gingival enlargement.pdf

The phenotypic overlap of syndromes associated with hereditarygingival fibromatosis: follow-up of a family for five yearsM. Cenk Haytaca and Onur Ozcelik,b, Adana, TurkeyCUKUROVA UNIVERSITY FACULTY OF DENTISTRY

Hereditary gingival fibromatosis (HGF) is characterized by the slowly progressive fibrous enlargement ofgingival tissue. It usually develops as an isolated disorder but can also be one feature of various syndromes. Thecurrently preferred terminology of these syndromes mainly describes the clinical features of the disorder withoutidentifying the cause. In this report, we present the 5-year follow up of a family with HGF and features of 3 previouslydescribed syndromes: Jones syndrome, Zimmerman-Laband syndrome, and HGF-hypertrichosis syndrome. The 45-year-old father had HGF, hypertrichosis, hearing loss, and short stubby fingers and toes with hypoplasia of the terminalphalanges and hypoplasia of the nails on the thumbs. The features of 13-year-old son were almost identical to those ofhis father except for hypertrichosis, but in addition he was mentally retarded. Although the 10-day-old son had HGFand defective fingers, the mother and 7-year-old daughter were unaffected. Owing to the overlap of these syndromes,we argue that the identification of the genetic pathways and mechanisms will be the most important factor inclassifying these disorders, with the phenotype playing a minor role. (Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2007;103:521-7)
Hereditary gingival fibromatosis (HGF) is a rare disor-der characterized by the slowly progressive, nonhem-orrhagic, fibrous enlargement of gingival tissue.1,2 Theclinical presentation of HGF is variable in both thedistribution and the severity of expression.3,4 The hy-perplastic gingiva may be localized or generalized,usually with normal color and firm consistency withabundant stippling.4,5 The enlargement usually beginsat the time of the eruption of the permanent dentition,although it may occur during the eruption of deciduousteeth or even at birth.3,6,7 HGF is reported under at least25 different names in the literature, mainly referring togeneralized forms.8

HGF is usually seen as an isolated disorder9-12 but itmay also develop as one feature of several rare mul-tisystem syndromes such as Zimmerman-Laband(ZLS),13,14 Jones,15,16 Ramon,17 and Rutherford6 syn-dromes, Juvenile hyaline fibromatosis,18 systemic in-fantile hyalinosis,19 and mannosidosis20,21 (Table I). Inthe comprehensive review by Hart et al.,3 more than 18different genetic forms of HGF are presented withhighly variable systemic findings. On the other hand,numerous case reports describe varying combinationsof the systemic manifestations, suggesting overlap be-tween these genetic disorders.5,9,14,22,23

aAssociate Professor, Department of Periodontology.bResearch Assistant, Department of Periodonology.Received for publication Dec. 2, 2005; returned for revision Jan. 20,2006; accepted for publication Feb. 16, 2006.1079-2104/$ - see front matter© 2007 Mosby, Inc. All rights reserved.
doi:10.1016/j.tripleo.2006.02.021
Genetic heterogeneity of HGF also exists by thepresence of both autosomal-dominant and autosomal-recessive inheritances.3 To date, several responsiblegene loci of isolated HGF have been identified at chro-mosomal locations of 2p21-p22,24 2p13-p16,10 and5q13-q22.25. A mutation in the SOS1 gene, which hasbeen mapped to 2p21-p22, has recently been discov-ered.24 Hart et al.3 suggested that the isolated HGF mayresult from a single gene mutation and the syndromicforms may result from alterations of multiple genes ora gene dosage effect.

This study presents HGF in a family with a combi-nation of systemic findings which overlap 3 previouslydescribed syndromes: Zimmerman-Laband syndrome,Jones syndrome, and gingival fibromatosis-hypertri-chosis syndrome.

CASE DESCRIPTION AND RESULTSThe family was first seen in June 2000. The father

(42 years old) was referred to the periodontology de-partment with a complaint of gingival enlargement. Hismedical history included moderate hearing deficitwhich was diagnosed at age 14. He denied taking anymedication which may cause gingival enlargement ordeafness. Because his parents were deceased when hewas 3 years old he did not know if either of them hada similar situation. He reported that he had had theproblem since childhood and gingivectomy, serial ex-tractions, and a bridge fixed in the maxillary anteriorregion at 20 years of age.

The extraoral examination revealed a broad nose,
thick floppy ears, thick eyelashes and eyebrows, short
521

noglobu

OOOOE522 Haytac and Ozcelik April 2007

stubby fingers and toes with hypoplasia of the terminalphalanges, hypoplasia of the nails on the thumbs, andmild hypertrichosis especially affecting the face andupper limbs (Fig. 1).

Intraorally, there was generalized severe gingivalenlargement in both the mandible and the maxilla in-volving the palate. The gingiva was pink with a firmand dense consistency covering the crowns of severalteeth (Fig. 2, A). Although there was no overgrowth ofgingiva in the edentulous posterior of the mandible, theposterior maxilla was the most severely affected region,with the bulky enlargement of maxillary tuberositiescontacting the mandibulardibler ridges (Fig. 3). Therewas spacing of the teeth, which the patient stated ashaving started about 5 years before. There were clini-cally observable root fragments that were embedded inthe overgrown tissue in the maxillary posterior (Fig. 3).The amount of the enlarged gingival tissue could easilybe traced from the panoramic radiograph. The radio-graph also showed the teeth and root fragments coveredby the gingiva (Fig. 4, A).

The son was 9 years old at the initial visit. Hismedical history was remarkable in that he had mildmental retardation and attended a special school. He didnot have a hearing deficit at that time. His extraoralfindings were almost identical to those of his father buthe did not have hypertrichosis. The intraoral examina-tion revealed prolonged retention of primary teeth with

Table I. Conditions associated with gingival fibromatoCondition

Gingival fibromatosis3,9 Gingival fibromatosGingival fibromatosis and mental

retardation3,9,10Gingival fibromatos

Gingival fibromatosis withhypertrichosis3,11

Gingival fibromatos

Gingival fibromatosis with distinctivefacies3,12

Gingival fibromatosdolynslantedpalpearched palate

Zimmerman-Laband syndrome3,13,14:gingival fibromatosis with abnormalfingers, fingernails, nose, and ears andsplenomegaly

Gingival fibromatoshepatomegaly, hy

Jones syndrome: gingival fibromatosis withprogressive deafness3,15,16

Gingival fibromatos

Ramon syndrome3,17 Gingival fibromatosjuvenile rheumato

Rutherfurd syndrome: gingival hypertrophywith corneal dystrophy3,6

Gingival hypertrophbehavior

Juvenile hyaline fibromatosis3,18 Gingival fibromatoswhitish nodules, o

Systemic infantile hyalinosis3,19 Gingival fibromatoscontractures, oste

Mannosidosis3,20,21 Gingival hypertrophretardation, immu

permanent first molars and mandibulardibler incisors

only, which were partially erupted. The primary teethhad no mobility. He also had pink firm overgrown

Findings

ental retardation

rtrichosis, mental retardation, muscular hypotonia

ocephaly, bushy eyebrows, synophys, hypertelorism,sures, flat nasal bridge, hypoplastic nares, cupid-bow mouth, high

rmal fingers, fingernails, nose, and ears, splenomegaly,nsible metacarpophalangela joints

ressive sensorineural hearing loss

ubism, seizures, mental deficiency, hypertricosis, stunted growth,tiseal opacity, mental retardation, failure of tooth eruption, aggressive

iple subcutaneous tumors, dysseborrhea, sclerodermiform atrophy,ic and osteoclastic skeletal lesionsened skin, focal skin nodularity, restricted movement, joint,

s, failure to thriveess, muscle hypotonia, craniofacial dysmorphism, mentallin deficiency

Fig 1. The extraoral view of the father with hypertrichosis,prominent ears, hypoplasia of the terminal phalanges of thefingers, and hypoplasia of the nail on the thumb.

sis

isis and m

is, hype

is, macrbral fis

is, abnoperexte

is, prog

is, cherid artriy, corn

is, multsteolyt

is, thickoporosiy, deafn

gingiva generalized in both arches, which prevented

OOOOEVolume 103, Number 4 Haytac and Ozcelik 523

adequate lip closure (Figs. 5, A, and 6, A). There wereno signs of gingival inflammation. The radiographicassessment revealed the presence of all permanentteeth; however, the physiologic root resorptions of theprimary teeth were delayed (Fig. 7, A).

The mother and 6-yr-old daughter were not affected,with no signs of HGF or any other systemic findings.

A treatment schedule which included gingivectomyand extractions either under local or general anesthesiawas planned; however, the father only agreed to haveextractions and refused any treatment for gingival fi-bromatosis both for his son and for himself. He stated

Fig 2. The intraoral view of the father in 2000 (A), 2003 (B),and 2005 (C). Note that the bridge on the anterior region hasbeen lost.

that “severe pain that he suffered after his previous

operation” and “highly probable recurrence rate ofHGF” were the reasons for his refusal of treatment.

After 3.5 years, the family was re-examined in De-

Fig 3. The initial intraoral view of the father in June 2000.Note the severe enlargement on the tuberosities contactingmandibler ridges and the root fragments in the overgrowntissue.

Fig 4. The panoramic radiographs of the father in 2000 (A)and 2005 (B), showing the teeth and the root fragmentscovered by the gingiva. The amount of enlargement on themaxilla can be traced in the radiograph (arrows).

cember 2003. The intraoral examination of the father


(Fig. 2, B) showed that the anterior bridge was brokenand the gingiva had covered the prepared teeth. Theovergrowth of the palatal gingival tissue was not in-creased significantly compared to the initial examina-tion. The patient stated that he had been biting andchewing on the gingiva and he had encountered noproblems. The son, now 12 years old, still retainedmany of his primary teeth (Fig. 6, B). The mandibularincisors were still partially erupted. During the ensuingyears, his maxillary primary central incisor had exfoli-ated and the incisal edge of the permanent incisor couldbe observed. The physiologic root resorptions of theprimary teeth were still defective. One important de-velopment of the boy’s case was that he was diagnosedas having mild hearing deficit at the age of 11.

The mother gave birth to a healthy boy in December2003. The intraoral examination of this 10-day-old boyalso revealed gingival enlargement, especially affectingthe maxillary anterior and tuberosities (Fig. 8, A). The

Fig 5. The intraoral view of the son in 2000 (A), 2003 (B),and 2005 (C). Note the malocclusion and prolonged retentionof primary teeth owing to gingival hyperplasia.

tissue was pink, firm, and dense in consistency, which

complicated breastfeeding for the mother. The terminalphalanges of the fingers of the baby were hypoplastic,but he did not have any other systemic findings, such ashypertrichosis.

The intraoral views of the patients in November 2005are shown in Figs. 2, C; 5, C; 6, C; and 8, B; and thepanoramic radiographs of the father and the older sonare shown in Figs. 4, B, and 7, B. The father againrefused periodontal treatment as well as a chromosalstudy of his family.

DISCUSSIONPatients with isolated or syndromic forms of HGF

have been widely described in medical and dental lit-erature. Although the various syndromes with HGF areconsidered to be distinct entities, significant overlap ofsymptoms has been noted occasionally.13,14,22,23,26 Fur-thermore, the phenotypic expression of the syndromesmay even vary within the same family,1,26 such as inthe one reported here. For the last 20 years, most of thepublished cases of syndromic HGF do not appear to fallexactly into any recognized patterns. The commonlyreported systemic manifestations of syndromes associ-ated with HGF include hypertrichosis,3,22,26 mental re-tardation,17,22 abnormal fingers, fingernails, nose, andears,13,26,27 epilepsy,17,28 hearing loss,15,16 and super-numerary teeth.1,13 The systemic findings of the presentfamily with HGF overlap with 3 previously describedsyndromes. The features of the father fit Zimmerman-Laband syndrome29 (ZLS, Online Mendelian Inheri-tance ın Man (OMIM) catalog number 135500) withthe hypoplasia of the terminal phalanges and nails ofthe extremities; HGF-hypertrichosis syndrome29

(OMIM 135400) with the hypertrichosis; and Jonessyndrome29 (OMIM 135550) with the hearing loss. Theelder son also had characteristics of ZLS and Jonessyndromes, whereas the features of the younger sononly fits ZLS. Besides the overlapping findings of thisfamily, Zimmerman-Laband syndrome with hypertri-chosis,17,22 in the forms of confluent and thick eye-brows, hairy arms, back, and legs, with mental defi-ciency17,30 and with hearing loss14 has been reported insporadic cases. On the other hand, congenital hypertri-chosis and deafness without HGF has also been de-scribed recently.31 Thus, it seems reasonable to assumethat the highly variable phenotypic overlap of thesesyndromes may represent a spectrum of a single disor-der. The currently preferred terminology of these syn-dromes mainly describes the clinical features of thedisorder without any attempt to identify the cause.

The father-to-son transmission observed in our fam-ily clearly demonstrates that the responsible geneticdefect is autosomal dominantly inherited. The presence
of hearing loss, which is unusual in HGF except for


Jones syndrome, in both father and son most likelysuggests that it is an internal feature of the geneticcondition and not a mere association. Although 3 geneloci and 1 gene (SOS1) have been are described forisolated HGF,24,10,25 there are only a few studies per-formed to clear the causative genes of syndromic HGF.Mangino et al.32 showed that linkage analysis excludedlinkage to previously mapped HGF loci on chromo-somes 2p21 and 5q13-q22 for HGF associated withhypertrichosis. If it is assumed that the clinical condi-tion described in our family is an allelic variant ofHGF-hypertrichosis syndrome, because of the above-mentioned overlap, the genetic defect in our familyshould be at another chromosomal locus. It is possiblethat different mutations in 1 gene may cause differentphenotypes considered to be ZLS, Jones, or HGF-hypertrichosis syndromes. Another possibility wouldbe the presence of deletions involving 2 or more neigh-boring genes, the phenotypic consequence of whichwould be bred true in a given family and heterogeneousphenotypes would be observed in unrelated patients.This situation is called “contiguous gene syndrome”and described as “a syndrome, which results owing tothe abnormalities of 2 or more genes that map next to

Fig 6. The intraoral view of the son in 2000 (A), 2003 (Btuberosities.

each other on a chromosome.” Recently, an apparently

balanced reciprocal translocation of chromosomes3p21.2 and 8q24.3 has been described for patients withZLS,33 suggesting that the responsible genetic defectmay be at one of these chromosomal positions. Oneautosomal recessive nonsyndromic deafness gene,TMIE (transmembrane inner ear expressed gene), mapsto 3p14-p21,34 which is found to be mutant in ZLS.33

Furthermore, several reports have linked isolated naildysplasias35,36 to the same region: 3p21. It will beinteresting to observe if an alteration in this gene isinvolved in the pathogenesis of phenotypic defects de-tected in our family.

It was of interest that although the father did not haveHGF on the edentulous posterior ridges of the mandi-ble, he had the most severe enlargement on the poste-rior maxilla, with teeth and root fragments completelycovered by the overgrown tissue. Although we have noexplanation for this finding; maxillary posterior andpalatal regions are reported to be the most affectedregions in previous cases.2,29 Another interesting find-ing was the prolonged retention of primary teeth in the13-year-old son. Apart from the retentive effect ofdense overgrown gingiva, further analyses are neededto clear the reasons of delayed root resorption of the

2005 (C). Note the gingival enlargement in the maxillary
), and
primary teeth and delayed emergence of permanent


teeth from alveolar bone. And the 10-day-old child is,to our knowledge, the youngest patient with GF in theliterature. The long-term follow-up of this family mayhighlight some important characteristics of the naturalprogress of HGF, because the father strongly refusesany treatment.

In conclusion, the findings from this family providefurther evidence that the clinical presentation of thesyndromic forms of HGF is highly variable. The com-plexity of reviewing cases such as this family is basedon different mutations causing the same syndrome (ge-netic heterogeneity), the same essential mutation beingexpressed differently from case to case (variable ex-pression), and the fact that neighboring mutationssometimes can be inherited as a block (contiguous genesyndromes). Owing to the clinical overlap betweendiagnosed and undiagnosed (or unclassified) syn-dromes, the identification of the genetic pathways andmechanisms will be the most important factor in clas-sifying these disorders, with the phenotype playing aminor role.

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Fig 7. The panoramic radiograph of the son in 2000 (A) and2005 (B), showing the prolonged retention and delayed rootresorption of the primary teeth.

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Fig 8. The gingival enlargement of the son born in June2003, at 10 days old (A) and at 2 yrs old with the enlargementbecoming more prominent in the maxillary tuberosities (B).

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Reprint requests:

Dr. Onur OzcelikCukurova University Faculty of DentistryBalcali/Adana 01330Turkey
[email protected]
http://www.ncbi.nlm.nih.gov/omim/

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