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Hereditary GingivalFibromatosisA ReviewAbstract

S a m u e l D e A n g e l o D D S M SPrivate PracticeApex, North CarolinaJ a m e s M u r p h y D D S . M SClinical Assistant ProfessorSectionotPeriodontology

L e w i s C l a m a n D D S M SAssociate ProfessorDirectorof Predoctoral PeriodontoiogyProgram

J o h n K a lm a r D M D P h DProtessofGraduate Program Directorofthe Oral nd

Maxillofacial PathologyB i n n a z L e b l e b i c i o g lu D D S M S P h DAssistant ProfessorSectionofPeriodontologyThe Ohio State University, Collegeof

Dentistryfl Columbus, Ohio

Hereditary gingival fibromatosis (HGF)is a rare gingival lesion that presentsaslocal-izedorgeneralized enlargementofthe aitached gingiva.Thegingivaisch aracterizedas pink, firm,and very fibrous, with little tendency tobleed. HGFcanpresentas anisolated featureor aspartofa syndrome . Recent findings reportadefect inthe Sonoseveniess-i geneon chromosome 2p21-p22 (HGFl)as apossible causeofthis clini-cal presentation. HGF inheritance istransmitted ihrough both autosomal dominantand recessive mo des. W hile clinicians disagreeon themodalitiesandtimingoftreat-mentforHGF,theclinical cond ition gen erally requires repeated reseciive period ontalsurgical procedures overthepatient's lifetime. This article reviews differential diag no-s i s eiiology, complications,andtreatmentofHGE

Learning ObjectivesAfter re ding this article there dershould be ble to :

explainlheehnical presentationofhereditary gingival fibromatosis(HGF)andmajor differences betweenHGF and other typesofgingivalenlargements.

describe different treatmen t modali-tiesforvarious age groups. discuss postoperative care and treat-ment outcomesforlong-term success

The diagnosis and treatment ofgingival enlargementhasraisedmany questions among clini-ciansand researchers for many years.Recently, the term "enlargement"wasrecommended inlieuofhyperplasiaorovergrowthtodefineabroader clinicalfinding and to differentiate specificpathologic lesions from common signsof inflammatory changesaitissue level(eg, edemaandhypervascularization).'Gingival enlargement, defined as anovergrowth or increase in the sizeofthe gingiva, is a common feature in gin-gival diseases,and may becausedby avarietyoffactors.^ Inflammation,medications, systemic diseases, and neoplastic tissue changesall can beclassi-fiedas tbeetiologic features.

Basedon the American Academyof Periodontology 1999 Classificationof Periodonlal Diseases and Conditions,gingival enlargement can occur because

of pregnancy-associated bortnonachanges, various medications causingchanges in extracellular matrix physiology, or genetic disorders.'^ Independent from inflammator\' etiologicafactors, periodontal tumors and cystalsomaypresent as localized gingivaenlargements.' Tbetissue enlargemenmaybe localized orgeneralized,confined tothemarginal gingivaor to thepapillary tissue,and involve botbthetnarginal and attached gingivae.'Tbedegree of enlargement can becategorizedasfollows": Grade 0: No gingiva enlargem ent Grade1:Enlargement confinedtointerdental papilla. Grade 2: Enlargement invoKinpapillaandmarginal gingivae. Grade 3 :Enlargement covering threquartersormoreofthe crown.Hereditary gingival fibromatosis(HGF), also referred to as idiopatbic

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Figure 1iiuiwl t.:u:>^i.\^Ui^ .. ^ ; J > jau vv lh l- ieredi laiy y ir iy iv ul l ibmm ulosis HGF ]. Fiyuies l A, i B, and IC pieseni bucca l v iews f iom an HGF case beforet ieoiment . Figures I D . IE, an d 1F pieseni ocdu sal v iev i ; of the same case. No le thai gmgiva l enbrge menr af fects bot f i f ree and oito ched git i g lvo l t issue, Theenlargemeni was severe and the pat ient was bit ing on her gingiwa.

gingival hy perplasia, 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 anatomictooth crowns/ The onset of the disease is common dur-ing the eruption of the permanent incisors,' but severalreports also have mentioned involvement of the decidu-ous dentition.**" It is classified as a non-plaque-inducedgingival lesion caused by various genetic disorders.'

HGF may occur as an isolated disorder, but it also hasbeen reported lo be associated with various syndromesand oiber abnormalities.'' Case reports liave associatedHGF with Zimmerman-La band syndrome (ear, nose, bone,and nail defects), Murray-Puretic-Drescher sj'ndrome(juvenile hyaline fibromatosis), Cowden syndrome (mul-tiple hamarioma). Cross syndrome (microphthalinia,mental retardation, athetosis, hypopigmentation), Ruther-ford syndrome (comeal dystrophy), and Prune belly syn-

drome (absence of 1 or more layers of abdominal mus-cles).'"'' In addition, there may be a relationship hetweena deficiency in growth-related hormones and gingivalenlargement." Features found in association with HGFinclude mental retardation, epilepsy, progressive sen-sorineural hearing loss, and abnormalities of the toes andfingers, but bypertricbosis is tbe ancillary abnormalitymost comm only seen."

Tliis review focuses on the clinical differentiation ofHGF from otber types of gingival enlargements and onknown regulatory meclianisms thatm y beimportant in thetreatment outcome and control of the disease ot:cuiTem:e.Clinical PresentationHGF features an asymptomatic, nonhemorrbagic,nonexudative, and proliferative lesion of the gingival tis-sue." Gingival tissue is generally pink and stippled, but it

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Figure In i t iat prHsenlal ion of the second cose wi l t i HGF, Figures 2A, 2B,on d 2C piesenJ fauccol v iews f rom a second cose with H GF This case wa s fhesiiter of the f irst case presenled in Figure 1, ond exominolion of the family mem-bers revealed s imibr c l in ical f indings in 2 of the 7 s ibl ings,

may become red w ith superimposed m flammation becauseof plaque accumulation. The lissue is libroiic and displaysa nodular or minutely pebbled surface.'^ Often an exagger-ated stippling ij; present."' The tissue can become so f irmand fibrous ihat it feels like hone on palpation,'' This is incontrast to many other presentations of gingival enlarge-ment (eg_ those that are drug induced) where the tissue issomewhat moveable,"" Both free and attached gingival tis-sue are affected, but tbe enlargement does not extend be-yond the mucogingival junction (Figures and 2),' '

Two different tyjies of HGF have heen cla.ssined hasedon HGF clinical presentations. Tbe nod ular form is charac-terized hy multiple focal enlargements in ihe denial papillae,and the s)Tnmetric forni results in a more unifonn enlarge-ment of the gingival tissue. These clinical modalities canoccur in conjunction witb eacb o ther or as isolated lesions.

The symmetric form is more common, and the maxilla andmandible are equally affected (Figures 1 and 2} . ' " ' Tbelocalized form is generally seen in the maxillary tuberosityand molar area, predominately on the palatal aspect.'"

HCiF gingival enlargement can cover the coronal portion ofatooth, up to its occlusal surface. Tbis overgrowthalso may extend to the palaic. which alters its contourThe resultant effect may include speech difficulty andpainful mastication as food deflects onto the enlarged tis-sue. In severe cases, the jaws appear bulbous,'"" Othercommon side effects are diastema, malocclusion, and pro-longed retention of primary teeth." Perhaps most impor-tantly, (he enlarged tissue creates retention for plaque.Although Emerson reported no significant associationbetween oral bygiene (the amount of calculus present)and the degree of enlargement, the inability to removeplaque from the teetb is well known to contribute to den-tal caries, the development of gingivitis, and periodontitisin individuals affected witbEtiology and Histopathology of HGFEvidence for Hereditary Jnvohement

HGF is inherited in both autosomal dominant andrecessive modes. It is reported to have a phcnotype fre-quency of 1:175 000 and a gene frequency of L:350,000assuming that the condition to be inherited is tbe result ofan autosomal dominant gene.'" In a study by Rusbton, 54of tbe 109 total cases were tbe offspring of marriages ofaffected and unaffected persons.'" Weski documented 5generations and9 marriages between affected and unaffect-ed subjects and reported that of the 38 offspring, 9 w omenand 5 men were affected,"' Barros and colleagues alsoreported that 50 of96alTected persons were con sistent witban autosontal dominant mode of inheritance with comp letepenetrance,-' Several reports of recessive tratismission ofthe disorder also exist in the literature.'""-'*

Recently, researchers have identified 3 geneticallyseparate loci,''" These loci are on chromosome 2p21-p22 (GINGF), 2p22.3-23,3 {GINGF3), and 5ql3-q22(G1NGF2). Hart and colleagues identified a mutation intheSon of sevenless l SOSl)g ene, which results in a sigle nucleotide insertion mutation in codon 1083 ofGINGE^ Tbis mutation appears as autosoma dominant.The exact method of transmission of expression for iherecessive form of HGF is still being studied,HistopathologyHGF causes enlargement of the attached gingival tis-sue because of an increase in the amount of connectivetisstie. This fibrosis is characterized by densely arrangedcollagen bundles, numerous fibroblasts, and connectivetissue tbat is relatively avascular."'" Thickened and acan-tbotic epithelium also is present with elongated rete pegs(Figure 3),' Small calcified particles, islands of osseousmetaplasia, ulceration of the overlying mucosa, andinflammation can be occasionally observed.^"

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Figure 3Pholomicrograph5 of biopsy specimen from an HGF patient Slender elongation of the surface epitiie lial rete pegs and a densely collogenousconneclive tissue slroma are observed. Figure 3A Hemaloxylin and eosin stain, otiginal m agnllicdtion 4x . Note thfe hophazardly arrange d c diog enof 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 gingivalenlorgement. Periodontist used o gingivectomy technique with a scalpel toremove excess tissue,

Barros and colleagues found that ihe organization oflhe collagen fibers in eonnective tissue ohiained iromMGF lesions carried fibrils with an irregular outline,sometimes in loops, interspersed throughout normal fib-rils.^* This was attributed to the increased number ofmatrix substances and filaments in a branching network.They also observed that oxytalan fibers were common,but the number of elastic fibers was diminished. Similardegenerative changes of elastic fibers, coupled with theincrease of fine fibrils, interspersed among defective col-lagen fibrils have been commonly reported in diseases inwhich there are close pathogenic relationships betweenelastic fiber alteration and collagen fiber alteration.*'

Two morphologically different fibroblast types exist inHGF gingiva.^^ One phenotype exhibits relatively littlecytoplasm and is considered inactive, and the otherphenotype has fully developed Golgi apparatus and roughendoplasmic reticulum, suggesting a highly active pheno-type.^^ 'The concurrent development of HGF with toothemption suggests that a particular cell selection or activa-tion of certain fibroblast clones by physical trauma ormononuclear cell products may participate in fiGF patho-genesis. ' ^ Thus, the HGF fibroblasts appear to be pheno-lypicatly activated during tooth development.

There are controversial reports on fibroblast growthrate and the amount of collagen production by fibroblastsisolated from gingiva of HGF patients. Johnson and col-leagues and Shirasuma and colleagues reported that HGFfibroblasts grew more slowly than or equal to normal gingi-vai fibroblast growth,'- but a more recent study by Tiptonand colleagues found HGF fibroblasts to have an increasedproliferative ra te . Similarly, thereisa disagreement regard-ing the amount of collagen production. According toTipton and colleagues. HGF fibroblasts p roduce up to twicethe amount of type I collagen as normal fibroblasts, whichcontributes to the enlargement and fibrosis of the gingiva.In contrast, Johnson and colleagues reported that HGFfibroblasts synthesized 50% of the amount of collagenreleased from the nomial gingival fibrobtasts.'' These dis-parities appear to rest on the poorly understood role of theheterogeneous phenotypic expression of the fibrobtast.Tbe possible disturbance in tbe homeosiaiic equilib-rium between s)'nthesis and degradation of extracellularmatrix molecules also has been recently studied.'*^Matrixmetalloproteinases (MMPs) are a family of enz\Tnesinvolved in degrading various components of the extra-cellular matrix. It has been reported that MMP-1 andMMP-2 expression and production are lower in fibrob-lasts from HGF patients.'' It has been postulated thatenhanced transforming growth factor-beta 1 (TGF-pl)and interleukin-6 (lL-6) production increases the synthe-sis and reduces the proteolytic activities of fibroblastsfrom patients with HGF, which may favor observed aecu-mulation of the extracellular matrix.^*TrealmenlHistorically, clinicians have reported several ap-proaches to alleviate gingival enlargement. Treatmentmodalities have ranged from conservative and surgicalprocedures to extraction of all teeth and reduction of thealveolar bone to prevent recurrence.^^* Most of tbesereports discuss a necessity for repeated surgical excisionof the tissue to restore the gingival contours because ofthe high recurrence of the condition.^

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Figure One year follow-up almaininin reasonable oral heatlh.

Noie IS able lo

Factors lo consider in ireatmeni planning includeesthetic and functional needs, as well as the onset ofpuberty because recurrence is predominately observed inchildren and teenagers rather than in adults." In addilion,active orthodo ntic treatmeni may play a role in inducinggingival enlargement in these patients."Currenily available surgical methods for ibe excisionof large quantities of tissue include conventional gin-giveciomy w ith a scalpel, electiocaulery, and laser surgery(Figure 4). Restoration of physiological contours of ihegingiva and maintaining good postoperative care to mini-mize recurrence are important for a successful treatmentoulcome.'" Some reports suggested that laser use is moreadvantageous than alternative surgical protocol because ithas the ability to coagulate and seal blood vessels, vapor-

ize the tissue, make accurate incisions, and itnprove heal-ing because ol its antimicrobial properties."' Hovk'ever,there are not enough scientific evidence and clinical find-ings to prove these advantages.*^'There is disagreement among clinical reports aboutthe timing of surgical treatment, how many surgeriesshould be performed, and hi.tw far apart the treatmentsshould be. Nevertheless, postoperative care protocol gen-erally includes chlorhexidine m oulhrinse and periodontaldressing with or without hemostatic reagents. Recurrenceof the lesion, in whieh the gingiva returns to the originalstate, may occur within to 2 years depending on the ini-

tiation age of the HGF symptoms (Figure 5)."^

ConclusionAlthough there are similarities in the clinical presen

tation, recent studies reveal that etiology and palhogenesiof HGF are distinct frotn other tj-pes of gingival enlargements. Treatment p lanning, the actual treatment, and evaluation of the treatment outcome sliould include varioumodalities. This review gives an update on recent investigations and tlie clinical relevance of this infonnation.References1. Amiitagc GC. Devclopmfnl of a classificalion sysiem for per

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