Fibromatosis, Gingival, 5

A number sign (#) is used with this entry because of evidence that gingival fibromatosis-5 (GINGF5) is caused by heterozygous mutation in the REST gene (600571) on chromosome 4q12.

Description

Gingival fibromatosis-5 is an autosomal dominant benign overgrowth disorder characterized by slowly progressive fibrous enlargement of the keratinized gingival tissues. Affected individuals may have diastema, malposition of the teeth, and prolonged retention of primary teeth. Onset is in the first decade. Treatment by surgical resection is generally followed by regrowth of the gingival tissues (summary by Pehlivan et al., 2009).

Clinical Features

Pehlivan et al. (2009) reported a large 3-generation Turkish family in which 6 individuals had severe generalized gingival hyperplasia involving both the mandibular and maxillary arches with onset around age 3 years. Keratinized gingival tissues covered at least one-third of the clinical crowns. Bayram et al. (2017) reported 11 patients from 3 unrelated Turkish families with gingival fibromatosis, including the family reported by Pehlivan et al. (2009). The patients, who ranged in age from 9 to 48 years, presented in childhood (age 3 to 8) with gingival overgrowth. Three patients had pectus deformities, including a girl who also had short stature, hiatal hernia, and recurrent upper respiratory infections. One boy had osteoporosis and osteomyelitis, but his brother with gingival fibromatosis did not have those additional features.

Inheritance

The transmission pattern of GINGF5 in the families reported by Bayram et al. (2017) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 11 patients from 3 unrelated Turkish families with GINGF5, Bayram et al. (2017) identified 3 different heterozygous truncating mutations in the REST gene (600571.0004-600571.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorders in 2 families; the mutation in the proband of the third family occurred de novo. A mildly affected father in 1 of the families was mosaic for the mutation. All mutations occurred in the final exon of the gene, which may result in escape from nonsense-mediated mRNA decay, suggesting that the alleles may act through a dominant-negative or gain-of-function effect. Bayram et al. (2017) noted that studies have suggested that the disorder results from excessive accumulation of extracellular matrix components, particularly collagen type I, which may be due to abnormal expression of TGF-beta (TGFB1; 190180) and IL6 (147620). The mutant transcripts may reduce the repressor function of REST on the collagen synthesis pathway, resulting in the accumulation of collagen in gingiva. However, functional studies of the REST variants and studies of patient cells were not performed.