"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.

Epilepsy in KCNH1-related syndromes.

KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres. Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed. Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. Cerebral folate deficiency and an increase in urinary hypoxanthine and uridine were observed in one patient. Epilepsy is a key phenotypic feature in most individuals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood.

Gingival fibromatosis: a case report.

AIM: Gingival Fibromatosis is characterised by a large increase in the gingival dimension which extends above the dental crowns, covering them partially or completely. The causes of the disease may have a genetic origin, in which case gingival hyperplasia may occur in isolation or be part of a syndrome, or acquired origin, which comes from specific drugs administered systemically. A form of gingival fibromatosis of idiopathic origin has been described. The therapy involves mainly the surgical removal of the hyperplastic gingival tissue, although in these cases recurrences are frequent. CASE REPORT: A 9 years old male patient came to observation at the Clinic of Pediatric Dentistry of the Tor Vergata Polyclinic of Rome. After Primary Gingival Fibromatosis was diagnosed, the therapeutic choice was to wait and postpone gingivectomy at the end of the development phase.

Effect of cannabidiol on human gingival fibroblast extracellular matrix metabolism: MMP production and activity, and production of fibronectin and transforming growth factor ß.

BACKGROUND AND OBJECTIVE: Marijuana (Cannabis sativa) use may be associated with gingival enlargement, resembling that caused by phenytoin. Cannabidiol (CBD), a nonpsychotropic Cannabis derivative, is structurally similar to phenytoin. While there are many reports on effects of phenytoin on human gingival fibroblasts, there is no information on effects of Cannabis components on these cells. The objective of this study was to determine effects of CBD on human gingival fibroblast fibrogenic and matrix-degrading activities. MATERIAL AND METHODS: Fibroblasts were incubated with CBD in serum-free medium for 1-6 d. The effect of CBD on cell viability was determined by measuring activity of a mitochondrial enzyme. The fibrogenic molecule transforming growth factor ß and the extracellular matrix molecule fibronectin were measured by ELISA. Pro-MMP-1 and total MMP-2 were measured by ELISA. Activity of MMP-2 was determined via a colorimetric assay in which a detection enzyme is activated by active MMP-2. Data were analysed using ANOVA and Scheffe's F procedure for post hoc comparisons. RESULTS: Cannabidiol had little or no significant effect on cell viability. Low CBD concentrations increased transforming growth factor ß production by as much as 40% (p < 0.001), while higher concentrations decreased it by as much as 40% (p < 0.0001). Cannabidiol increased fibronectin production by as much as approximately 100% (p < 0.001). Lower CBD concentrations increased MMP production, but the highest concentrations decreased production of both MMPs (p < 0.05) and decreased MMP-2 activity (p < 0.02). CONCLUSION: The data suggest that the CBD may promote fibrotic gingival enlargement by increasing gingival fibroblast production of transforming growth factor ß and fibronectin, while decreasing MMP production and activity.

Gingival fibromatosis and significant tooth eruption delay in an 11-year-old male: a 30-month follow-up.

This case report describes the dental management of an unusual case of idiopathic gingival fibromatosis with multiple impacted primary teeth, and the absence of eruption of permanent teeth, in an 11-year-old boy and at the 30-month follow-up. The patient presented with severely enlarged gingival tissues affecting both arches and multiple retained and non-erupted primary teeth. He had already been subjected to localized gingivectomies at the ages of 7 and 9 years. He had no known syndrome and there was no family history of any similar disorder. The patient was treated under general anaesthesia to remove the excessive gingival tissues using apically positioned flaps. During the surgical procedure, over-retained and unerupted impacted primary teeth were extracted in order to facilitate the eruption of the permanent successors. Two years postoperatively, there was no recurrence of the gingival enlargement. Overdentures were then constructed because none of the permanent teeth had yet erupted. Furthermore, pre-eruptive coronal resorption was detected radiographically affecting the crown of the unerupted 36. Thirty months postoperatively, no recurrence of gingival enlargement was seen, but the permanent teeth had still not erupted.

Transforming growth factor-beta1 autocrine stimulation regulates fibroblast proliferation in hereditary gingival fibromatosis.

BACKGROUND: Hereditary gingival fibromatosis (HGF) is a rare oral disease characterized by a slow and progressive enlargement of both the maxilla and mandible gingiva. Increased proliferation, elevated synthesis of extracellular matrix, particularly collagen, and reduced levels of matrix metalloproteinases seem to contribute to the pathogenesis of gingival overgrowth in HGF patients. Transforming growth factor-beta1 (TGF-beta1) is an important cytokine thought to play a major role in fibrotic disorders such as HGF due to its ability to stimulate the synthesis and reduce the degradation of extracellular matrix. In HGF fibroblasts, TGF-beta1 autocrine stimulation reduces expression and production of matrix metalloproteinases. However, the role of TGF-beta1 in fibroblast growth modulation has not been established in this disease. METHODS: The aim of this study was to confirm the increased proliferation rate of HGF fibroblast cell lines and to explore a possible autocrine role of TGF-beta1 as a cell growth stimulator by blocking production of this endogenous cytokine using 2 well-established systems: antisense oligonucleotides and neutralizing antibodies. RESULTS: Four different cellular proliferation assays, bromodeoxyuridine labeling, argyrophilic nucleolar organizing region staining, proliferating cell nuclear antigen, and mitotic indexes, confirmed that fibroblasts from HGF proliferate significantly faster than those from normal gingiva. Antisense oligonucleotides reduced TGF-beta1 production as demonstrated by capture enzyme-linked immunosorbent assay, whereas TGF-beta1 expression levels were not significantly modified. Blocking TGF-beta1 synthesis with oligonucleotides or its activity with specific antibodies resulted in a decreased magnitude of HGF fibroblast proliferation. CONCLUSION: These results are consistent with the existence of an autocrine role of TGF-beta1 as a stimulator of HGF fibroblast proliferation.

Fibroma ossificante periférico e fibroma ossificante: estudo utilizando a técnica do AgNOR / Paripheral ossifyng fibroma and ossifyng fibroma: study with the AgNOR technique

Avaliaçäo da proliferaçäo celular através da análise quantitativa e morfométrica das regiöes organizadoras nucleolares (NORs) foi realizada em 10 casos de fibromas ossificantes periféricos e em 10 casos de fibromas ossificantes, com a finalidade de coletar informaçöes sobre essas duas entidades. Para a identificaçäo das NORs, realizamos a técnica da prata coloidal, conhecida como técnica do AgNOR. Com a análise dos parâmetros das NORs, verificamos, para ambas as lesöes que apresentam comportamento benigno; entretanto, essa própria análise demonstrou uma atividade proliferativa maior do fibroma ossificante em relaçäo ao fibroma ossificante periférico