Hereditary Gingival Fibromatosis A Review

Abstract
Samuel DeAngelo, DDS, MS
Private Practice Apex, North Carolina

James Murphy, DDS. MS

Clinical Assistant Professor Section ot Periodontology

Lewis Claman, DDS, MS

Associate Professor Director of Predoctoral Periodontoiogy Program

Hereditary gingival fibromatosis (HGF) is a rare gingival lesion that presents as localized or generalized enlargement of the aitached 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 seveniess-i gene on chromosome 2p21-p22 (HGFl) as a possible cause of this clinical presentation. HGF inheritance is transmitted ihrough both autosomal dominant and recessive modes. While clinicians disagree on the modalities and timing of treatment for HGF, the clinical condition generally requires repeated reseciive periodontal surgical procedures over the patient's lifetime. This article reviews differential diagnosis, eiiology, complications, and treatment of HGE

John Kalmar, DMD, PhD

Protessof Graduate Program Director of the Oral and Maxillofacial Pathology

Learning Objectives
After reading this article, the reader should be able to:

Binnaz Leblebicioglu, DDS, MS, PhD

Assistant Professor Section of Periodontology The Ohio State University, College of Dentistry Columbus, Ohio

explain lhe ehnical presentation of hereditary gingival fibromatosis (HGF) and major differences between HGF and other types of gingival enlargements.

describe different treatment modalities for various age groups. discuss postoperative care and treatment outcomes for long-term success. of pregnancy-associated bortnonal changes, various medications causing changes in extracellular matrix physiology, or genetic disorders.'^ Independent from inflammator\' etiological factors, periodontal tumors and cysts also may present as localized gingival enlargements.' Tbe tissue enlargement may be localized or generalized, confined to the marginal gingiva or to the papillary tissue, and involve botb the tnarginal and attached gingivae.' Tbe degree of enlargement can be categorized as follows": Grade 0: No gingiva! enlargement. Grade 1: Enlargement confined to interdental papilla. Grade 2: Enlargement invoKing papilla and marginal gingivae. Grade 3: Enlargement covering three quarters or more of the crown. Hereditary gingival fibromatosis (HGF), also referred to as idiopatbic

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he diagnosis and treatment of gingival enlargement has raised many questions among clinicians and researchers for many years. Recently, the term "enlargement" was recommended in lieu of hyperplasia or overgrowth to define a broader clinical finding and to differentiate specific pathologic lesions from common signs of inflammatory changes ai tissue level (eg, edema and hypervascularization).' Gingival enlargement, defined as an overgrowth or increase in the size of the gingiva, is a common feature in gingival diseases, and may be caused by a variety of factors.^ Inflammation, medications, systemic diseases, and neoplastic tissue changes all can be classified as tbe etiologic features. Based on the American Academy of Periodontology 1999 Classification of Periodonlal Diseases and Conditions, gingival enlargement can occur because

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Figure 1iiuiwl t.:u:>^i.\^Ui^'.. ^; J >.jau vv^lh l-ieredilaiy yiriyivul libmmulosis (HGF]. Fiyuies l A , i B, and I C pieseni buccal views fiom an HGF case before tieoiment. Figures I D . IE, and 1F pieseni ocdusal vievi;^ of the same case. Nole thai gmgival enbrgemenr affects botfi free and oitoched gitiglvol tissue, The enlargemeni was severe and the patient was biting on her gingiwa.

gingival hyperplasia, is one type of gingival enlargement. It is a rare disease of the gingiva characterized by firm, enlarged gingiva! tissue that covers most of lhe anatomic tooth crowns/ The onset of the disease is common during the eruption of the permanent incisors,' but several reports also have mentioned involvement of the deciduous dentition.**" It is classified as a non-plaque-induced gingival lesion caused by various genetic disorders.' HGF may occur as an isolated disorder, but it also has been reported lo be associated with various syndromes and oiber abnormalities.'' Case reports liave associated HGF with Zimmerman-La band syndrome (ear, nose, bone, and nail defects), Murray-Puretic-Drescher sj'ndrome (juvenile hyaline fibromatosis), Cowden syndrome (multiple hamarioma). Cross syndrome (microphthalinia, mental retardation, athetosis, hypopigmentation), Rutherford syndrome (comeal dystrophy), and Prune belly syn-

drome (absence of 1 or more layers of abdominal muscles).'"'' In addition, there may be a relationship hetween a deficiency in growth-related hormones and gingival enlargement." Features found in association with HGF include mental retardation, epilepsy, progressive sensorineural hearing loss, and abnormalities of the toes and fingers, but bypertricbosis is tbe ancillary abnormality most commonly seen." Tliis review focuses on the clinical differentiation of HGF from otber types of gingival enlargements and on known regulatory meclianisms that may be important in the treatment outcome and control of the disease ot:cuiTem:e.

Clinical Presentation
HGF features an asymptomatic, nonhemorrbagic, nonexudative, and proliferative lesion of the gingival tissue." Gingival tissue is generally pink and stippled, but it

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The symmetric form is more common, and the maxilla and mandible are equally affected (Figures 1 and 2}.'"' Tbe localized form is generally seen in the maxillary tuberosity and molar area, predominately on the palatal aspect.'" HCiF gingival enlargement can cover the coronal portion of a tooth, up to its occlusal surface. Tbis overgrowth also may extend to the palaic. which alters its contour. The resultant effect may include speech difficulty and painful mastication as food deflects onto the enlarged tissue. In severe cases, the jaws appear bulbous,'"" Other common side effects are diastema, malocclusion, and prolonged retention of primary teeth." Perhaps most importantly, (he enlarged tissue creates retention for plaque. Although Emerson reported no significant association between oral bygiene (the amount of calculus present) and the degree of enlargement, the inability to remove plaque from the teetb is well known to contribute to dental caries, the development of gingivitis, and periodontitis in individuals affected witb

Etiology and Histopathology of HGF Evidence for Hereditary Jnvohement

HGF is inherited in both autosomal dominant and recessive modes. It is reported to have a phcnotype frequency of 1:175,000 and a gene frequency of L:350,000. assuming that the condition to be inherited is tbe result of an autosomal dominant gene.'" In a study by Rusbton, 54 of tbe 109 total cases were tbe offspring of marriages of affected and unaffected persons.'" Weski documented 5 generations and 9 marriages between affected and unaffected subjects and reported that of the 38 offspring, 9 women and 5 men were affected,"' Barros and colleagues also reported that 50 of 96 alTected persons were consistent witb an autosontal dominant mode of inheritance with complete penetrance,-' Several reports of recessive tratismission of the disorder also exist in the literature.'""-'*
Figure 2Initiat prHsenlalion of the second cose wilti HGF, Figures 2A, 2B, ond 2C piesenJ fauccol views from a second cose with HGF This case was fhe siiter of the first case presenled in Figure 1, ond exominolion of the family members revealed simibr clinical findings in 2 of the 7 siblings,

may become red with superimposed mflammation because of plaque accumulation. The lissue is libroiic and displays a nodular or minutely pebbled surface.'^ Often an exaggerated stippling ij; present."' The tissue can become so firm and fibrous ihat it feels like hone on palpation,'' This is in contrast to many other presentations of gingival enlargement (eg_ those that are drug induced) where the tissue is somewhat moveable,"" Both free and attached gingival tissue are affected, but tbe enlargement does not extend beyond the mucogingival junction (Figures 1 and 2),'' Two different tyjies of HGF have heen cla.ssined hased on HGF clinical presentations. Tbe nodular form is characterized hy multiple focal enlargements in ihe denial papillae, and the s)Tnmetric forni results in a more unifonn enlargement of the gingival tissue. These clinical modalities can occur in conjunction witb eacb other or as isolated lesions.

Recently, researchers have identified 3 genetically separate loci,''" These loci are on chromosome 2p21p22 (GINGF), 2p22.3-23,3 {GINGF3), and 5ql3-q22 (G1NGF2). Hart and colleagues identified a mutation in the Son of sevenless-l (SOSl) gene, which results in a single nucleotide insertion mutation in codon 1083 of GINGE^ Tbis mutation appears as autosoma! dominant. The exact method of transmission of expression for ihe recessive form of HGF is still being studied,

Histopathology
HGF causes enlargement of the attached gingival tissue because of an increase in the amount of connective tisstie. This fibrosis is characterized by densely arranged collagen bundles, numerous fibroblasts, and connective tissue tbat is relatively avascular."'" Thickened and acantbotic epithelium also is present with elongated rete pegs (Figure 3),' Small calcified particles, islands of osseous metaplasia, ulceration of the overlying mucosa, and inflammation can be occasionally observed.^"

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Figure 3Pholomicrograph5 of biopsy specimen from an HGF patient Slender elongation of the surface epitiielial rete pegs and a densely collogenous conneclive tissue slroma are observed. Figure 3AHemaloxylin and eosin stain, otiginal magnllicdtion 4x. Note thfe hophazardly arranged cdiogen of the iomina propria, Scattered vascular chonneis and small artifactuol cbfts ore present. Figure 3BHematoxyiin eosin stain, originol magnification 20x

Figure 4The docuiTienloiion ol the surgery performed lo reduce gingival enlorgement. Periodontist used o gingivectomy technique with a scalpel to remove excess tissue,

Barros and colleagues found that ihe organization of lhe collagen fibers in eonnective tissue ohiained irom MGF lesions carried fibrils with an irregular outline, sometimes in loops, interspersed throughout normal fibrils.^* This was attributed to the increased number of matrix substances and filaments in a branching network. They also observed that oxytalan fibers were common, but the number of elastic fibers was diminished. Similar degenerative changes of elastic fibers, coupled with the increase of fine fibrils, interspersed among defective collagen fibrils have been commonly reported in diseases in which there are close pathogenic relationships between elastic fiber alteration and collagen fiber alteration.*' Two morphologically different fibroblast types exist in HGF gingiva.^^ One phenotype exhibits relatively little cytoplasm and is considered inactive, and the other phenotype has fully developed Golgi apparatus and rough endoplasmic reticulum, suggesting a highly active phenotype.^^ "^' The concurrent development of HGF with tooth emption suggests that a particular cell selection or activation of certain fibroblast clones by physical trauma or mononuclear cell products may participate in fiGF pathogenesis."'"^ Thus, the HGF fibroblasts appear to be phenolypicatly activated during tooth development.

There are controversial reports on fibroblast growth rate and the amount of collagen production by fibroblasts isolated from gingiva of HGF patients. Johnson and colleagues and Shirasuma and colleagues reported that HGF fibroblasts grew more slowly than or equal to normal gingivai fibroblast growth,'- " but a more recent study by Tipton and colleagues found HGF fibroblasts to have an increased proliferative rate." Similarly, there is a disagreement regarding the amount of collagen production. According to Tipton and colleagues. HGF fibroblasts produce up to twice the amount of type I collagen as normal fibroblasts, which contributes to the enlargement and fibrosis of the gingiva." In contrast, Johnson and colleagues reported that HGF fibroblasts synthesized 50% of the amount of collagen released from the nomial gingival fibrobtasts.'' These disparities appear to rest on the poorly understood role of the heterogeneous phenotypic expression of the fibrobtast. Tbe possible disturbance in tbe homeosiaiic equilibrium between s)'nthesis and degradation of extracellular matrix molecules also has been recently studied.'*^Matrix metalloproteinases (MMPs) are a family of enz\Tnes involved in degrading various components of the extracellular matrix. It has been reported that MMP-1 and MMP-2 expression and production are lower in fibroblasts from HGF patients.'' It has been postulated that enhanced transforming growth factor-beta 1 (TGF-pl) and interleukin-6 (lL-6) production increases the synthesis and reduces the proteolytic activities of fibroblasts from patients with HGF, which may favor observed aecumulation of the extracellular matrix.^*" Trealmenl Historically, clinicians have reported several approaches to alleviate gingival enlargement. Treatment modalities have ranged from conservative and surgical procedures to extraction of all teeth and reduction of the alveolar bone to prevent recurrence.^^ * Most of tbese reports discuss a necessity for repeated surgical excision of the tissue to restore the gingival contours because of the high recurrence of the condition.^

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Conclusion
Although there are similarities in the clinical presentation, recent studies reveal that etiology and palhogenesis of HGF are distinct frotn other tj-pes of gingival enlargements. Treatment planning, the actual treatment, and evaluation of the treatment outcome sliould include various modalities. This review gives an update on recent investigations and tlie clinical relevance of this infonnation.

References
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Figure 5One year follow-up al maininin reasonable oral heatlh. Noie IS able lo

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Factors lo consider in ireatmeni planning include esthetic and functional needs, as well as the onset of puberty because recurrence is predominately observed in children and teenagers rather than in adults." In addilion, active orthodontic treatmeni may play a role in inducing gingival enlargement in these patients." Currenily available surgical methods for ibe excision of large quantities of tissue include conventional gingiveciomy with a scalpel, electiocaulery, and laser surgery (Figure 4). Restoration of physiological contours of ihe gingiva and maintaining good postoperative care to minimize recurrence are important for a successful treatment oulcome.'" Some reports suggested that laser use is more advantageous than alternative surgical protocol because it has the ability to coagulate and seal blood vessels, vaporize the tissue, make accurate incisions, and itnprove healing because ol its antimicrobial properties."' Hovk'ever, there are not enough scientific evidence and clinical findings to prove these advantages.*^' There is disagreement among clinical reports about the timing of surgical treatment, how many surgeries should be performed, and hi.tw far apart the treatments should be. Nevertheless, postoperative care protocol generally includes chlorhexidine moulhrinse and periodontal dressing with or without hemostatic reagents. Recurrence of the lesion, in whieh the gingiva returns to the original state, may occur within 1 to 2 years depending on the initiation age of the HGF symptoms (Figure 5)."^

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