Segmental Ipsilateral Odontognathic Dysplasia (Mandibular Involvement in Segmental Odontomaxillary Dysplasia?) and Identification of PIK3CA Somatic Variant in Lesional Mandibular Gingival Tissue.

Segmental odontomaxillary dysplasia (SOD) is a developmental condition of the middle and posterior maxilla featuring dysplastic bone overgrowth, dental abnormalities and, occasionally, various homolateral cutaneous manifestations. Herein, we describe an individual with maxillary abnormality akin to SOD and associated ipsilateral segmental odontomandibular dysplasia. Also, the result of the evaluation of lesional mandibular gingival tissue for overgrowth-related gene variants is reported. An 8-year-old girl presented clinically with congenital maxillary and mandibular alveolar soft tissue enlargement in the area of the premolars. A panoramic radiograph revealed abnormal trabeculation essentially similar to SOD in the maxilla and mandible with congenitally missing maxillary and mandibular first and second premolars and mandibular canines. Diagnostic mandibular bone biopsy was performed and lesional mandibular gingival hyperplastic tissue was obtained for variant analysis of somatic overgrowth genes PIK3CA, AKT1, AKT3, GNAQ, GNA11, MTOR, PIK3R2. Cone beam computerized tomography (CBCT) disclosed osseous abnormalities on the left side of the maxilla and mandible and very mild osseous expansion in the mandible. Histologically, abnormal bone exhibiting prominent reversal lines was present and associated with fibrocollagenous tissue. Genomic DNA analysis disclosed PIK3CAc.1571G>A; pArg524Lys which was seen at a low mosaic level in the blood, indicating a post-zygotic change. Although this case may be a unique disorder, by sharing features with SOD, one can suggest the possibility of mandibular involvement in SOD. The presence of a PIK3CA variant may support the hypothesis that these segmental disorders could be part of the PIK3CA-related overgrowth spectrum.

Drug-induced gingival hyperplasia: An in vitro study using amlodipine and human gingival fibroblasts.

Gingival overgrowth is a serious side effect that accompanies the use of amlodipine. Several conflicting theories have been proposed to explain the fibroblast's function in gingival overgrowth. To determine whether amlodipine alters the inflammatory responses, we investigated its effects on gingival fibroblast gene expression as compared with untreated cells. Fragments of gingival tissue of healthy volunteers (11 years old boy, 68 years old woman, and 20 years old men) were collected during operation. Gene expression of 29 genes was investigated in gingival fibroblast cell culture treated with amlodipine, compared with untreated cells. Among the studied genes, only 15 (CCL1, CCL2D, CCL5, CCL8, CXCL5, CXCL10, CCR1, CCR10, IL1A, IL1B, IL5, IL7, IL8, SPP1, and TNFSF10) were significantly deregulated. In particular, the most evident overexpressed genes in treated cells were CCR10 and IL1A. These results seem to indicate a possible role of amlodipine in the inflammatory response of treated human gingival fibroblasts.

Further evidence for causal FAM20A mutations and first case of amelogenesis imperfecta and gingival hyperplasia syndrome in Morocco: a case report.

BACKGROUND: Amelogenesis imperfecta represents a group of developmental conditions, clinically and genetically heterogeneous, that affect the structure and clinical appearance of enamel. Amelogenesis imperfecta occurred as an isolated trait or as part of a genetic syndrome. Recently, disease-causing mutations in the FAM20A gene were identified, in families with an autosomal recessive syndrome associating amelogenesis imperfecta and gingival fibromatosis. CASE PRESENTATION: We report, the first description of a Moroccan patient with amelogenesis imperfecta and gingival fibromatosis, in whom we performed Sanger sequencing of the entire coding sequence of FAM20A and identified a homozygous mutation in the FAM20A gene (c.34_35delCT), already reported in a family with this syndrome. CONCLUSION: Our finding confirms that the mutations of FAM20A gene are causative for amelogenesis imperfecta and gingival fibromatosis and underlines the recurrent character of the c.34_35delCT in two different ethnic groups.

Genome-wide expression analysis of hereditary hyperplastic gingivitis in silver foxes (Vulpes vulpes) using canine microarrays.

Hereditary hyperplastic gingivitis (HHG) is an autosomal recessive condition found predominantly in farmed silver foxes, first documented in Europe in the 1940s. Hereditary gingival fibromatosis (HGF) is an analogous condition occurring in humans. HGF has a heterogeneous aetiology with emphasis placed on the autosomal dominant forms of inheritance for which there are three known loci: HGF1, HGF2, and HGF3. Among these, only one causative mutation has been determined, in the Son of sevenless homolog 1 (SOS1) gene. The goal of this study was to explore potential molecular or cellular mechanisms underlying HHG by analysis of global gene expression patterns from Affymetrix Canine 2.0 microarrays cross-referenced against candidate genes within the human loci. We conclude that the SOS1 gene involved in HGF1 is not significantly up-regulated in HHG. However, the structurally and functionally similar SOS2 gene is up-regulated in affected foxes, and we propose this as a candidate gene for HHG. At HGF2 we identify RASA1 (rat sarcoma viral p21 protein activator 1) as a candidate gene for HHG, as it is up-regulated in affected foxes and is involved in MAPK signalling. From comparison to the genes within the HGF3 locus, we find evidence for a role of androgens in HHG phenotype severity by differential up-regulation of SRD5A2 in HHG-affected foxes. We hypothesize that the putative mutation occurs upstream of RAS in the extracellular signal-regulated kinase component of MAPK signalling.

Dentition abnormalities in a Timothy syndrome patient with a novel genetic mutation: a case report.

The purpose of this paper was to present the case of a two-year-old male diagnosed with Timothy syndrome who presented with generalized enamel defects in the primary dentition. Timothy syndrome is an autosomal dominant condition characterized by a de novo missense mutation in the Cav1.2 L-type calcium channel CACNA1C. Timothy syndrome patients present with multiple clinical manifestations, including: cardiac arrhythmias; syndactyly; immune deficiency; intermittent hypoglycemia; and neurologic issues, including seizures, mental retardation, hypotonia, and autism. Craniofacial abnormalities reported include: low-set ears; flat nasal bridge; small upper jaw; thin upper lip; round face; and baldness at birth. Abnormalities in the dentition have been reported, including small, misplaced teeth with poor enamel and severe caries. At present, there is no thorough description of the dental abnormalities seen in a patient with Timothy syndrome.

Oral manifestations of allograft recipients before and after renal transplantation.

Renal transplantation is considered the best treatment option for patients with end-stage renal disease. In this study, the prevalence of oral lesions was studied in a cohort of renal transplant recipients before and after transplantation. Fifty-nine kidney transplant recipients were examined one week before and four months after transplantation. The information gathered included age, sex, smoking history, duration on dialysis, drugs and their doses. There were 41 males (69.5%) and 18 females (30.5%) with a mean age of 37 years. Before surgery, two patients had non-specific lesions and two other patients had leukoedema. Following transplantation, 24 patients (40.7%) did not have any specific lesion. In six patients, we observed non-specific erythematous lesions (10.2%). Other recorded observations are as follows: Gingival hyperplasia in five patients (8.5%), oral candidiasis of the erythematous type in five patients (8.5%), hairy leukoplakia in four patients (6.8%) and leukoedema in seven patients (11.9%). In our study patients, the prevalence of oral lesions increased after transplantation, although it was lower than that reported in other studies. This could be due to the differences in sample size, differences between Iranian race and other races and different pharmaceutical formulation of the drug produced in Iran.

Craniofacial and dental development in Costello syndrome.

Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development.

FAM20A mutations associated with enamel renal syndrome.

We identified two families with an autosomal-recessive disorder manifested by severe enamel hypoplasia, delayed and failed tooth eruption, misshapen teeth, intrapulpal calcifications, and localized gingival hyperplasia. Genetic analyses identified novel FAM20A mutations associated with the disease phenotype in both families. The proband of Family 1 had an altered splice junction in Intron 1 (g.502011G>C; c.405-1G>C) and a missense mutation in Exon 8 (g.65094G>A; c.1207G>A; p.D403N). The missense mutation is notable because D(403) is strictly conserved among FAM20A homologues, and the corresponding defect in FAM20C caused osteosclerotic bone dysplasia and a loss of kinase activity. The proband at age 12 yrs tested negative for nephrocalcinosis. The proband and her affected father in Family 2 were homozygous for a single nucleotide deletion that altered a splice junction in Intron 10 (g.66622del; c.1361+4del). Minigene analyses demonstrated that this alteration precluded normal splicing. Immunohistochemistry (IHC) of mouse maxillary first molars localized FAM20A in secretory-stage ameloblasts, in odontoblasts, and in the eruption pathway. IHC of kidneys localized FAM20A in the renal tubules. We conclude that FAM20A is likely a secretory pathway kinase and that loss-of-function mutations cause pathology where its phosphorylations are necessary for normal development or homeostasis.

Common dental features and craniofacial development of three siblings with Ter Haar syndrome.

BACKGROUND: Ter Haar syndrome is a rare genetic syndrome with <30 cases reported worldwide. There is nothing within the published literature regarding the dental development and dental features of these patients. CASE REPORT: This case series examines three patients with Ter Haar syndrome and tracks their dental development and identifies common dental and skeletal features. FOLLOW-UP: All three patients received dental treatment and regular follow-up at Great Ormond Street Hospital Dental Department. CONCLUSION: These patients have many common dental and craniofacial features which poses the question as to whether these features are due to Ter Haar syndrome.

The role of MDR1 C3435T gene polymorphism on gingival hyperplasia in Turkish renal transplant patients treated with cyclosporine in the absence of calcium channel blockers.

OBJECTIVE: To investigate the occurrence of MDR1 C3435T gene polymorphisms in the Turkish renal transplant patients treated with cyclosporine (CsA), and correlate these findings with prevalence and degree of gingival hyperplasia (GH). METHODS: Before to renal transplantation, dental treatment and oral hygiene education of 300 renal disease patients was completed. Peripheral blood samples were collected from 154 renal transplant recipients on CsA treatment without calcium channel blockers. MDR1 C3435T gene polymorphism and GH were analyzed at posttransplant month 6. RESULTS: No difference was detected among groups for age, posttransplant period, creatine levels, serum concentration of CsA, or plaque and bleeding indices (P > .05). Out of all transplanted patients, 42.8% were found to have the heterozygote genotype. This was reduced to 37.5% when individuals with GH were taken into account. However, when degree of GH was analyzed, those with severe GH were found to have the heterozygote genotype significantly more often (P < .05). CONCLUSIONS: The MDR1 gene polymorphism is not associated with GH frequency, but may be associated with GH severity.

Inflammatory environment induces gingival tissue-specific mesenchymal stem cells to differentiate towards a pro-fibrotic phenotype.

BACKGROUND INFORMATION: Human gingival tissues are prone to hyperplasia under inflammatory stimuli. We have identified gingival tissue-specific mesenchymal stem cells (GMSCs) and found their functional change being correlated with drug-induced gingival hyperplasia. However, whether these cells exhibit characteristics of pro-fibrotic phenotype under inflammatory condition remains unknown. RESULTS: GMSCs isolated from human normal gingival tissues (N-GMSC) and inflammatory gingival tissues (I-GMSC) were cultured in vitro, representative cytokines were added to simulate the in vivo inflammatory environment. Under the influence of the inflammatory cytokines, GMSCs exhibited higher rate of proliferation than those under normal condition, while their potential for osteogenic and adipogenic differentiation was suppressed. The expression of matrix metalloproteinases (MMP)-1, MMP-2, IL-1, IL-6, TNF-α and type 1 collagen was significantly higher in I-GMSCs than in N-GMSCs. Furthermore, compared with dental pulp stem cells, GMSCs showed different pattern of gene expression and extracellular matrix formation in inflammatory environment. CONCLUSIONS: Inflammatory microenvironment induces GMSCs to differentiate towards a pro-fibrotic phenotype, which could underlie the hyperplastic appearance of inflammatory gingiva.

ABCB1 polymorphisms are associated with cyclosporine-induced nephrotoxicity and gingival hyperplasia in renal transplant recipients.

PURPOSE: There is a great deal of controversy regarding the clinical impact of genetic variants in patients receiving cyclosporine (CsA) as immunosuppressant therapy. We have investigated the effect of polymorphisms in the CYP3A and ABCB1 genes on CsA pharmacokinetics, acute rejection incidence and drug-related side effects in renal transplant recipients METHODS: The presence of CYP3A5*3, CYP3A4*1B and ABCB1 C1236T, G2677T/A and C3435T polymorphisms was assessed in 68 patients and retrospectively associated with pharmacokinetic and clinical parameters at 1 week and 1, 5 and 12 months after transplantation. RESULTS: Only minor associations were found between the tested polymorphisms and CsA pharmacokinetics. Most notably, CYP3A5 expressers showed lower blood trough levels than non-expressers in the first week after grafting (32.5 ± 14.7 vs. 55.1 ± 3.8 ng/ml per mg/day per kilogram). In terms of CsA-induced adverse effects, the incidence of nephrotoxicity was higher in carriers of the ABCB1 3435TT genotype and in those patients carrying four to six variants in the three ABCB1 loci [odds ratio (OR) 4.2, 95 % confidence interval (CI) 1.3-13.9, p = 0.02 and OR 3.6, 95 % CI 1.1-11.8, p = 0.05, respectively]. These subjects with four to six ABCB1 variants were also at higher risk for gingival hyperplasia (OR 3.29, 95 % CI 1.1-10.3, p = 0.04). Renal function and the incidence of neurotoxicity and of acute rejection did not vary across the different genotypes. CONCLUSIONS: ABCB1 polymorphisms may be helpful in predicting certain CsA-related side effects in renal transplant recipients. Our results also suggest that the mechanisms underlying these genetic associations are most likely independent of the drug's trough blood concentrations.

Hereditary gingival hyperplasia associated with amelogenesis imperfecta: a case report.

Hereditary gingival fibromatosis (HGF) and amelogenesis imperfecta (AI) are two rare oral conditions with genetic etiologies. The case of a 17-year-old boy affected by HGF, AI, anterior open bite, and pyramidal impaction of the maxillary molars is reported. Internal bevel gingivectomies were carried out to reduce gingival overgrowth. Clinical examination of the family revealed the presence of HGF and AI in his 12-year-old sister (both in milder forms) and of HGF in his older half brother. Genetic sequencing analyses were performed to detect any of the known mutations leading to HGF and AI. Histologic analysis revealed the presence of fibroepithelial hyperplasia, consistent with a diagnosis of GF. Sequencing genetic analysis failed to identify any of the common mutations leading to HGF (SOS-1) or AI (enamelin and amelogenin genes). This phenotype, similar to what has been described in other families, may represent a new syndrome caused by an as-yet unknown genotype.

Identification of 2 novel ANTXR2 mutations in patients with hyaline fibromatosis syndrome and proposal of a modified grading system.

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are rare, autosomal recessive disorders of the connective tissue caused by mutations in the gene encoding the anthrax toxin receptor 2 protein (ANTXR2) located on chromosome 4q21. Characteristically, these conditions present with overlapping clinical features, such as nodules and/or pearly papules, gingival hyperplasia, flexion contractures of the joints, and osteolytic bone defects. The present report describes a pair of sibs and three other JHF/ISH patients whose diagnoses were based on typical clinical manifestations and confirmed by histopathologic analyses and/or molecular analysis. A comparison of ISH and JHF, additional thoughts about new terminology (hyaline fibromatosis syndrome) and a modified grading system are also included.

Diagnosis and treatment of a hereditary gingival fibromatosis case.

Hereditary gingival fibromatosis (HGF) is a rare condition characterised by severe gingival hyperplasia, which could result in serious aesthetic and emotional problems and functional impairment. Here the present authors report a case of a 28-year-old female patient with generalised severe gingival enlargement covering almost all of the teeth and diagnosed as HGF. Her family history was of significance, since her father and 3-year-old daughter suffered from the same symptoms. Many studies have agreed that surgical removal should be used in the treatment of HGF, and gingivectomy is the most common method. This study tried both external and internal bevel incisions. The results suggest that the former is better for shaping gingival contour, if the attached gingiva is adequate. Correct physiological contour of the marginal gingiva, good oral hygiene and periodic recall can decrease recurrence risk. Post-surgical follow-up after 26 months demonstrated no recurrence and the patient was satisfied with her appearance.

A case report on autosomal recessive Robinow syndrome.

BACKGROUND: Robinow syndrome or "foetal face" syndrome is an extremely rare genetic disorder with characteristic skeletal and orofacial findings. The purpose of the present case report is to describe the clinical findings of an 8 year-old female patient with autosomal recessive Robinow syndrome. CASE REPORT: The patient was born to consanguineous parents and had anomalies typical of the recessive type of the syndrome such as short stature, mesomelic limb shortening, vertebral anomalies and dysmorphic facial features. Besides typical orodental findings, she also had root malformation in mandibular incisors, which is unusual finding of recessive type of Robinow syndrome. This case report emphasizes the importance of oral and dental manifestations of this syndrome.

Heterogeneity and atypical presentation in infantile systemic hyalinosis with severe labio-gingival enlargement: first Egyptian report.

Infantile systemic hyalinosis (ISH) (MIM 236490) is a rare, progressive, fatal autosomal recessive condition characterized by widespread deposition of hyaline material in many tissues. Our proband was a 4-year-old male with growth retardation, severe labio-gingival enlargement, generalized stiff skin, joint contractures, and intractable diarrhea. We discovered a history of a brother and sister who suffered a more severe disease course. A final diagnosis of systemic hyalinosis was made; we report this case and discuss the clinical and orodental heterogeneity among these siblings in the first report of an Egyptian family with ISH. We present a very rare entity, infantile systemic hyalinosis, a cause of joint contracture, protein-losing enteropathy, and growth retardation in infancy with a review of the relevant literature.

Copy-number mutations on chromosome 17q24.2-q24.3 in congenital generalized hypertrichosis terminalis with or without gingival hyperplasia.

Congenital generalized hypertrichosis terminalis (CGHT) is a rare condition characterized by universal excessive growth of pigmented terminal hairs and often accompanied with gingival hyperplasia. In the present study, we describe three Han Chinese families with autosomal-dominant CGHT and a sporadic case with extreme CGHT and gingival hyperplasia. We first did a genome-wide linkage scan in a large four-generation family. Our parametric multipoint linkage analysis revealed a genetic locus for CGHT on chromosome 17q24.2-q24.3. Further two-point linkage and haplotyping with microsatellite markers from the same chromosome region confirmed the genetic mapping and showed in all the families a microdeletion within the critical region that was present in all affected individuals but not in unaffected family members. We then carried out copy-number analysis with the Affymetrix Genome-Wide Human SNP Array 6.0 and detected genomic microdeletions of different sizes and with different breakpoints in the three families. We validated these microdeletions by real-time quantitative PCR and confirmed their perfect cosegregation with the disease phenotype in the three families. In the sporadic case, however, we found a de novo microduplication. Two-color interphase FISH analysis demonstrated that the duplication was inverted. These copy-number variations (CNVs) shared a common genomic region in which CNV is not reported in the public database and was not detected in our 434 unrelated Han Chinese normal controls. Thus, pathogenic copy-number mutations on 17q24.2-q24.3 are responsible for CGHT with or without gingival hyperplasia. Our work identifies CGHT as a genomic disorder.