Zimmermann-Laband syndrome and infantile systemic hyalinosis: an enigma with two separate terms with overlapping features: a case report.

BACKGROUND: Zimmermann-Laband Syndrome (ZLS) and infantile systemic hyalinosis (ISH) are rare genetic disorders. They are characterized by various spectrum manifestations. In spite of other case reports, this case with features of both syndromes was reported by oral medicine specialists and oral and maxillofacial surgeons. CASE PRESENTATION: In this study, we reported an 18-months old female patient with gingival overgrowth. This phenomenon completely embedded all the erupted teeth. In this case, the presence of multiple papulonodular cutaneous lesions is a newly observed aspect that has rarely been reported in the existing literature. Gingival overgrowth was excised under general anesthesia. At six months of follow-up after surgery, mastication and breathing problems were improved. Aesthetic aspects were ameliorated in terms of gingival appearance. CONCLUSIONS: To date, due to the ambiguous presentations, both syndromes remain an enigma for specialists. A timely diagnosis could be crucial for prognosis and preventing severe further surcharge. Dentists could play an important role in the diagnosis of rare disorders.

Double heterozygous pathogenic mutations in KIF3C and ZNF513 cause hereditary gingival fibromatosis.

Hereditary gingival fibromatosis (HGF) is a rare inherited condition with fibromatoid hyperplasia of the gingival tissue that exhibits great genetic heterogeneity. Five distinct loci related to non-syndromic HGF have been identified; however, only two disease-causing genes, SOS1 and REST, inducing HGF have been identified at two loci, GINGF1 and GINGF5, respectively. Here, based on a family pedigree with 26 members, including nine patients with HGF, we identified double heterozygous pathogenic mutations in the ZNF513 (c.C748T, p.R250W) and KIF3C (c.G1229A, p.R410H) genes within the GINGF3 locus related to HGF. Functional studies demonstrated that the ZNF513 p.R250W and KIF3C p.R410H variants significantly increased the expression of ZNF513 and KIF3C in vitro and in vivo. ZNF513, a transcription factor, binds to KIF3C exon 1 and participates in the positive regulation of KIF3C expression in gingival fibroblasts. Furthermore, a knock-in mouse model confirmed that heterozygous or homozygous mutations within Zfp513 (p.R250W) or Kif3c (p.R412H) alone do not led to clear phenotypes with gingival fibromatosis, whereas the double mutations led to gingival hyperplasia phenotypes. In addition, we found that ZNF513 binds to the SOS1 promoter and plays an important positive role in regulating the expression of SOS1. Moreover, the KIF3C p.R410H mutation could activate the PI3K and KCNQ1 potassium channels. ZNF513 combined with KIF3C regulates gingival fibroblast proliferation, migration, and fibrosis response via the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways. In summary, these results demonstrate ZNF513 + KIF3C as an important genetic combination in HGF manifestation and suggest that ZNF513 mutation may be a major risk factor for HGF.

New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes.

BACKGROUND: Hereditary gingival fibromatosis (HGF) is an uncommon genetic condition characterized by slow but progressive fibrous, non-hemorrhagic, and painless growth of the gingival tissues due to the increased deposition of collagen and other macromolecules of the extracellular matrix. HGF occurs in approximately 1:750,000 individuals and can exhibit dominant or recessive inheritance. To date, five loci (2p21-p22, 2p22.3-p23.3, 4q12, 5q13-q22, and 11p15) and three genes [REST (RE1-silencing transcription factor), SOS1 (Son-of-Sevenless-1), and ZNF862 (zinc finger protein 862 gene)] have been associated with HGF. Here, our study aimed to identify genetic variants associated with HGF by applying whole-exome sequencing (WES) and bioinformatics analyses. METHODS: Thirteen Brazilian individuals with HGF and nine relatives without HGF from four unrelated families were chosen for our investigation. Blood collected from the patients and their relatives were used for WES. Five Web-available tools, namely, CADD, PolyPhen, SIFT, Mutation Taster, and Franklin's algorithms, were used to predict protein damage. RESULTS: WES revealed pathogenic variants affecting the known HGF genes REST (c.1491_1492delAG) and SOS1 (c.3265_3266insTAAC) in two families. Additionally, potentially pathogenic variants segregating in the other two families were mapped to ALK receptor tyrosine kinase gene (ALK) (c.361C > T) and to collagen type I receptor and thrombospondin receptor gene (CD36) (c.1133G > T). CONCLUSION: Our findings reinforce the high genetic heterogeneity of HGF, identifying new variants in HGF known genes (REST and SOS1) and ALK and CD36 as new genes that cause HGF.

Modified gingivoplasty for hereditary gingival fibromatosis: two case reports.

BACKGROUND: Hereditary gingival fibromatosis (HGF) is characterized by sub-epithelial fibromatosis of keratinized gingiva resulting in a fibrotic enlargement of keratinized gingiva. The treatment choice is gingivectomy, which can be performed with an internal or external bevel incision conventionally. However, both techniques can hardly resume the natural status of gingiva, and have a certain recurrence rate, especially in the cases which have limited width of attached gingiva. CASE DESCRIPTION: Two cases of HGF with the chief complaint of difficulty in mastication, pronunciation, and poor esthetics were presented. After the initial periodontal therapy, a novel gingivoplasty modified with a crevicular incision was applied. A full thickness flap above the mucogingival junction and a split flap below the junction were raised. Then, fibrotic connective tissue was completely eliminated and keratinized gingival epithelium was preserved. The fibrotic alveolar bone was shaped by handpiece and bur. Finally, the flap was apically repositioned and sutured. Twelve months after surgery, the gingiva recovered with normal color, contour and consistency. CONCLUSIONS: Compared to traditional gingivectomy, modified gingivoplasty which focuses on eliminating pathological fibrotic connective tissue can completely resume the natural appearance of gingiva and demonstrate no tendency of recurrence.

A novel gene ZNF862 causes hereditary gingival fibromatosis.

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis which is featured as a localized or generalized overgrowth of gingivae. Currently two genes (SOS1 and REST), as well as four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15), have been identified as associated with HGF in a dominant inheritance pattern. Here, we report 13 individuals with autosomal-dominant HGF from a four-generation Chinese family. Whole-exome sequencing followed by further genetic co-segregation analysis was performed for the family members across three generations. A novel heterozygous missense mutation (c.2812G > A) in zinc finger protein 862 gene (ZNF862) was identified, and it is absent among the population as per the Genome Aggregation Database. The functional study supports a biological role of ZNF862 for increasing the profibrotic factors particularly COL1A1 synthesis and hence resulting in HGF. Here, for the first time we identify the physiological role of ZNF862 for the association with the HGF.

Pathogenesis of Enamel-Renal Syndrome Associated Gingival Fibromatosis: A Proteomic Approach.

The enamel renal syndrome (ERS) is a rare disorder featured by amelogenesis imperfecta, gingival fibromatosis and nephrocalcinosis. ERS is caused by bi-allelic mutations in the secretory pathway pseudokinase FAM20A. How mutations in FAM20A may modify the gingival connective tissue homeostasis and cause fibromatosis is currently unknown. We here analyzed conditioned media of gingival fibroblasts (GFs) obtained from four unrelated ERS patients carrying distinct mutations and control subjects. Secretomic analysis identified 109 dysregulated proteins whose abundance had increased (69 proteins) or decreased (40 proteins) at least 1.5-fold compared to control GFs. Proteins over-represented were mainly involved in extracellular matrix organization, collagen fibril assembly, and biomineralization whereas those under-represented were extracellular matrix-associated proteins. More specifically, transforming growth factor-beta 2, a member of the TGFß family involved in both mineralization and fibrosis was strongly increased in samples from GFs of ERS patients and so were various known targets of the TGFß signaling pathway including Collagens, Matrix metallopeptidase 2 and Fibronectin. For the over-expressed proteins quantitative RT-PCR analysis showed increased transcript levels, suggesting increased synthesis and this was further confirmed at the tissue level. Additional immunohistochemical and western blot analyses showed activation and nuclear localization of the classical TGFß effector phospho-Smad3 in both ERS gingival tissue and ERS GFs. Exposure of the mutant cells to TGFB1 further upregulated the expression of TGFß targets suggesting that this pathway could be a central player in the pathogenesis of the ERS gingival fibromatosis. In conclusion our data strongly suggest that TGFß -induced modifications of the extracellular matrix contribute to the pathogenesis of ERS. To our knowledge this is the first proteomic-based analysis of FAM20A-associated modifications.

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K+ channelopathies.

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.

Cantú syndrome versus Zimmermann-Laband syndrome: Report of nine individuals with ABCC9 variants.

Cantú syndrome (CS) is a rare developmental disorder characterized by a coarse facial appearance, macrocephaly, hypertrichosis, skeletal and cardiovascular anomalies and caused by heterozygous gain-of-function variants in ABCC9 and KCNJ8, encoding subunits of heterooctameric ATP-sensitive potassium (KATP) channels. CS shows considerable clinical overlap with Zimmermann-Laband syndrome (ZLS), a rare condition with coarse facial features, hypertrichosis, gingival overgrowth, intellectual disability of variable degree, and hypoplasia or aplasia of terminal phalanges and/or nails. ZLS is caused by heterozygous gain-of-function variants in KCNH1 or KCNN3, and gain-of-function KCNK4 variants underlie the clinically similar FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) syndrome; KCNH1, KCNN3 and KCNK4 encode potassium channels. Within our research project on ZLS, we performed targeted Sanger sequencing of ABCC9 in 15 individuals tested negative for a mutation in the ZLS-associated genes and found two individuals harboring a heterozygous pathogenic ABCC9 missense variant. Through a collaborative effort, we identified a total of nine individuals carrying a monoallelic ABCC9 variant: five sporadic patients and four members of two unrelated families. Among the six detected ABCC9 missense variants, four [p.(Pro252Leu), p.(Thr259Lys), p.(Ala1064Pro), and p.(Arg1197His)] were novel. Systematic assessment of the clinical features in the nine cases with an ABCC9 variant highlights the significant clinical overlap between ZLS and CS that includes early developmental delay, hypertrichosis, gingival overgrowth, joint laxity, and hypoplasia of terminal phalanges and nails. Gain of K+ channel activity possibly accounts for significant clinical similarities of CS, ZLS and FHEIG syndrome and defines a new subgroup of potassium channelopathies.

"Electrifying dysmorphology": Potassium channelopathies causing dysmorphic syndromes.

Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.

Generalized hereditary gingival fibromatosis in a child: clinical, histopathological and therapeutic aspects

Hereditary gingival fibromatosis (HGF) is a rare genetic condition characterized by slow and progressive gingival enlargement. The gingival overgrowth often delays teeth eruption and may cause serious functional and aesthetic problems. We reported a case of a 10-year-old female child presenting a generalized gingival enlargement covering almost all the maxillary and mandibular teeth and resulted in problems for swallowing, speaking, and poor aesthetics. An incisional biopsy was performed and revealed a hypocellular and hypovascular dense collagenous tissue covered by squamous epithelium exhibiting acanthosis and elongated rete ridges. The diagnosis was HGF. The treatment instituted was an association of gingivectomy with a rigorous program of oral hygiene and follow-up. Herein, we describe a rare non-syndromic case of generalized HGF, including clinical and microscopical features, as well as highlighting the importance of correct diagnosis of this genetic condition.

Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca2+-Activated K+ Channel SK3 Cause Zimmermann-Laband Syndrome.

Zimmermann-Laband syndrome (ZLS) is characterized by coarse facial features with gingival enlargement, intellectual disability (ID), hypertrichosis, and hypoplasia or aplasia of nails and terminal phalanges. De novo missense mutations in KCNH1 and KCNK4, encoding K+ channels, have been identified in subjects with ZLS and ZLS-like phenotype, respectively. We report de novo missense variants in KCNN3 in three individuals with typical clinical features of ZLS. KCNN3 (SK3/KCa2.3) constitutes one of three members of the small-conductance Ca2+-activated K+ (SK) channels that are part of a multiprotein complex consisting of the pore-forming channel subunits, the constitutively bound Ca2+ sensor calmodulin, protein kinase CK2, and protein phosphatase 2A. CK2 modulates Ca2+ sensitivity of the channels by phosphorylating SK-bound calmodulin. Patch-clamp whole-cell recordings of KCNN3 channel-expressing CHO cells demonstrated that disease-associated mutations result in gain of function of the mutant channels, characterized by increased Ca2+ sensitivity leading to faster and more complete activation of KCNN3 mutant channels. Pretreatment of cells with the CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole revealed basal inhibition of wild-type and mutant KCNN3 channels by CK2. Analogous experiments with the KCNN3 p.Val450Leu mutant previously identified in a family with portal hypertension indicated basal constitutive channel activity and thus a different gain-of-function mechanism compared to the ZLS-associated mutant channels. With the report on de novo KCNK4 mutations in subjects with facial dysmorphism, hypertrichosis, epilepsy, ID, and gingival overgrowth, we propose to combine the phenotypes caused by mutations in KCNH1, KCNK4, and KCNN3 in a group of neurological potassium channelopathies caused by an increase in K+ conductance.

Rare case report of idiopathic gingival fibromatosis in childhood and its management.

Idiopathic gingival fibromatosis (GF), also known as gingivomatosis, is a rare condition in childhood, with an unknown aetiology. The oral manifestations of the condition are varied and depend on the severity and age of involvement. This paper describe the case of a 5-year-old male child with extensive gingival enlargement covering almost all the maxillary and mandibular teeth resulted in difficulty with speech, mastication and poor aesthetics. Clinical and radiographic examination along with haematological investigations ruled out any systemic association. The case was managed with conventional scalpel blade surgery along with electrocautery under general anaesthesia yielding good results without any recurrence after a 12-month follow-up. The results revealed that the oral manifestations of GF depend on its severity and the age of onset. Timely intervention can help to prevent associated complications in a growing child.

Fibroblasts from recurrent fibrotic overgrowths reveal high rate of proliferation in vitro - findings from the study of hereditary and idiopathic gingival fibromatosis.

PURPOSE: Investigate the content of fibrotic fibrils in gingival tissue and the proliferation of fibroblasts collected from recurrent and non-recurrent hereditary gingival fibromatosis (HGF) and idiopathic gingival fibromatosis (IGF). METHODS: Gingival biopsies were collected from HGF (n = 3) and IGF (n = 3) donors with recurrent and non-recurrent gingival overgrowths and from a control group (Ctrl, n = 3). Hematoxylin staining was performed to evaluate the histomorphology of gingival tissue. Heidenhain's AZAN trichrome staining served for visualization of fibrotic fibrils in gingiva. Quantitative analysis of the content of fibrotic fibrils in gingival tissue was performed using a polarized light microscope. Proliferation was evaluated at 24 h, 48 h, and 72 h in fibroblast cultures using a cell proliferation ELISA assay based on 5-bromo-2'-deoxyuridine (BrdU). RESULTS: Numerous blood vessels and fibroblasts were observed in recurrent overgrowths, whereas moderate blood vessels and moderate to scanty fibroblasts were detected in non-recurrent overgrowths. Heidenhain's staining revealed numerous collagen fibers in both recurrent and non-recurrent overgrowths. Quantitative analysis in a polarizing microscope showed significant accumulation of fibrotic fibrils exclusively in the overgrowths with the recurrence. In all time-points, increased proliferation of cells from all recurrent overgrowths was observed, but not from overgrowths which do not reoccur. CONCLUSIONS: The study revealed that recurrent gingival overgrowths consist of highly fibrotic and dense connective tissue with numerous blood vessels and abundant fibroblasts. We also demonstrated that unlike fibroblasts derived from overgrowths, which did not present recurrence, fibroblasts derived from highly fibrotic and recurrent overgrowths maintain high rate of proliferation in vitro.

TIMP-1 association with collagen type I overproduction in hereditary gingival fibromatosis.

OBJECTIVES: To investigate the processes associated with the excessive production of collagen I in hereditary gingival fibromatosis (HGF). MATERIALS AND METHODS: Three HGF subjects and five controls were enrolled in the study. Histomorphological and immunohistological analyses were performed on gingival tissues. The expression of heat-shock protein 47 (HSP47), collagen I, transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) by gingival fibroblasts isolated from HGF and controls was analysed using qRT-PCR, Western blotting and ELISA. RESULTS: Considerable accumulation of fibrotic fibrils and increased synthesis of HSP47 were noted in HGF gingival tissues. The synthesis of collagen I, HSP47, TGF-ß1, CTGF and TIMP-1 was significantly elevated in HGF gingival fibroblasts compared with controls, while the production of MMP-1 was decreased. CONCLUSIONS: We report that fibrosis in HGF gingival tissues is associated with increased synthesis of HSP47. This finding was confirmed by an in vitro study, where excessive production of collagen I was associated with increased synthesis of HSP47, TGF-ß1 and CTGF by HGF gingival fibroblasts. Moreover, the shift in the TIMP-1/MMP-1 ratio identifies increased synthesis of TIMP-1 as one of the processes associated with collagen I overproduction in HGF fibroblasts.

Analysis of mutations in the SOS-1 gene in two Polish families with hereditary gingival fibromatosis.

OBJECTIVES: To establish whether two families from Malopolska and Mazovia provinces in Poland are affected by hereditary gingival fibromatosis type 1, caused by a single-cytosine insertion in exon 21 of the Son-of-Sevenless-1 gene. MATERIAL AND METHODS: Six subjects with hereditary gingival fibromatosis and five healthy subjects were enrolled in the study. Gingival biopsies were collected during gingivectomy or tooth extraction and used for histopathological evaluation. Total RNA and genomic DNA were purified from cultured gingival fibroblasts followed by cDNA and genomic DNA sequencing and analysis. RESULTS: Hereditary gingival fibromatosis was confirmed by periodontal examination, X-ray, and laboratory tests. Histopathological evaluation showed hyperplastic epithelium, numerous collagen bundles, and abundant-to-moderate fibroblasts in subepithelial and connective tissue. Sequencing of exons 19-22 of the Son-of-Sevenless-1 gene did not reveal a single-cytosine insertion nor other mutations. CONCLUSIONS: Patients from two Polish families under study had not been affected by hereditary gingival fibromatosis type 1, caused by a single-cytosine insertion in exon 21 of the Son-of-Sevenless-1 gene. Further studies of the remaining regions of this gene as well as of other genes are needed to identify disease-related mutations in these patients. This will help to unravel the pathogenic mechanism of gingival overgrowth.

Immunohistochemical Analysis of Cell Proliferation and Bcl-2 Expression in Drug-Induced Gingival Overgrowth

Objective: To compare the rate of cell proliferation and expression of antiapoptotic protein Bcl-2 between drug-induced gingival overgrowth (DIGO) and clinical healthy gingiva (CHG) and to establish associations with histopathological features. Material and Methods: Twenty specimens of DIGO and 20 CHG specimens were submitted to morphological and immunohistochemical analysis by light microscopy. Cell proliferation (Ki-67) and the expression of Bcl-2 were evaluated in epithelial cells and spindle-shaped mononuclear cells of the connective tissue by establishing the labeling index (LI). Results: In epithelial tissue, the mean LI for Ki-67 was 17.2% in DIGO and 21.71% in CHG (p = 0.137). The mean LIs for Bcl-2 in epithelial tissue were 14.67% and 10.24% in DIGO and CHG, respectively (p = 0.026). In connective tissue, DIGO and CHG specimens exhibited low LIs for Ki-67 and Bcl-2, with mean values of less than 0.5% in both groups. No significant differences in the LIs for Ki-67 or Bcl-2 in epithelial tissue were observed according to the degree of collagenization, degree of vascularization and intensity of inflammatory infiltration (p > 0.05). No significant correlations were observed between the LIs for Ki-67 and Bcl-2 (p > 0.05). Conclusion: The present results suggest that the pathogenesis of DIGO does not involve increased proliferation or decreased apoptosis of fibroblasts. On the other hand, the morphological pattern of elongated epithelial cristae observed in DIGO could mainly be due to the inhibition of keratinocyte apoptosis and not to increased proliferation of these cells.

Giant maxillary gingival fibromatosis.

We present a case of both unusual pathology and severity - giant maxillary gingival fibromatosis - and discuss the disease and its management, accompanied by clinical imaging. This represents an overlap between maxillofacial and oral surgery, and may present as demonstrated in this case.

Ultrastructural evaluation of gingival connective tissue in hereditary gingival fibromatosis.

OBJECTIVE: To describe the ultrastructural features of hereditary gingival fibromatosis (HGF) in affected family members and compare microscopic findings with normal gingival (NG) tissue. STUDY DESIGN: Gingival tissue samples from nine patients with HGF from five unrelated families were evaluated by transmission electron microscopy. Nine NG tissue samples were used for comparison. RESULTS: Areas containing collagen fibrils forming loops and folds were observed in both groups, whereas oxytalan fibers were frequently identified in the HGF group. The diameter of collagen fibrils and the interfibrillar space among them were more uniform in the NG group than in the HGF group. Fibroblasts were the most common cells found in both the HGF and NG groups and exhibited enlarged, rough endoplasmic reticulum, mitochondria with well-preserved crests, conspicuous nucleoli, and euchromatic chromatin. Other cells, such as mast cells, plasma cells, and macrophages, were also observed. CONCLUSIONS: HGF tissues had ultrastructural characteristics that were very similar to those of NG tissues. Oxytalan fibers were observed more frequently in the HGF samples than in the NG samples. Other studies of HGF in patients from different families should be performed to better understand the pathogenesis of this hereditary condition.

Genomic analysis of gum disease and hypertrichosis in foxes.

Since the 1940s, a proliferative gingival disease called hereditary hyperplastic gingivitis (HHG) has been described in the farmed silver fox, Vulpes vulpes (Dyrendahl and Henricson 1960). HHG displays an autosomal recessive transmission and has a pleiotropic relationship with superior fur quality in terms of length and thickness of guard hairs. An analogous human disease, hereditary gingival fibromatosis (HGF), is characterized by a predominantly autosomal dominant transmission and a complex etiology, occurring either as an isolated condition or as a part of a syndrome. Similar to HHG, the symptom most commonly associated with syndromic HGF is hypertrichosis. Here we explore potential mechanisms involved in HHG by comparison to known genetic information about hypertrichosis co-occurring with HGF, using an Affymetrix canine genome microarray platform, quantitative PCR, and candidate gene sequencing. We conclude that the mitogen-activated protein kinase pathway is involved in HHG, however despite involvement of the mitogen-activated protein kinase kinase 6 gene in congenital hypertrichosis with gingival fibromatosis in humans, this gene did not contain any fixed mutations in exons or exon-intron boundaries in HHG-affected foxes, suggesting that it is not causative of HHG in the farmed silver fox population. Differential up-regulation of MAP2K6 gene in HHG-affected foxes does implicate this gene in the HHG phenotype.

Idiopathic Gingival Fibromatosis: Case Report and Review of the Literature.

Gingival fibromatosis (GF) is a condition characterized by a progressive, normal colored enlargement of the gingiva caused by an increase in the size of submucosal connective tissue. Both familial and idiopathic variants of the condition exist. The authors present a case report of a 38-year-old African American man who presented with an impressive overgrowth of the maxillary and mandibular gingivae, subsequently diagnosed as idiopathic GF. In this report, the authors will review the etiologies, treatment, and clinical and histological findings of GF, review similar cases found in the literature, and discuss the differential diagnosis for diffuse gingival enlargements.