Alternative titles; symbols
SNOMEDCT: 109620006; ORPHA: 2024; DO: 0060466;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p22.1 | Fibromatosis, gingival, 1 | 135300 | Autosomal dominant | 3 | SOS1 | 182530 |
A number sign (#) is used with this entry because of evidence that gingival fibromatosis-1 (GINGF1) is caused by heterozygous mutation in the SOS1 gene (182530) on chromosome 2p22.
Gingival fibromatosis is a rare overgrowth condition characterized by a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of maxillary and mandibular keratinized gingiva (summary by Hart et al., 2002).
Genetic Heterogeneity of Hereditary Gingival Fibromatosis
Other loci for gingival fibromatosis have been mapped to chromosome 5q (GINGF2; 605544), chromosome 2p23.3-p22.3 (GINGF3; 609955), and chromosome 11p15 (GINGF4; 611010). GINGF5 (617626) is caused by mutation in the REST gene (600571) on chromosome 4q12. GINGF6 (620999) is caused by mutation in the ZNF862 gene (620974) on chromosome 7q36. There is some evidence for a locus on chromosome 2p16-p13 (see MAPPING).
Emerson (1965) reported a family in which 13 individuals in 4 generations had gingival fibromatosis. Becker et al. (1967) described gingival fibromatosis without other features in mother, son, and daughter.
Although Zackin and Weisberger (1961) stated that there was 'slight hypertrichosis in all members' of the Italian family they studied (see 135400), they did not clearly state whether persons without gingival fibromatosis as well as those with it were hirsute. Witkop (1971) described an extensively affected kindred in which none of 13 examined cases and none of many others reportedly with the disorder had hypertrichosis.
Gorlin (1977) suggested that the disorder described by Chatterjee and Mazumder (1967) as 'fibroosseous dysplasia of the jaws' in a man and his 2 sons may have been gingival fibromatosis in an unusually neglected form. The tumorous involvement reached amazing proportions as shown in the published photographs. The father had progressive swelling of the upper jaw from childhood; involvement of the lower jaw was later in onset.
Machado et al. (2023) reported 3 patients from a Brazilian family (family D) with gingival fibromatosis and mutation in the SOS1 gene. A 14-year-old girl, her 32-year-old mother, and a 34-year-old maternal aunt all exhibited severe gingival overgrowth. Her deceased maternal grandfather was said to have been affected as well. In the affected individuals, the clinical crown was partially covered due to increased gingival overgrowth, creating pseudopockets that facilitated the accumulation of biofilm. None of the 3 had been exposed to medications associated with gingival overgrowth. Microscopically, the gingival tissue showed hyperplastic parakeratinized stratified squamous epithelium, projecting long, thin, and deep epithelial ridges into the connective tissue, which was composed of increased amounts of collagen fiber bundles extending in all directions, with few fibroblasts present.
Jorgenson and Cocker (1974) stated that there are both dominant and recessive forms of gingival fibromatosis, with generalized and focal types being variable expression of the same disorder.
Both genetic and pharmacologically induced forms of gingival fibromatosis are known. The most common genetic form, hereditary gingival fibromatosis, is usually transmitted as an autosomal dominant trait, although sporadic cases are common and autosomal recessive inheritance has been reported. In most recessively inherited cases, gingival fibromatosis occurs as a part of a syndrome, e.g., 228560 and 266270. Syndromal forms of gingival fibromatosis, with autosomal dominant inheritance patterns, are represented by 135500 and 135400.
Hart et al. (1998) performed a genomewide search for linkage to polymorphic markers in an extended family with an autosomal dominant form of isolated gingival fibromatosis. They found a maximum lod score of 5.05 at theta = 0.00 for the 2p21 region, termed GINGF, bounded by loci D2S1788 and D2S441.
By genotyping 4 Chinese families with gingival fibromatosis using polymorphic microsatellite markers, Xiao et al. (2000) defined the disease locus as an 8.7-cM region on 2p21. This region overlaps by 3.8 cM with the previously reported GINGF locus.
Associations Pending Confirmation
Shashi et al. (1999) performed additional linkage studies on a family with gingival fibromatosis linked to 2p21 reported by Hart et al. (1998) and molecular cytogenetic studies on a boy with gingival fibromatosis and a duplication involving 2p21-p13 described by Fryns et al. (1989). These analyses refined the GINGF locus in the family to an 8-Mb region on 2p21 flanked by D2S1788 and D2S2298. In the boy, the region of duplication was shown to be proximal to this candidate region. Shashi et al. (1999) concluded that there are 2 loci on chromosome 2p, one at 2p21 and another at 2p16-p13, associated with gingival fibromatosis.
Nibali et al. (2013) studied a family with early-onset severe gingival fibromatosis, in which 8 members over 4 generations were affected. The proband was a 13-year-old girl who had initially presented with enlargement of the gingival tissues at 3 years of age, with recurrence despite multiple resective surgeries. Older affected family members had undergone extraction of erupted teeth and were fully edentulous. Histologic analysis of ulcerated mucosal nodules from the proband showed a core of woven bone trabeculae, osteoid, and scattered psammomatoid calcifications in a cellular fibrous stroma. This fibrous bone-like gingival overgrowth interfered with tooth eruption, and all affected individuals had unerupted or ankylosed teeth. Two sisters, maternal cousins of the proband, had undergone sequential gingivectomies and orthodontic treatment from 2 years of age in an attempt to facilitate tooth eruption, but several teeth remained impacted. Whole-genome SNP genotyping of all family members for multipoint parametric linkage analysis yielded lod scores greater than 1 on chromosomes 7, 10, 13, 15, 16, 17, 19, and 20, thus excluding known GINGF-associated genes and loci.
Hart et al. (2002) identified a heterozygous frameshift mutation in the SOS1 gene (182530.0001) as the cause of autosomal dominant hereditary gingival fibromatosis in a large Brazilian family showing linkage to 2p21.
By exome sequencing in 3 affected individuals from a Brazilian family (family D) with severe gingival overgrowth, Machado et al. (2023) identified heterozygosity for a 4-bp insertion in the SOS1 gene (182530.0008). The insertion was confirmed by Sanger sequencing; DNA was unavailable from unaffected family members for segregation analysis.
Associations Pending Confirmation
By exome sequencing in a 45-year-old Brazilian woman with mild gingival overgrowth and her 2 moderately affected children (family B), Machado et al. (2023) identified heterozygosity for a c.1133G-T transversion in the CD36 gene (173510), resulting in a gly378-to-val (G378V) substitution. The mutation was inherited from the proband's asymptomatic father, who was said to be edentulous but was not available for clinical evaluation. The proband's unaffected mother, sister, and husband did not carry the variant.
The estimated incidence of hereditary gingival fibromatosis is 1 in 750,000 (Pehlivan et al., 2009).
Becker, W., Collings, C. K., Zimmerman, E. R., De La Rosa, M., Singdahlsen, D. Hereditary gingival fibromatosis. A report on a family in which three members were affected with fibromatosis of the gingiva. Oral Surg. 24: 313-318, 1967. [PubMed: 5234265] [Full Text: https://doi.org/10.1016/0030-4220(67)90035-7]
Chatterjee, S. K., Mazumder, J. K. Massive fibro-osseous dysplasia of the jaws in two generations. Brit. J. Surg. 54: 335-340, 1967. [PubMed: 6023087] [Full Text: https://doi.org/10.1002/bjs.1800540505]
Emerson, T. G. Hereditary gingival hyperplasia: a family pedigree of four generations. Oral Surg. 19: 1-9, 1965. [PubMed: 14233392] [Full Text: https://doi.org/10.1016/0030-4220(65)90207-0]
Fryns, J.-P., Kleczkowska, A., Kenis, H., Decock, P., Van den Berghe, H. Partial duplication of the short arm of chromosome 2 (dup2;p13-p21) associated with mental retardation and an Aarskog-like phenotype. Ann. Genet. 32: 174-176, 1989. [PubMed: 2573314]
Gorlin, R. J. Personal Communication. Minneapolis, Minn. 1977.
Hart, T. C., Pallos, D., Bowden, D. W., Bolyard, J., Pettenati, M. J., Cortelli, J. R. Genetic linkage of hereditary gingival fibromatosis to chromosome 2p21. Am. J. Hum. Genet. 62: 876-883, 1998. [PubMed: 9529355] [Full Text: https://doi.org/10.1086/301797]
Hart, T. C., Zhang, Y., Gorry, M. C., Hart, P. S., Cooper, M., Marazita, M. L., Marks, J. M., Cortelli, J. R., Pallos, D. A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. Am. J. Hum. Genet. 70: 943-954, 2002. [PubMed: 11868160] [Full Text: https://doi.org/10.1086/339689]
Jorgenson, R. J., Cocker, M. E. Variation in the inheritance and expression of gingival fibromatosis. J. Periodont. 45: 472-477, 1974. [PubMed: 29538838] [Full Text: https://doi.org/10.1902/jop.1974.45.7.472]
Machado, R. A., de Andrade, R. S., Pego, S. P. B., Krepischi, A. C. V., Coletta, R. D., Martelli-Junior, H. New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes. J. Periodont. 94: 108-118, 2023. [PubMed: 35665929] [Full Text: https://doi.org/10.1002/JPER.22-0219]
Nibali, L., Medlar, A., Stanescu, H., Kleta, R., Darbar, U., Donos, N. Linkage analysis confirms heterogeneity of hereditary gingival fibromatosis. Oral Dis. 19: 100-105, 2013. [PubMed: 22849749] [Full Text: https://doi.org/10.1111/j.1601-0825.2012.01965.x]
Pehlivan, D., Abe, S., Ozturk, S., Kayhan, K. B., Gunduz, E., Cefle, K., Bayrak, A., Ark, N., Gunduz, M., Palanduz, S. Cytogenetic analysis and examination of SOS1 gene mutation in a Turkish family with hereditary gingival fibromatosis. J. Hard Tissue Biol. 18: 131-134, 2009.
Ramon, Y., Berman, W., Bubis, J. J. Gingival fibromatosis combined with cherubism. Oral Surg. 24: 435-448, 1967. [PubMed: 5235465] [Full Text: https://doi.org/10.1016/0030-4220(67)90416-1]
Shashi, V., Pallos, D., Pettenati, M. J., Cortelli, J. R., Fryns, J.-P., von Kap-Herr, C., Hart, T. C. Genetic heterogeneity of gingival fibromatosis on chromosome 2p. J. Med. Genet. 36: 683-686, 1999. [PubMed: 10507724]
Witkop, C. J., Jr. Heterogeneity in gingival fibromatosis. Birth Defects Orig. Art. Ser. VII(7): 210-221, 1971. [PubMed: 4950923]
Xiao, S., Wang, X., Qu, B., Yang, M., Liu, G., Bu, L., Wang, Y., Zhu, L., Lei, H., Hu, L., Zhang, X., Liu, J., Zhao, G., Kong, X. Refinement of the locus for autosomal dominant hereditary gingival fibromatosis (GINGF) to a 3.8-cM region on 2p21. Genomics 68: 247-252, 2000. [PubMed: 10995566] [Full Text: https://doi.org/10.1006/geno.2000.6285]
Zackin, S. J., Weisberger, D. Hereditary gingival fibromatosis: report of a family. Oral Surg. 14: 828-836, 1961. [PubMed: 13787614] [Full Text: https://doi.org/10.1016/s0030-4220(61)80013-3]