American Journal of Medical Genetics 116A:312–314 (2003)

Research Letter

Hereditary Gingival Fibromatosis (HGF) WithHypertrichosis Is Unlinked to the HGF1and HGF2 Loci

To the Editor:

Hereditary gingival fibromatosis (HGF;MIM135300)is a progressive hyperplasia of gingival tissues, occur-ring either as an isolated feature [Bozzo et al., 1994] orin association with a few syndromes [Jones et al., 1977;Hartsfield et al., 1985; Pina-Neto et al., 1986; Wynneet al., 1995]. Gingival fibromatosis may be induced alsoby certain drugs, such as phenytoin, a tendency thatcould have a genetic basis [Hassell and Hefti, 1991].Hereditary isolated HGF, eventually associated withhypertrichosis, is usually transmitted as an autosomaldominant trait [Xiao et al., 2001]. A gene for HGF(HGF1) has been identified on chromosome 2p21 andcodes for a guanine nucleotide-exchange factor (SOS1)[Hart et al., 2002]. A second gene (HGF2) has beenassigned to chromosome 5q13-q22 [Xiao et al., 2001].

We have analyzed for linkage to both the HGF1 andHGF2 loci a three-generation HGF Italian family, in-cluding seven affected and six unaffected individuals,usingmicrosatellitemarkers from theLinkageMapping

Set V.2 (Applied Biosystem). In addition to obvious gin-gival hyperplasia (Fig. 1), the affected males showedbushy eyebrows with synophris, which was less evidentin females. Marked hypertrichosis was present in twomales.Otheraffectedsubjectspresentedwith lessseverehypertrichosis. Patients did not report history of hear-ing loss or epilepsy, and all had normal intelligence.Informed consent was obtained from all subjects in-cluded in the study.

Haplotype analysis of chromosome 2 (Fig. 2A) showedthat individual III:5 and her unaffected sister III:6shared the samematernal chromosomeacross thewholeHGF1 region. ThreeHGF subjects (III:1, III:3, and III:4)did not share the same D2S165–D2S2291 intervalmarkers. Unaffected individual III:2 had the same hap-lotype of her affected brothers III:1 and III:3. Linkageanalysis at the HGF2 locus (Fig. 2B) showed thataffected individuals III:1, III:3, and III:4 shared differ-ent haplotypes. Patient III:5 and the unaffected sisterIII:6 had inherited the same maternal haplotype.

The exclusion of linkage to both the HGF1 and theHGF2 regions in this family suggests that geneticheterogeneity of HGF could be wider than previouslyconsidered. It has been questioned if gingival fibro-matosis is clinically distinct from autosomal dominantgingival fibromatosiswith hypertrichosis (MIM135400)[Garn and Hatch, 1950]. However, the possibility thathypertrichosis could be less severe in some subjects hasbeen considered [Zackin and Weisberger, 1961]. In thepresent family, hypertrichosis was a variable feature,less marked in the females. Since variable expressionoccurs in autosomal dominant conditions and synophris,bushy eyebrows and hypertrichosis were not present inunaffected family members, the diagnosis of gingivalfibromatosis with hypertrichosis was considered likely.Interestingly, HGF1- and HGF2-linked families did notshow hypertrichosis [Shashi et al., 1999; Xiao et al.,2000, 2001; Hart et al., 2002]. Therefore, the presentdata argues that isolated gingival hyperplasia andHGF

Grant sponsor: The Italian Ministry of Health; Grant number:RC2002.

*Correspondence to: Antonio Pizzuti, CSS-Mendel Institute,Viale Regina Margherita 261, 00162 Rome, Italy.E-mail: a.pizzuti@css-mendel.it

Received 26 April 2002; Accepted 17 June 2002

DOI 10.1002/ajmg.a.10850

� 2002 Wiley-Liss, Inc.

associated with hypertrichosis could well be geneticallydistinct entities.

REFERENCES

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Fig. 2. The HGF family: haplotype analysis of chromosome 2p21 (HGF1) and 5q13-22 (HGF2). Black symbols denote affected subjects with gingivalhyperplasia.

Fig. 1. Gingival fibromatosis and synophris in two affected family members.

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Massimo ManginoAntonio Pizzuti*Bruno DallapiccolaDepartment of ExperimentalMedicine and Pathology

University La Sapienza, and CSSHospital

San Giovanni Rotondo andCSS-Mendel Institute

Rome, Italy

Aldo BonfanteDonatella SaccilottoDepartment of PathologyBassano del Grappa HospitalBassano del Grappa, Italy

Elena CucchiaraCSS HospitalSan Giovanni Rotondo andCSS-Mendel Institute

Rome, Italy

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