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Background: Hereditary gingival fibromatosis (HGF) is a rare hereditary condition characterized by abnormal enlargement of the gingival tissue with a variable clinical manifestation. Typically, the hyperplastic gingiva is normal in color and consistency, and the tendency of bleeding is minimal. The swelling may be limited to a particular location or generalized over the whole gingiva. Usually, the symptoms appear during and after the eruption of permanent dentition. Gingival proliferation in HGF causes a variety of esthetic and practical issues. Depending on the size and intensity of the overgrowth, speech and chewing may be impaired. Moreover, diastema and prolonged primary dentition retention may occur. Case Reports: This article describes the identification, management, and treatment approaches of four cases affecting a Syrian family who lived in Arbat refugee camp in Sulaymaniyah, Kurdistan, Iraq. Conclusion: Proliferative fibrous outgrowth of the gingival tissue, with different degrees of involvement, is a hallmark of HGF. Surgery is frequently necessary to restore function and appearance, though varying degrees of recurrence is anticipated. Nonetheless, the psychological advantages of cosmetic improvement exceed the dangers of recurrence by a wide margin, especially in teenagers. [ABSTRACT FROM AUTHOR]

Abnormal hyperpolarization of the KCNK4 gene, expressed in the nervous system, brain, and periodontal ligament fibroblasts, leads to impaired neurotransmitter sensitivity, cardiac arrhythmias, and endocrine dysfunction, as well as, progressive cell proliferation. De novo gain of function variants in the KCNK4 gene were reported to cause a recognizable syndrome characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth (FHEIG, OMIM# 618381). FHEIG is extremely rare with only three reported cases in the literature. Herein, we describe the first inherited KCNK4 variant (c.730G>C, p.Ala244Pro) in an Egyptian boy and his mother. Variable phenotypic expressivity was noted as the patient presented with the full‐blown picture of the syndrome while the mother presented only with hypertrichosis and gingival overgrowth without any neurological manifestations. The c.730G>C (p.Ala244Pro) variant was described before in a single patient and when comparing the phenotype with our patient, a phenotype–genotype correlation seems likely. Atrial fibrillation and joint laxity are new associated findings noted in our patient extending the clinical phenotype of the syndrome. Dental management was offered to the affected boy and a dramatic improvement was noted as the patient regained his smile, restored the mastication function, and resumed his psychological stability. [ABSTRACT FROM AUTHOR]

Hereditary gingival fibromatosis (HGF) has been defined as a rare disorder characterized by a benign, nonhemorrhagic, fibrous gingival overgrowth that can appear in isolation or as part of a syndrome. Because it has no specific cause, it is also known as idiopathic gingival fibromatosis. HGF starts in its mildest form and progresses very slowly to reach a severe form that can cover the teeth, causing severe functional and cosmetic problems. Clinically, it appears as diffuse or localized gingival overgrowth, pinkish, and firm in consistency that could be seen in both the buccal and lingual gingiva of both the mandible and maxilla. There could be ulceration and bleeding secondary to traumatic biting on the lesion. We report a case of a 12-year-old boy who presented with 5-year history of multiple gingival lesions clinically diagnosed with HGF. The relevant literature and important aspect in the management of this condition has also been discussed. [ABSTRACT FROM AUTHOR]

The pathogenesis of hereditary gingival fibromatosis (HGF) is largely unknown; however, the removal of excess tissue may often be necessary as it often causes aesthetic and functional problems. Gingivectomy is usually a treatment option that can be performed using a scalpel, cryotherapy, electrosurgery, or laser. This paper aims to evaluate the results of HGF treatments using a diode laser of five people from the same family. Three members of a family of five (two females and three males; 9–36 years old) underwent gingivectomy with a 3 W 300‐micron fiber‐tipped diode laser (Doctor Smile, Vicenza, Italy) at 810 nm wavelength. While all teeth of one member were extracted, the other member refused treatment. Relapse occurred in three members due to poor oral hygiene. The diode laser was reapplied and oral hygiene instructions were repeated. Patients were followed during the postoperative period for up to two years. HGF is a rare condition that clinicians should pay attention to in the diagnosis, treatment, and follow‐ups. Since recurrences are due to dental plaque, oral hygiene instructions are essential and compliance is mandatory. Although there are many treatment approaches, the diode laser is the most indicated method due to many advantages such as providing a bloodless and more sterile operation field, performing an atraumatic surgery, ensuring earlier and ideal recovery, and minimizing postoperative pain. [ABSTRACT FROM AUTHOR]

Introduction: Nephroblastoma (Wilms tumor (WT)) is an embryonal tumor accounting for >90% of pediatric renal cancers. About 10% of WTs harbor pathogenic germline mutations. The REST gene, classified as a putative tumor suppressor, is affected in 2% of WTs. High-throughput molecular methods facilitate advanced diagnostics of cancer. In addition to this, germline mutations in REST are also associated with familial gingival fibromatosis (GFM). Reciprocally, none of the articles on RESTmut WT mentions GFM as a comorbid condition. This report provides unique evidence on the WT-GFM comorbidity in RESTmut carriers. Case presentation: Patient 1 (a 5-year-old boy with unilateral WT) is a proband, who has two healthy siblings. Patient 2 (a 4-year-old girl with bilateral WT) is a proband from in vitro fertilization (IVF) triplets, with a sister and brother without WT. We analyzed probands' DNA extracted from peripheral blood leucocytes with a custom-targeted next-generation sequencing (NGS)-198 gene panel. The detected variants were checked in family members by Sanger sequencing. Patient 1 had a pathogenic germline mutation in REST: c.1035_1036insTA, p.(E346*), as did his mother and both brothers. There were two other WT cases in this family (proband's maternal uncles). Patient 2 had a pathogenic germline variant in REST: c.2668_2671del, p.(E891Pfs*6), as well as her sister. The mutation was probably inherited from their deceased father, as he had gingival fibromatosis. Family members with REST mutations from both families had gingival fibromatosis. A somatic REST c.663C>A p.C221* mutation was identified in one patient with WT. At the moment both patients with WT are under dynamic observation without signs of the disease. Conclusion: Here, we describe two clinical cases of WT in nonrelated young children with germline-inactivating REST variants identified by next-generation sequencing. Both patients present with familial gingival fibromatosis, regarded as clinically useful comorbidity indicative of the tumor predisposition syndrome. The two cases illustrate Wilms tumor-gingival fibromatosis comorbidity in carriers of germline-inactivated REST alleles previously identified as a predisposition factor for both conditions. [ABSTRACT FROM AUTHOR]

Gingival fibromatosis is an enlargement of the gingiva with firm consistency without bleeding and can affect the maxilla or mandible. Gingival enlargement is caused by many factors, including inflammatory conditions, side effects of systemic drugs, hereditary, or idiopathic. A 7-year-old girl with a chief complaint of gingival enlargement throughout the maxillary and mandible. The condition was noted 3 years ago. This condition was not found in any member of the family, and there was no history of taking any medication. During intraoral examination, a complete enlargement of the maxillary gingiva and mandible was the same around, and bleeding did not exist. The patient was referred for a biopsy, and the histopathology result is consistent with gingival fibromatosis. Gingival enlargement can be caused by many factors; in this case, reported gingival fibromatosis is due to an idiopathic condition.

Gingival fibromatosis is an enlargement of the gingiva with firm consistency without bleeding and can affect the maxilla or mandible. Gingival enlargement is caused by many factors, including inflammatory conditions, side effects of systemic drugs, hereditary, or idiopathic. A 7-year-old girl with a chief complaint of gingival enlargement throughout the maxillary and mandible. The condition was noted 3 years ago. This condition was not found in any member of the family, and there was no history of taking any medication. During intraoral examination, a complete enlargement of the maxillary gingiva and mandible was the same around, and bleeding did not exist. The patient was referred for a biopsy, and the histopathology result is consistent with gingival fibromatosis. Gingival enlargement can be caused by many factors; in this case, reported gingival fibromatosis is due to an idiopathic condition. [ABSTRACT FROM AUTHOR]

Background: Although the molecular mechanisms that cause the development of hereditary gingival fibromatosis are not fully understood, multiple theories have been suggested to clarify its pathogenesis. However, the overlying keratinocytes' function is poorly comprehended. This work aimed to investigate the expression of TGF-β and MMP-2 in hereditary gingival fibromatosis epithelial cells compared to the normal gingival epithelium to give an insight into the mechanism of the development of this condition. Methods: Biopsies were obtained from 20 hereditary gingival fibromatosis patients and 20 healthy controls. Biopsies were stained immunohistochemically and statistically analyzed for MMP-2 and TGF-β expression. Results: Regarding MMP-2, The hereditary gingival fibromatosis group recorded a higher mean value compared to the normal gingiva, with a mean difference of 3.29 ± 0.34. This difference was statistically significant (p = 0.00). Regarding TGF-β, a higher mean value was recorded in the HGF group compared to the normal gingiva, with a mean difference of 15.88 ± 1.05 The difference was statistically significant (p = 0.00). A strong positive correlation was detected between MMP-2 and TGF-β (R = 0.534, p = 0.015). Conclusions: In hereditary gingival fibromatosis, the epithelium expresses higher levels of TGF-β and MMP-2 than normal gingival tissue. There was an evident positive correlation between MMP-2 and TGF-β. Our data suggest that the expression of TGF-β and MMP2 by epithelial cells of HGF may play a role in the epithelial-mesenchymal transition pathogenic pathway.

IntroductionNephroblastoma (Wilms tumor (WT)) is an embryonal tumor accounting for >90% of pediatric renal cancers. About 10% of WTs harbor pathogenic germline mutations. The REST gene, classified as a putative tumor suppressor, is affected in 2% of WTs. High-throughput molecular methods facilitate advanced diagnostics of cancer. In addition to this, germline mutations in REST are also associated with familial gingival fibromatosis (GFM). Reciprocally, none of the articles on RESTmut WT mentions GFM as a comorbid condition. This report provides unique evidence on the WT-GFM comorbidity in RESTmut carriers.Case presentationPatient 1 (a 5-year-old boy with unilateral WT) is a proband, who has two healthy siblings. Patient 2 (a 4-year-old girl with bilateral WT) is a proband from in vitro fertilization (IVF) triplets, with a sister and brother without WT. We analyzed probands’ DNA extracted from peripheral blood leucocytes with a custom-targeted next-generation sequencing (NGS)-198 gene panel. The detected variants were checked in family members by Sanger sequencing. Patient 1 had a pathogenic germline mutation in REST: c.1035_1036insTA, p.(E346*), as did his mother and both brothers. There were two other WT cases in this family (proband’s maternal uncles). Patient 2 had a pathogenic germline variant in REST: c.2668_2671del, p.(E891Pfs*6), as well as her sister. The mutation was probably inherited from their deceased father, as he had gingival fibromatosis. Family members with REST mutations from both families had gingival fibromatosis. A somatic REST c.663C>A p.C221* mutation was identified in one patient with WT. At the moment both patients with WT are under dynamic observation without signs of the disease.ConclusionHere, we describe two clinical cases of WT in nonrelated young children with germline-inactivating REST variants identified by next-generation sequencing. Both patients present with familial gingival fibromatosis, regarded as clinically useful comorbidity indicative of the tumor predisposition syndrome. The two cases illustrate Wilms tumor-gingival fibromatosis comorbidity in carriers of germline-inactivated REST alleles previously identified as a predisposition factor for both conditions.

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. [ABSTRACT FROM AUTHOR]

Amelogenesis imperfecta is a genetic disorder that manifests as a defect in the quality or quantity of enamel in both deciduous and permanent teeth, affecting some teeth or the entire dentition. A fraction of cases occur in conjunction with systemic involvement. Enamel renal syndrome is a rare entity diagnosed based on a combined presentation of amelogenesis imperfecta and renal calculi. The ambiguity surrounding succinct diagnostic criteria results in a significant underestimation of prevalence. A 12-year-old male presented with discoloration of teeth for two years with no relevant past medical or dental history. Intraoral examination revealed yellowish discoloration of the entire dentition and fibrotic gingival enlargement. Abdominal ultrasound revealed renal calculi. Based on the clinical, pathological, and radiographic features, a diagnosis of enamel renal syndrome was made. This case underscores the need for a comprehensive diagnostic workup to prevent complications that may arise from systemic involvement., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rebello et al.)

Although the molecular mechanisms that cause the development of hereditary gingival fibromatosis are not fully understood, multiple theories have been suggested to clarify its pathogenesis. However, the overlying keratinocytes' function is poorly comprehended. This work aimed to investigate the expression of TGF-β and MMP-2 in hereditary gingival fibromatosis epithelial cells compared to the normal gingival epithelium to give an insight into the mechanism of the development of this condition. Biopsies were obtained from 20 hereditary gingival fibromatosis patients and 20 healthy controls. Biopsies were stained immunohistochemically and statistically analyzed for MMP-2 and TGF-β expression. Regarding MMP-2, The hereditary gingival fibromatosis group recorded a higher mean value compared to the normal gingiva, with a mean difference of 3.29 ± 0.34. This difference was statistically significant (p = 0.00). Regarding TGF-β, a higher mean value was recorded in the HGF group compared to the normal gingiva, with a mean difference of 15.88 ± 1.05 The difference was statistically significant (p = 0.00). A strong positive correlation was detected between MMP-2 and TGF-β (R = 0.534, p = 0.015). In hereditary gingival fibromatosis, the epithelium expresses higher levels of TGF-β and MMP-2 than normal gingival tissue. There was an evident positive correlation between MMP-2 and TGF-β. Our data suggest that the expression of TGF-β and MMP2 by epithelial cells of HGF may play a role in the epithelial-mesenchymal transition pathogenic pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Zimmermann–Laband syndrome is a rare, heterogeneous disorder characterized by gingival hypertrophy or fibromatosis, aplastic/hypoplastic nails, hypoplasia of the distal phalanges, hypertrichosis, various degrees of intellectual disability, and distinctive facial features. Three genes are considered causative for ZLS: KCNH1, KCNN3, and ATP6V1B2. We report on a pair of female concordant monozygotic twins, both carrying a novel pathogenic variant in the KCNN3 gene, identified using exome sequencing. Only six ZLS patients with the KCNN3 pathogenic variant have been reported so far. The twins show facial dysmorphism, hypoplastic distal phalanges, aplasia or hypoplasia of nails, and hypertrichosis. During infancy, they showed mild developmental delays, mainly speech. They successfully completed secondary school education and are socio‐economically independent. Gingival overgrowth is absent in both individuals. Our patients exhibited an unusually mild phenotype compared to published cases, which is an important diagnostic finding for proper genetic counseling for Zimmermann–Laband syndrome patients and their families. [ABSTRACT FROM AUTHOR]

Idiopathic gingival fibromatosis (IGF) is a rare, benign, slow-growing proliferation of the gingival tissues involving both maxillary and mandibular gingiva. It is exacerbated during the eruptive phase of both primary and permanent dentitions. The purpose of this article is to report the case of a 10-year-old boy who presented with IGF whose gingival enlargement covered the occlusal surfaces of many teeth and displaced the erupting dentition, compromising the patient's cosmetics, function, speech and development. The treatment involved gingivectomy and gingivoplasty, combining both surgical and laser methods. The case showed remarkable esthetic and functional improvement, without signs of recurrence one year post-treatment. [ABSTRACT FROM AUTHOR]

Objective To explore the etiology, clinical manifestations, diagnosis, differential diagnosis and treatment of idiopathic gingival fibromatosis, and to provide references for clinical diagnosis and treatment. Methods The clinical data and related literatures of a case of idiopathicgingival fibroma that occurred in the oral cavity were retrospectively analyzed. Results Total periodontal treatment was performed for the patient, and the gingival morphology was improved after periodontal surgery in the anterior region. Idiopathic gingival fibromatosis is a rare disease characterized by gingival tissue hyperplasia. The etiology and pathogenesis are unknown. The disease can occur in young children. Generally, it occurs after the permanent teeth erupt, and it manifests as extensive gingival hyperplasia, which can affect the entire gingival margin, gingival papilla and attached gingival, and can even reach the membrane-gingival junction. The pathological changes include thickening of the spinous layer of the gingival epithelium, significant increases in the epithelial styloid process, increases in the connective tissue volume, and filling with large collagen fiber bundles and a large number of fibroblasts. The blood vessels are relatively small, and inflammation is not obvious. Clinically, this disease needs to be distinguished from drug-induced gingival hyperplasia and chronic gingivitis with hyperplasia as the main manifestation. At present, the treatment of idiopathic gingival fibromatosis is mainly gingival angioplasty. The disease easily relapses after surgery. The recurrence rate is related to the quality of oral hygiene. After recurrence, it can be treated again. Conclusion Idiopathic gingival fibromatosis is relatively rare, and the diagnosis mainly depends on the history of inquiry, clinical manifestations and pathological examination. The treatment is mainly surgical resection, and future research should focus on finding a more effective treatment.

The progressive overgrowth of the gingiva is the hallmark of idiopathic gingival fibromatosis (IGF). Excess gingival tissue can obscure the crown of a tooth, resulting in spaces between teeth, displacement, retention of primary or permanent teeth, and difficulties with feeding, speaking, and appearance. The diagnosis and management of inherited gingival fibromatosis are the focus of this case report. A 12-year-old girl was referred from the Department of Orthodontics to Oral Medicine as a result of progressive gingival enlargement, which impeded orthodontic treatment for misaligned lower front teeth. The patient underwent a conservative periodontal treatment regimen that encompassed gingivectomy and debridement. The excised gingival tissues were submitted for histopathological examination. Tissue sections stained with hematoxylin and eosin showed connective tissue with dense bundles of collagen fibers and little inflammation. The patient was reviewed after three months, and advised of orthodontic management for further aesthetic correction. The findings indicated that the oral symptoms of gingival fibromatosis are influenced by the severity of the condition and the age at which it begins. Early intervention helps mitigate potential difficulties for younger individuals., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Shree Abiraami et al.)

A six-year-old boy presented with short stature and gingival fibromatosis (GF). Dysmorphic features included slant optic fissures, a high-arched palate, thick earlobes, and an edematous face. Laboratory tests showed low levels of serum insulin-like growth factor-1 and serum free thyroxine but normal serum thyrotropin levels. Provocative tests suggested growth hormone deficiency, central hypocortisolemia, and hypothalamic hypothyroidism. At 12 years old, hypogonadotropic hypogonadism was observed. Next-generation sequencing revealed a heterozygous missense variant, KCNQ1 p. (P369L), in the proband and mother. The coexistence of multiple pituitary hormone deficiencies and GF helps diagnose KCNQ1-variant dysmorphic syndrome through genetic testing.

Zimmermann-Laband Syndrome (ZLS; MIM 135500) is a rare genetic disorder with the main clinical manifestations of gingival fibromatosis and finger/toe nail hypoplasia. KCNH1 (potassium channel, voltage-gated, subfamily H, member-1), KCNN3 (potassium channel, voltage-gated, subfamily H, member-3) and ATP6V1B2 (ATPase H + transporting V1 subunit B2) genes are considered causative genes for ZLS. However, there are limited reports about the diverse clinical presentation and genetic heterogeneity. Reporting more information on phenotype-genotype correlation and the treatment of ZLS is necessary. This case reported a 2-year-old patient with gingival enlargement that failure of eruption of the deciduous teeth and severe hypoplasia of nails. Based on a systemic examination and a review of the relevant literature, we made an initial clinical diagnosis of ZLS. A novel pathogenic variant in the KCNH1 gene was identified using whole-exome sequencing to substantiate our preliminary diagnosis. The histopathological results were consistent with gingival fibromatosis. Gingivectomy and gingivoplasty were performed under general anesthesia. After surgery, the gingival appearance improved significantly, and the masticatory function of the teeth was restored. After 2-year follow-up, the gingival showed slightly hyperplasia. Systemic examination and gene sequencing firstly contribute to provide information for an early diagnosis for ZLS, then timely removal of the hyperplastic gingival facilitates the establishment of a normal occlusal relationship and improves oral aesthetics., Competing Interests: The authors declare no conflict of interest., (©2024 The Author(s). Published by MRE Press.)

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 TGFβ 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 TGFβ 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 TGFβ effector phospho-Smad3 in both ERS gingival tissue and ERS GFs. Exposure of the mutant cells to TGFB1 further upregulated the expression of TGFβ 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 TGFβ -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. [ABSTRACT FROM AUTHOR]

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 TGFβ 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 TGFβ 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 TGFβ effector phospho-Smad3 in both ERS gingival tissue and ERS GFs. Exposure of the mutant cells to TGFB1 further upregulated the expression of TGFβ 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 TGFβ -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.

Objective: The aim of systematic review was to describe the phenotypes and molecular profiles of syndromes with gingival fibromatosis (GF). Methods: A comprehensive search of PubMed, LILACS, Livivo, Scopus, and Web of Science was conducted using key terms relevant to the research questions and supplemented by a gray literature search. The Methodological Quality and Synthesis of Case Series and Case Reports in association with the Case Series and Prevalence Studies from the Joanna Briggs Institute critical appraisal tools were used for the risk of bias. We followed the PRISMA checklist guidelines. Results: Eighty‐four studies reporting GF as an oral manifestation of a syndrome were identified in this review. Enamel renal syndrome was the most frequently reported syndrome with GF, represented by 54 individuals in 19 studies, followed by Zimmermann–Laband syndrome with 24 individuals in 15 studies and Costello syndrome, which was presented in a case series study with 41 individuals. Among reported cases, other clinical manifestations such as hypertrichosis, ectopic gingival calcification, and cherubism were described. Conclusions: The results emphasize the need of systematic oro‐dental‐facial phenotyping for future descriptions as well as further molecular analysis in order to better understand the occurrence of syndromic GF. [ABSTRACT FROM AUTHOR]

Introduction: Hereditary gingival fibromatosis (HGF) is a rare disease characterized by gingival enlargement, normal color with benign and firm consistency. This growth may be exacerbated by use of drugs and plaque build-up. The treatment for this clinical condition is surgical excision of the enlarged gingival tissue or the extraction of all teeth. Case Report: A 20-year-old Brazilian female handicapped patient with a chief complaint of exaggerated gingival enlargement who had been prescribed Carbamazepine and Gardenal was referred to our center. According to the clinical presentation and family history, the final diagnosis of gingival enlargement was HGF. Full dental treatment was performed, including basic periodontal treatment, restorations, sealants, and gingivoplasty with internal bevel. Special care was taken to ensure that there was no change in patient’s anticonvulsant medication. The patient has been monitored for seven years without signs of recurrence of gingival hyperplasia due to constant professional and home control of plaque.

Amelogenesis imperfecta type IG (AI1G) is caused by mutations in FAM20A. Genotypic and phenotypic features of AI1G are diverse and their full spectra remain to be characterized. The aim of this study was to identify and summarize variants in FAM20A in a broad population of patients with AI1G. We identified a Thai female (Pt-1) and a Saudi male (Pt-2) affected with AI1G. Both had hypoplastic enamel, gingival hyperplasia, and intrapulpal calcification. Pt-1 also had rapidly progressive embedding of unerupted teeth, early eruption of permanent teeth, and spontaneous dental infection. Uniquely, Pt-2 had all permanent teeth erupted which was uncommon in AI1G patients. Whole exome sequencing (WES) identified that Pt-1 was heterozygous for FAM20A, c.758A > G (p.Tyr253Cys), inherited from her father. The mutation on maternal allele was not detected by WES. Pt-2 possessed compound heterozygous mutations, c.1248dupG (p.Phe417Valfs*7); c.1081C > T (p.Arg361Cys) in FAM20A. Array comparative genomic hybridization (aCGH), cDNA sequencing, and whole genome sequencing successfully identified 7531 bp deletion on Pt-1's maternal allele. This was the largest FAM20A deletion ever found. A review of all 70 patients from 50 independent families with AI1G (including two families in this study) showed that the penetrance of hypoplastic enamel and gingival hyperplasia was complete. Unerupted permanent teeth were found in all 70 patients except Pt-2. Exons 1 and 11 were mutation-prone. Most mutations were frameshift. Certain variants showed founder effect. To conclude, this study reviews and expands phenotypic and genotypic spectra of AI1G. A large deletion missed by WES can be detected by WGS. Hypoplastic enamel, gingival hyperplasia, and unerupted permanent teeth prompt genetic testing of FAM20A. Screening of nephrocalcinosis, early removal of embedded teeth, and monitoring of dental infection are recommended. [ABSTRACT FROM AUTHOR]

Gingival enlargement refers to any increase in the size of normal gingiva. The gingiva may be enlarged in response to various interactions between the host and the environment. It can be of various types including inflammatory, drug induced, associated with systemic disease, neoplastic, false, and idiopathic. Idiopathic gingival enlargement is a rare condition of undetermined etiology. The enlargement can be localized or generalized to entire dentition and is usually associated with the emergence of the teeth into the oral cavity and may regress after extraction. Treatment aims to solve patient's psychological, esthetic, and masticatory needs. This is a case series of four siblings (3 boys and 1 girl) who reported to the Department of Periodontology with a chief complaint of swollen gums and difficulty in eating. After careful clinical examination and histopathological evaluation, a diagnosis of familial gingival fibromatosis was made. Treatment plan included gingivectomy and gingivoplasty and follow-ups.

Gingival fibromatosis with hypertrichosis syndrome is an extremely rare genetic condition characterized by profound overgrowth of hair and gums, as well as other variable features. Gingival fibromatosis is characterized by a large increase in the gingival dimension which extends above the dental crowns, covering them partially or completely. They were found to have a genetic origin, may also occur in isolation or be part of a syndrome, or acquired origin, due to specific drugs administered systemically. Congenital generalized hypertrichosis is a heterogeneous group of diseases with continuing excessive growth of terminal hair without androgenic stimulation. It has informally been called werewolf syndrome because the appearance is similar to that of a werewolf. Various syndromes have been associated with these features such as epilepsy, mental retardation, cardiomegaly, or osteochondrodysplasia. As so far very few cases have been reported in literature, we are reporting a series of three cases with management of the same. The excess gingival tissues, in these cases, were removed by conventional gingivectomy under general anesthesia. The postoperative result was uneventful and the patient's appearance improved significantly. Good esthetic result was achieved to allow patient to practice oral hygiene measures. Though this is not a serious condition clinically, psychosocial trauma cannot be neglected owing to the cosmetic disfigurement it produces.

Objective This study used exosomes derived from Idiopathic gingival fibromatosis （IGF-GFs） to investigate the influence on the cell cycle of normal gingival fibroblasts （N-GFs） . Methods The IGF-GFs and N-GFs were cultured，the exosomes were extracted after the supernatant of IGF-GFs was collected. The cell cycle transitions of N-GFs were detected after co-cultured with N-GFs-exosomes for 24h and 48h by flow cytometry （FCM） . Western blot （WB） were performed to detect the expressions of cyclin E1 proteins and cell cycle dependent kinase （CDK2） . Results The S phase proportions of NC-GFs treatmented with IGF-GFs-exsomes for 24h and 48h were significantly increased （ < 0.01） . Western blot results showed that after co-culture with IGF-GFs-exsomes, the relative expressions of cyclin E1 and CDK2 increased at 24h and 48h, and the different expressions of protein were statistically significant （ < 0.01） . Conclusion Exosomes derived from IGF-GFs possibly promote the transition of N-GFs cell cycle from G1 phase to S phase by regulating the expressions of cyclin E1 and CDK2 proteins, indicating that exosomes may promote the progress of cell cycles and promote cell proliferation. [ABSTRACT FROM AUTHOR]

Objective Using high- throughput sequencing technology to analyze differentially expressed miRNAs in exosomes secreted by gingival fibroblasts from idiopathic gingival fibromatosis and normal individuals， and to predict target genes and related signaling pathways through bioinformatics analysis， to further lay the foundation for the study of the pathogenesis of idiopathic gingival fibromatosis. Methods Gingival fibroblasts from Idiopathic gingival fibromatosis and normal individuals were cultured and the cell supernatant was collected to extract exosomes. High- throughput sequencing was used to detect differential expressions of exosomal- miRNAs in normal gingival fibroblasts（N- GFs） and Idiopathic gingival fibromatosis gingival fibroblasts（IGF- GFs） . Meanwhile target gene prediction and KEGG pathway prediction were performed on partially expressed miRNAs using software of TargetScan， miRDB， miRTarBase， miRWalk and KEGG databases， and the Real- time quantitative PCR was used to verify the expression of differential miRNAs in exosomes. Results Exosomal- miRNAs derived from IGF- GFs and N- GFs accounted for 0.74% and 0.46% of the non- coding RNA respectively; 92 genes with significantly different expression were screened by high- throughput sequencing. 12 candidate miRNAs were predicted 1304 target genes， as well as were predicted multiple signaling pathways．Three miRNAs were differentially expressed in IGF- GFs and N- GFs- derived exosomes ， which were detected by the Real- time quantitative PCR， and the differences were statistically significant （P < 0.05） . Conclusion There are differential expressions of exosome miRNAs derived from IGF- GFs and N- GFs， and differentially expressed miRNAs may play an important regulatory role in the pathogenesis of IGF. These miRNAs may mediate the development process of idiopathic gingival fibromatosis by targeting the 3'Un- Translation Region of target genes orvia predictive signaling pathways. [ABSTRACT FROM AUTHOR]

Objective: To present five cases of symmetrical palatal fibromatosis (SPF), a lesion reported very rarely in the English language literature, under more than a dozen different names, and to recommend the most appropriate name. Methods: Five SPF cases are characterized with a literature review. Results: Three females and two males, aged 20–39 years, presented with bilateral, symmetrical, asymptomatic, sessile, moderately firm, or soft (n = 2) masses of the lateral posterior hard palate; two were isolated to the tuberosities. All masses were normal in color, with smooth, non‐ulcerated surfaces and occasional surface nodularity. Underlying bone was radiographically normal, and adjacent teeth were asymptomatic. All masses originated from supra‐periosteal tissues over palatal bone, only secondarily extending to gingivae and/or crestal tuberosity. Cases were present between 4 months and 15 years, with no familial or environmental etiologies identified. Histopathologically, masses were comprised of dense, avascular fibrous tissue with scattered thick bands of collagen. Surface epithelium showed occasional long, thin, sometimes pointed rete processes, and subepithelial stroma contained scattered large, angular fibroblasts. Conservative surgical excision appeared curative in all cases. Conclusions: The present investigators propose SPF as the most accurate name for this rare entity. [ABSTRACT FROM AUTHOR]

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-2ʹ-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. [ABSTRACT FROM AUTHOR]

Idiopathic gingival fibromatosis is a rare genetically heterogeneous condition characterized by recurrent gingival enlargement without any identifiable cause. We report a case of 14-year-old female patient affected with sporadic, nonsyndromic, progressive gingival enlargement. It manifested more severely on the right side of the mouth with history of recurrence after prior conventional surgical excision. Electrosurgical resection of the enlargement was done, and overall patient management had a successful outcome along with achieving preservation of teeth with poor prognosis in the 2 years follow-up.

A case is reported of a 20-year-old woman with generalized severe gingival overgrowth covering almost all of the teeth with diastemata, diagnosed as idiopathic gingival fibromatosis. After initial therapy, the patient underwent surgery consisting of a full-mouth internal beveled gingivectomy. Postoperatively, the maxillary anterior teeth spontaneously moved to almost optimal positions. Removing the cause by gingivectomy can lead to spontaneous correction of the pathologic tooth migration. With supportive periodontal treatment, the patient showed no recurrence of gingival enlargement or repositioning of the teeth at the 5-year follow-up. [ABSTRACT FROM AUTHOR]

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Congenital generalized hypertrichosis associated with gingival hyperplasia are rare cases published in literature. The frequency incidence of generalized congenital hypertrichosis is about one to billions of people. Hypertrichosis and gingival hyperplasia are termed as Ambras syndrome (AS), which can be noticed at birth or soon after. Here, is a rare case report of 4-year-old male child who presented with generalized hypertrichosis with gingival fibromatosis and dysmorphic facial features.

Background: Zimmermann-Laband-1 syndrome (ZLS-1; OMIM# 135500) is a rare genetic disorder whose oral pathognomonic sign is the development of progressive, diffuse, and severe gingival hypertrophy. Most children with abnormally gingival hyperplasia may also present multiple unerupted teeth and skeletal deformities of maxillary arches (i.e., skeletal anterior open bite). Despite phenotypic variability of the clinical spectrum, gingival fibromatosis is the hallmark of ZLS-1. Method: In this study, we report a 3-year-old male patient with a ZLS-1-related gingival overgrowth and failure of eruption of the deciduous teeth in the molar area. Surgical excision was performed under general anesthesia. Results: At three weeks follow-up, esthetics was significantly improved in terms of gingival appearance, and teeth eruption allowed an adequate masticatory function. Conclusion: In severe cases, surgical removal of the hyperplasic fibrous tissue may be required to expose unerupted teeth and establish a proper gingival contour. Surgical excision under general anesthesia is an elective procedure for patients with special needs, mental disability, as well as young and adult patients with dental anxiety type II and IV associated with poor oral health.

Hereditary gingival fibromatosis is a disorder for which the etiology remains unknown. We aimed to evaluate the fibroblasts and histological alterations to give new clues. A father and a daughter of a family showing gingival hereditary fibromatosis were treated, and gingival biopsies were obtained. A histological study revealed dense fibrous tissue, basal lamina disruption, and epithelial cell migration into the connective tissue. Fibroblasts were cultured from the father and daughter and compared with those from a healthy control patient. The results of the biochemical analysis showed increased collagen synthesis, reduced antioxidant CoQ10 content, and high levels of lipid peroxidation. Additionally, fibroblasts culture incubation with the oxidant H2O2 increased collagen levels that have been reduced by the addition of the antioxidant CoQ10. We conclude that some fibroblasts metabolic alterations play a significant role in initiating and maintaining persistent fibrotic tissue. Oxidative stress influences the fibroblasts collagen production and could play a particular role in the pathogenesis of hereditary gingival fibromatosis.

Gingival fibromatosis is a condition characterized by a slow, progressive increase in the gingival tissue that develops as either an isolated disorder or as part of the clinical characteristics of diverse syndrome. The present case report describes a rare case of gingival fibromatosis and its management using scalpel in combination with electrosurgery. A 15-year-old girl patient presented with a chief complaint of gingival overgrowth covering all the surfaces upper and lower teeth. The growth was excised with periodontal knife in combination with electrosurgery under local anesthesia. After 1-year of follow-up, healing was uneventful with no recurrence. Combined technique for the removal of gingival overgrowth represents a unique treatment approach where minimal postoperative bleeding and discomfort were observed.

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3–p22.3, 5q13–q22, and 11p15) have been mapped to autosomes and one gene ( SOS1 ) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor ( REST ) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype. [ABSTRACT FROM AUTHOR]

Gingival fibromatosis with hypertrichosis syndrome is an extremely rare genetic condition characterized by profound overgrowth of hair and gums, as well as other variable features. Gingival fibromatosis is characterized by a large increase in the gingival dimension which extends above the dental crowns, covering them partially or completely. They were found to have a genetic origin, may also occur in isolation or be part of a syndrome, or acquired origin, due to specific drugs administered systemically. Congenital generalized hypertrichosis is a heterogeneous group of diseases with continuing excessive growth of terminal hair without androgenic stimulation. It has informally been called werewolf syndrome because the appearance is similar to that of a werewolf. Various syndromes have been associated with these features such as epilepsy, mental retardation, cardiomegaly, or osteochondrodysplasia. As so far very few cases have been reported in literature, we are reporting a series of three cases with management of the same. The excess gingival tissues, in these cases, were removed by conventional gingivectomy under general anesthesia. The postoperative result was uneventful and the patient's appearance improved significantly. Good esthetic result was achieved to allow patient to practice oral hygiene measures. Though this is not a serious condition clinically, psychosocial trauma cannot be neglected owing to the cosmetic disfigurement it produces. [ABSTRACT FROM AUTHOR]

Gingival enlargement refers to any increase in the size of normal gingiva. The gingiva may be enlarged in response to various interactions between the host and the environment. It can be of various types including inflammatory, drug induced, associated with systemic disease, neoplastic, false, and idiopathic. Idiopathic gingival enlargement is a rare condition of undetermined etiology. The enlargement can be localized or generalized to entire dentition and is usually associated with the emergence of the teeth into the oral cavity and may regress after extraction. Treatment aims to solve patient's psychological, esthetic, and masticatory needs. This is a case series of four siblings (3 boys and 1 girl) who reported to the Department of Periodontology with a chief complaint of swollen gums and difficulty in eating. After careful clinical examination and histopathological evaluation, a diagnosis of familial gingival fibromatosis was made. Treatment plan included gingivectomy and gingivoplasty and follow-ups. [ABSTRACT FROM AUTHOR]