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.

Gingival Fibromatosis with Significant De Novo Formation of Fibrotic Tissue and a High Rate of Recurrence.

BACKGROUND Hereditary gingival fibromatosis is characterized by slowly progressive enlargement of the gingiva that can present as an isolated condition or present as part of various syndromes. CASE REPORT An 11-year-old female reported with a gingival lesion that caused masticatory problems and poor oral hygiene. Periodontal examination revealed a dense tissue covering 30% of her teeth crowns within both jaws. Panoramic x-ray showed a normal bone height and teeth positioning. The patient did not use any medications, but a similar condition was also present in other family members. The patient was diagnosed with hereditary gingival fibromatosis. Surgery was carried out to remove excess of gingival tissue. Post-surgical healing was uneventful, but four weeks after the first surgery, the condition recurred amounting to 45% of the initial tissue volume presenting in the mandible, and 25% in the maxilla. Two months later, no significant growth was noted in the mandible, while in the maxilla, growth increased to 40% of the preoperative state. Analysis by polarized microscope showed a significant increase of thin fibrotic fibrils that contributed 80% of the total pool of collagen fibrils in the patient's gingiva, but only 25% in healthy gingiva. The patient was receiving outpatient care for follow-up every three months and surgical intervention had not been planned as long as her periodontal health was not be compromised.  CONCLUSIONS It is currently not clear whether the extent of the fibrosis had a mechanistic association with the ratio of gingival tissue re-growth in our case study. Further studies are needed to explain this association and improve the management of this condition.

Gingival fibromatosis: clinical, molecular and therapeutic issues.

Gingival fibromatosis is a rare and heterogeneous group of disorders that develop as slowly progressive, local or diffuse enlargements within marginal and attached gingiva or interdental papilla. In severe cases, the excess tissue may cover the crowns of the teeth, thus causing functional, esthetic, and periodontal problems, such as bone loss and bleeding, due to the presence of pseudopockets and plaque accumulation. It affects both genders equally. Hereditary, drug-induced, and idiopathic gingival overgrowth have been reported. Hereditary gingival fibromatosis can occur as an isolated condition or as part of a genetic syndrome. The pathologic manifestation of gingival fibromatosis comprises excessive accumulation of extracellular matrix proteins, of which collagen type I is the most prominent example. Mutation in the Son-of-Sevenless-1 gene has been suggested as one possible etiological cause of isolated (non-syndromic) hereditary gingival fibromatosis, but mutations in other genes are also likely to be involved, given the heterogeneity of this condition. The most attractive concept of mechanism for drug-induced gingival overgrowth is epithelial-to-mesenchymal transition, a process in which interactions between gingival cells and the extracellular matrix are weakened as epithelial cells transdifferentiate into fibrogenic fibroblast-like cells. The diagnosis is mainly made on the basis of the patient's history and clinical features, and on histopathological evaluation of affected gingiva. Early diagnosis is important, mostly to exclude oral malignancy. Differential diagnosis comprises all pathologies in the mouth with excessive gingival overgrowth. Hereditary gingival fibromatosis may present as an autosomal-dominant or less commonly autosomal-recessive mode of inheritance. If a systemic disease or syndrome is suspected, the patient is directed to a geneticist for additional clinical examination and specialized diagnostic tests. Treatments vary according to the type of overgrowth and the extent of disease progression, thus, scaling of teeth is sufficient in mild cases, while in severe cases surgical intervention is required. Prognosis is precarious and the risk of recurrence exists.

Generalised fibrotic gingival enlargement in a psoriatic patient: an association or a coincidence?

Gingival fibromatosis is a rare, benign, slow progressive fibrous overgrowth of gingiva, with great genetic and clinical heterogeneity. It can be inherited as an isolated trait (hereditary/idiopathic gingival fibromatosis), and/or as a component of a syndrome. We report a case of a young girl suffering from psoriasis who also presented with an unusual generalised idiopathic gingival fibromatosis. Psoriasis, a chronic inflammatory skin disease, of multifactorial origin, is characterised by keratinocyte hyperproliferation, dedifferentiation, neoangiogenesis and inflammation. T cell-mediated immunity is considered to be the key element in the disease process. The existence of oral mucosal alterations in patients with psoriasis is a controversial topic, as histopathological correlations are not clearly evident, and oral and cutaneous lesions do not follow a parallel course. However, this article highlights a possible association of T-lymphocyte stimulation inducing fibroblasts to undergo epidermal hyperproliferation and increased collagen production in the gingiva, which in turn may be responsible for inducing gingival hyperplasia.

Role of smoking and type 2 diabetes in the immunobalance of advanced chronic periodontitis.

BACKGROUND: This study evaluates the tissue levels of interleukin (IL)-17(+), IL-15(+), Foxp3(+) cells, fibrosis, and plasma B-cell infiltration in sites with chronic periodontitis in smokers and subjects with type 2 diabetes. METHODS: Gingival biopsies were harvested from the following groups: systemically and periodontally healthy subjects (healthy group, n = 10); non-smokers and subjects with advanced periodontitis and without diabetes (non-risk factor/periodontitis group, n = 10); heavy smokers with advanced periodontitis and without diabetes (smoking/periodontitis group, ≥20 cigarettes per day for at least the past 5 years, n = 10); and non-smoking poorly controlled subjects with diabetes (glycated hemoglobin levels ≥9%) with advanced periodontitis (diabetes mellitus/periodontitis group [DMP], n = 10). The number of IL-17(+), IL-15(+), and Foxp3(+) cells was analyzed by immunohistochemistry, whereas the amount of fibrosis and plasma B-cell infiltration in gingival tissue was analyzed by histomorphometry. RESULTS: The number of Foxp3(+) cells was significantly higher in the periodontitis groups compared to the healthy group (P <0.05). The DMP group presented higher levels of Foxp3(+) cells than other periodontitis groups (P <0.05). The levels of IL-15(+) and IL-17(+) cells and the amount of fibrosis were higher in the DMP group than in the other groups (P <0.05). There was a trend for a decreased B-cell infiltration in the DMP group (P >0.05). There was a slightly significant negative correlation between B-cell infiltration and the amount of fibrosis (P <0.05). CONCLUSION: Upregulation of IL-17(+), IL-15(+), and Foxp3(+) cells and increased amounts of fibrosis were observed in chronic periodontitis sites in subjects with type 2 diabetes, suggesting that periodontitis development in these subjects may be influenced by the T helper 17/T regulatory axis.

Current concepts on gingival fibromatosis-related syndromes.

Gingival fibromatosis is a rare, benign, slowly-growing fibrous overgrowth of the gingiva, with great genetic and clinical heterogeneity. Gingival fibromatosis/overgrowth can be inherited as an isolated trait (hereditary gingival fibromatosis) and/or as a component of a syndrome, or it can be drug induced. As a clinical manifestation of a syndrome, gingival fibromatosis is usually associated with generalized hypertrichosis, mental retardation, or epilepsy. Gingival fibromatosis and its related syndromes are mainly inherited in an autosomal-dominant manner, but autosomal-recessive inheritance has also been reported. Clinical syndromic presentation includes Zimmermann-Laband syndrome, Ramon syndrome, Rutherford syndrome, Cowden syndrome, Cross syndrome, Göhlich-Ratmann syndrome, Avani syndrome, and I-cell disease. However, a phenotypic overlap has been suggested, as many combinations of their systemic manifestations have been reported. Treatment of choice is usually gingivectomy with gingivoplasty. Before any therapy, clinical practitioners must take into consideration the clinical course of a particular syndrome and every possible functional and esthetic disorder.

Oral findings in 58 adults with tuberous sclerosis complex.

BACKGROUND: Gingival fibromas and dental pitting are among the diagnostic criteria for tuberous sclerosis complex (TSC). OBJECTIVE: Our goal was to document the oral findings in 58 adult patients with TSC. RESULTS: Forty patients (69%) had oral fibromas, appearing mostly on the attached or interdental gingiva. Other oral mucosal sites with fibromas included buccal and labial mucosa, the superior labial frenulum, palate, and tongue. In all, 56 patients (97%) had multiple dental enamel pits. LIMITATIONS: This case series comprised predominantly adult women with TSC and lymphangioleiomyomatosis. CONCLUSIONS: Oral fibromas in TSC are mostly, but not exclusively, gingival. Dental pits are present in nearly all patients. The multiple oral papules in TSC may appear similar to those observed in Cowden syndrome, Birt-Hogg-Dubé syndrome, and rarely in multiple endocrine neoplasia type 1.

Epulis granulomatosa as an oral manifestation of Klippel-Trénaunay syndrome.

The Klippel-Trénaunay syndrome (KTS) was first described by Klippel and Trénaunay in 1900. It is characterized by the triad of hemihypertrophy of soft and hard tissue, naevus flammeus and venous varicosity in the affected area. Though all oral tissues may be affected, only 5% of KTS show manifestations in the head and neck region. Only three cases are described with an oral manifestation, showing gingival overgrowth clinically and histologically corresponding to a pyogenic granuloma. It is still uncertain whether the combination of gingival fibromatosis and KTS is significant or coincidental. We report about a 25-year-old patient with KTS and recidivous gingival fibromatosis, clinically and histologically corresponding to an epulis fibromatosa in a case report. It is suggested that this occurrence is significant.

Treatment of gingival fibromatosis associated with Zimmermann-Laband syndrome.

BACKGROUND: Gingival fibromatosis is a rare condition characterized by a generalized enlargement of the buccal and lingual aspects of the attached and marginal gingiva. METHODS: This case report describes the periodontal management of a 13-year-old female patient with gingival fibromatosis associated with Zimmermann-Laband syndrome. The patient presented with gingival enlargement involving the maxillary and the mandibular arches, anterior open bite, and non-erupted teeth. Periodontal treatment included gingivectomy in all four quadrants. RESULTS: Histopathologic evaluation of the excised tissue supported the diagnosis of gingival fibromatosis. A significant improvement in esthetic appearance and eruption of the non-erupted teeth were obtained. The patient was referred for appropriate orthodontic treatment and has been closely followed for the earliest signs of recurrence of gingival enlargement. CONCLUSIONS: The successful therapy for gingival fibromatosis depends on correctly identifying the etiological factors and improving the impaired function and esthetic appearance through surgical intervention and adjunctive orthodontics. Maintaining treatment results depends on preservation of periodontal health.

Oral manifestations of juvenile hyaline fibromatosis: a case report.

Hyaline fibromatosis is a rare autosomal recessive disease of connective tissue, characterised by an accumulation of hyaline in the skin as well as various organs. The clinical features include: multiple cutaneous nodules, joint contractures, osteolytic lesions and gingival hypertrophy. This paper reports the case of an 11-year-old boy, who was referred to our dental clinic complaining of pain in his mouth. On examination, the patient had gross maxillary and mandibular gingival hyperplasia, which caused severe feeding difficulties. He also had severe dental decay, mal-positioned teeth and limited mouth opening. Treatment was done under general anesthesia to remove excess gingival tissue and extract the severely decayed teeth. Histological examination confirmed the diagnosis of juvenile hyaline fibromatosis. It was concluded that patients with this condition have special dental needs. Early diagnosis of the affected children is important in order to start early preventive dental therapy.

Gengivite plasmocitária: relato de caso clínico / Plasma cell gingivitis: a case report

A gengivite plasmocitária é uma condição caracterizada clinicamente por um aspecto eritematoso e edemaciado da gengiva. O tecido conjuntivo apresenta um proeminente infiltrado de plasmócitos. Esta condição foi muitas vezes relacionada a processos alérgicos ou de hipersensibilidade a goma de mascar e a aditivos de sabor presentes em diversas substâncias. Este artigo relata um caso clínico no qual o diagnóstico foi de gengivite plasmocitária de origem idiopática

Fibromatosis gingival hereditaria: reporte de un caso familiar de cuatro miembros / Hereditary fibromatosis gingival: report of family case of four members

La presencia de deformidades mucogingivales generalmente tiene un impacto en cuanto se refiere a la estética y función, la variedad de presentaciones de estas deformidades impide hacer una única definición. Las deformidades mucogingivales como se define aqui, puede ser congénita, del desarrollo o por inducción farmacológica. Estas pueden ocurrir alrededor de piezas dentarias naturales o de implantes, pueden localizarse en tejidos blandos o ser asociados con defectos de la estructura ósea. Pueden también mostrar diferentes grados de severidad o extensión. Cualquier clasificación de deformidades mucogingivales deberán incluir un método de identificación de las diferentes condiciones que incluyan un buen diagnóstico, identificación etiológica, investigación y el tratamiento adecuado además de su evolución posterior. Este es el reporte de un caso familiar de cuatro hermanas que presentaron y presentan la enfermedad, cuyas evidencias clínicas y la historia de la enfermedad familiar hacen pensar en una fibromatosis gingival hereditaria, asociadas a la no erupción de piezas dentarias, especialmente premolares superiores e inferiores que han provocado la formación de quistes dentigeros, además de un probable hirsutismo.

Congenital defect of maxillary primary central incisor associated with exposed pulp and gingival [fibrosis]: case report.

This report describes a rare case of hypoplastic primary incisor in which the pulp was exposed at the crown portion and covered by the gingiva in a 1-year-11-month-old boy. The patient was referred to us due to swelling of his labial cervical gingiva of the maxillary right primary central incisor, and on examination, extended to the hypoplastic labial surface. Radiographically, there was a round radiolucent area on the crown including the edge. Surgical removal of the swollen gingiva revealed a large defect of the labial aspect of the incisor, showing pulpal tissue inside. The tooth was treated by vital pulpotomy. Histopathologically, the removed gingival tissue contained many pieces of dysplastic tooth elements in the lamina propria portion which should have been connected to the exposed pulp. The findings suggested that pulp exposure resulted from focal dental hypoplasia not from resorption of the tooth.

Fibroma de células gigantes: estudo histomorfológico de 21 casos e discussäo dos conceitos atuais / Giant cell fibroma: histomorphological study of the 21 cases and discussion of actual concepts

Foram analisados clínica e histomorfologicamente 21 casos de fibroma de células gigantes, diagnosticados no Serviço de Anatomia Patológica de Departamento de Odontologia da UFRN. Verificou-se maior ocorrência no sexo feminino (71,4 por cento) e de raça branca (66,6 por cento); a gengiva revelou-se o sítio anatômico preferencial. Microscopicamente, estas lesöes foram caracterizadas por proliferaçäo de células estreladas ou angulares volumosas, muitas delas exibindo aspecto dendrítico, ocasionalmente, contendo numerosos núcleos, e imersas em um tecido conjuntivo fibroso frouxamente arranjado. Também fotam discutidos alguns conceitos atuais acerca da histogênese desta patologia

[Syndromes 20. Tuberous sclerosis complex]. / Syndromen 20. Het tubereuze sclerosecomplex.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disease. It is clinically a very variable disorder. Hamartomas can develop in many different organs, including the skin, kidneys, heart and brain. Diagnosis of patients with minimal expression of the disease can be very difficult. The dentist can contribute to the (early) diagnosis of the disease.

Fibromatose gengival e a necessidade de um diagnóstico diferencial: casos clínicos / Gingival fibromatosis: and the racional for a diferencial diagnosis: a clinical report

Descrevendo as diferentes formas etiológicas da fibromatose gengival e ilustrando-as com casos clínicos, com este trabalho procurou-se fornercer aos leitores informaçöes relevantes para facilitar o diagnóstico e tratamento destas doenças

Gingival fibromatosis with prune-belly syndrome.

A case is described in which a child appeared for evaluation with marked gingival overgrowth, facial dysmorphism, and abdominal defects consistent with prune-belly syndrome. The relationship between this case and other reports of gingival enlargement are discussed. Coincidence of the oral, facial, and abdominal abnormalities has not been previously reported.

Juvenile hyaline fibromatosis of gingiva: a case report.

Juvenile hyaline fibromatosis is an extremely rare inherited condition, probably resulting from an inborn error of metabolism. It is characterized by cutaneous nodules, gingival hypertrophy and joint contractions. It affects children but usually it is not present at birth, and is microscopically characterized by a conspicuous hyalinization of the connective tissue.