existence of a novel locus for autosomal dominant HGF and showed that this rare disorder is far more heterogeneous than previously expected.     

遗传性牙龈纤维瘤病1例

遗传性牙龈纤维瘤病是一种罕见的以牙龈组织缓慢、渐进性增生为主要特征的良性病变。本文对1例遗传性牙龈纤维瘤病的临床检查、病史进行报道,并结合文献对其进行讨论。