Hereditary gingival fibromatosis with a recessive mode of inheritance. Case reports

Hereditary gingival fibromatosis is characterized by varying degrees of attached gingival hyperplasia and may in rare cases present as a feature of a generalized syndrome. It is usually inherited as an autosomal dominant condition though recessive forms are described. The dental and genetic features of an affected brother and sister with a probably unique autosomal recessive hereditary fibromatosis syndrome are presented.     

Current concepts on gingival fibromatosis‐related syndromes

Gingival fibromatosis is a rare, benign, slowly‐growing fibrous overgrowth of the gingiva, with great genetic and clinical heterogeneity. Gingival fibromatosis/overgrowth can be inherited as an isolated trait (hereditary gingival fibromatosis) and/or as a component of a syndrome, or it can be drug induced. As a clinical manifestation of a syndrome, gingival fibromatosis is usually associated with generalized hypertrichosis, mental retardation, or epilepsy. Gingival fibromatosis and its related syndromes are mainly inherited in an autosomal‐dominant manner, but autosomal‐recessive inheritance has also been reported. Clinical syndromic presentation includes Zimmermann–Laband syndrome, Ramon syndrome, Rutherford syndrome, Cowden syndrome, Cross syndrome, Göhlich–Ratmann syndrome, Avani syndrome, and I‐cell disease. However, a phenotypic overlap has been suggested, as many combinations of their systemic manifestations have been reported. Treatment of choice is usually gingivectomy with gingivoplasty. Before any therapy, clinical practitioners must take into consideration the clinical course of a particular syndrome and every possible functional and esthetic disorder.     

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。     

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（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。     

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.     

遗传性牙龈纤维瘤病家系永生化细胞库的建立及染色体初步分析

目的:建立遗传性牙龈纤维瘤病(HGF)家系外周血永生化淋巴细胞系,以永久保存现有患病家系特有的基因组资源,并探讨将其作为HGF发病机理研究的生物材料的可行性和可靠性.方法:在知情同意原则下,收集5个常染色体显性遗传HGF家系外周血样品,采用新鲜血法和冻存白细胞法,通过EB病毒(EBV)联合环孢霉素A(CyA)转化处理获得外周血永生化淋巴母细胞系,制备并分析细胞系的中期染色体片,检测建系前后的遗传稳定性.结果:成功建立5个HGF家系的永生化B淋巴母细胞系,所有建成细胞系冻存后复苏成功率达100%,转化前后的淋巴母细胞系G带显色核型分析无明显差异.结论:EB病毒转化构建的永生化淋巴细胞系遗传学特性稳定,可永久保存HGF家系资源,为今后在细胞和分子水平上开展HGF发病机理、诊断和治疗提供随时可取的实验材料奠定了基础.     

Hereditary gingival fibromatosis: Report on three families and dermatoglyphic analysis

Some syndromes that include gingival fibromatosis are associated with abnormalities of the hands and feet. The purpose of this work was to establish whether gingival fibromatosis, as an isolated disease, can be connected with disturbances in the development of the digitopalmar structures. In three families with 40 members, fibromatosis manifested in 16 (7 males and 9 females). The disease was transmitted as an autosomal dominant trait. Dermatoglyphics were analyzed in the proband in each family and in their fathers who had fibromatosis. The analysis showed the presence of patterns in IV interdigital areas in all patients. The fathers of 2 probands had double loops in the IV interdigital area, which is very rare in the general population (frequency, 0.6%). The position of the axial triradius was moderately distal (t') in 1, and markedly distal (t") in another, and in 4 it was borderline (tb). Total finger ridge count was increased, which indicated the increased size of the volar embryonal pads. Distorted dermatoglyphic findings may be considered microform abnormalities of the fingers and hands. Since dermatoglyphics are highly genetically controlled and reflect the status of the embryonal pads, the results suggest disharmony in the development of the mesodermal structures of the hands.     

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--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.     

Oral manifestations of juvenile hyaline fibromatosis: a case report

Hyaline fibromatosis is a rare autosomal recessive disease of connective tissue, characterised by an accumulation of hyaline in the skin as well as various organs. The clinical features include: multiple cutaneous nodules, joint contractures, osteolytic lesions and gingival hypertrophy. This paper reports the case of an 11-year-old boy, who was referred to our dental clinic complaining of pain in his mouth. On examination, the patient had gross maxillary and mandibular gingival hyperplasia, which caused severe feeding difficulties. He also had severe dental decay, mal-positioned teeth and limited mouth opening. Treatment was done under general anesthesia to remove excess gingival tissue and extract the severely decayed teeth. Histological examination confirmed the diagnosis of juvenile hyaline fibromatosis. It was concluded that patients with this condition have special dental needs. Early diagnosis of the affected children is important in order to start early preventive dental therapy.     

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.     

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.     

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.     

Gingival hyperplasia in hyaline fibromatosis--a report of two cases

Hyaline fibromatosis is a rare inherited autosomal recessive disorder affecting connective tissue, characterized by an accumulation of hyaline material in the skin and other organs. This paper reports the oral findings of two cases of hyaline fibromatosis referred to our dental clinic due to extensive overgrowth of gingival tissue in the oral cavity that affected their eating and breathing. One patient was diagnosed with infantile systemic hyalinosis while the other was diagnosed with juvenile hyaline fibromatosis. Both cases showed similar clinical and histopathological findings, but one patient exhibited a more severe form of the disease, therefore it is difficult not to consider them as part of the same disorder. Children with such conditions have special dental needs, thus early dental consultation is important to begin caries prevention measures and dental therapy. No known therapy exists for hyaline fibromatosis. Currently, the only treatment is surgical excision of the lesions to improve esthetics and function.     

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.     

Hereditary gingival fibromatosis: review of the literature and a case report.

Hereditary gingival fibromatosis is a proliferative fibrous lesion of the gingival tissue that causes esthetic and functional problems. Both genetically and pharmacologically induced forms of gingival fibromatosis exist. This paper reports a case of severe generalized hereditary gingival fibromatosis in a 5-year-old girl. Treatment consisted of surgical removal of the hyperplastic fibrous tissue in a series of conventional gingivectomies. Postoperative examination 36 months after the final procedure revealed no signs of recurrence.     

Idiopathic gingival fibromatosis: a review of the literature and a case report

Gingival fibromatosis is characterized by localized or generalized fibrous enlargement of the gingivae, mainly around permanent teeth. Gingival fibromatosis affects only the masticatory mucosa and does not extend beyond the muco-gingival junction. This article describes an unusual case of idiopathic gingival fibromatosis with delayed eruption of permanent teeth in an 8 year-old boy. The pathogenic mechanisms that bring about gingival fibromatosis are discussed.     

Heterogeneity in gingival fibromatosis

Five cases of familial and idiopathic gingival fibromatosis were reported. One case exhibited peculiar histologic features, which consisted of active growth of the fibroblastic cells. One hundred and ninety-six cases of gingival fibromatosis, whose clinical and/or pathologic findings were known, were collected from foreign literatures. The heterogeneity in gingival fibromatosis was discussed.