PHACES syndrome and multi-regional odontodysplasia: a case report.

PHACES syndrome is an acronym for the syndromic presentation of Posterior fossa malformation, Hemangioma, Arterial anomalies, Coarctation of aorta/cardiac defects, Eye abnormalities and Sternal malformations. Infantile hemangiomas are the most common tumors of infancy. Regional odontodysplasia, commonly referred to as "ghost teeth", is a rare localized developmental malformation of enamel and dentin with varying levels of severity that results in unusual clinical and radiographic appearances of affected teeth. This report describes a rare case of a two-year-old Caucasian male diagnosed with PHACES syndrome also presenting with multi-regional odontodysplasia. Ten of twenty teeth were dysplastic. The patient was treated under general anesthesia in a hospital setting. All affected primary teeth were extracted due to sensitivity, abscess and extremely poor long-term prognosis. Moving forward, a long-term interdisciplinary approach will be necessary to address this child's dentition as it develops.

DDX58 variant triggers IFN-ß-induced autophagy in trabecular meshwork and influences intraocular pressure.

Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-ß-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-ß on TM cells. Our study is the first to demonstrate that IFN-ß significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-ß remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-ß-induced autophagy in TM cells, we performed microarray analysis in IFN-ß-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-ß-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-ß. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-ß, which elevates IOP by modulating autophagy through RSAD2 in TM cells.

[Research progress in regional odontodysplasia].

Regional odontodysplasia (ROD) is a rare localized dental developmental anomaly. The typical clinical manifestations of ROD are abnormal tooth eruption, abnormal development of enamel and dentin. The radiographic characteristic is "ghost teeth". Its etiology still remains unknown. The care and treatment of a patient with ROD needs a multidisciplinary approach. And the treatment should be taken after the assessment of each individual case of ROD. This paper reviews the definition, etiology, epidemiological features, clinical manifestations, imaging features, dental microstructure and treatment strategies of ROD to provide reference for clinical diagnosis and treatment.

Regional odontodysplasia with facial cellulitis: a case report and literature review.

Regional odontodysplasia (ROD) is a localized developmental anomaly involving deciduous and permanent dentition, with a significant impact on patients. The affected teeth display unique ghost-like radiological characteristics, clinically manifesting as delayed tooth eruption, abnormal tooth morphology, and recurrent swelling of gingiva. In this paper, we report a case of a 2-year-old patient with ROD whose chief complaint was facial cellulitis. We analyze the medical history, clinical examination, radiographic findings, and histologic findings, and review the pathological features, pathogenesis, multidisciplinary diagnosis, and treatment of ROD. This rare case, which offers clinical samples for its further study, can provide a deeper study of ROD.

Evaluation of lymph node findings in patients with and without odontogenic infection: A clinical and ultrasonographic study / Evaluación de hallazgos ganglionares en pacientes con y sin infección odontogénica: un estudio clínico y ecográfico

Background: The present study aimed to evaluate the ultrasonographic findings of submandibular and submental lymph nodes in patients with and without odontogenic infection. Material and Methods: Systemically healthy patients aged 18-30 years old with or without odontogenic infections were included in this study. Clinical examinations were performed on all patients; those with any odontogenic infection were placed in the study group, and those without were placed in the control group. Ultrasonographic examinations of bilateral submental and submandibular lymph nodes were performed for both groups. The data were statistically analyzed using Pearson’s Chi-square test and Student’s t-test.Results: A total of 150 patients voluntarily participated (female: n=86 (57%), male: n=64 (43%)), 75 in the study group and 75 in the control group. During the ultrasonographic examination, patients in the study group had more than one lymph node the same patient was mostly detected, in the study group (right submandibular: n=42, 56%, and left submandibular: n=43, 57.3%). The long-axis diameter of the submandibular lymph nodes was 9.30±5.30 mm and 5.50±5.20 mm in the study and control groups, respectively. Conclusions: Ultrasonography revealed that the presence, number, and long-axis diameter of the submandibular lymph nodes in the patients with and without odontogenic infection were statistically different.(AU)

Mandibular Involvement Associated With Segmental Odontomaxillary Dysplasia: A Case Series.

Segmental odontomaxillary dysplasia (SOD) is an uncommon and likely underrecognized developmental condition. In rare cases, SOD can also result in anomalies of the ipsilateral mandibular alveolar process and teeth. This report presents two cases of SOD with mandibular involvement to highlight this potential variation in SOD presentation. These cases help shed new light on our understanding of the disease mechanism and pathoetiology, while also informing clinicians to be diligent in imaging the ipsilateral mandible for dental anomalies in their patients with SOD. Based on the involvement of both jaws, the name change to 'segmental ipsilateral odontognathic dysplasia' is justified to better reflect its pathophysiology.

Regional odontodysplasia diagnosed and treated via multidisciplinary approach: a case report.

Regional odontodysplasia (RO) is a rare non-hereditary dental anomaly associated with dysplasia. Its etiology remains unclear but is known to affect both the mesodermal and ectodermal dental components, as well as deciduous and permanent dentitions. Its young age of onset and complexity has great physical and psychological impact on the affected patients. However, the clinical management of RO remains unified without standardized treatment guidelines. Thus, this study aimed to report an RO case, the first from Jiangxi Province, China, and discuss its clinical diagnosis and treatment to provide a reference to treat similar cases more effectively in the future.

Regional odontodysplasia on the left side of the mandible: report of an unusual case.

Regional odontodysplasia (RO) is a rare developmental abnormality of epithelial and mesenchymal dental tissues. Due to its poorly understood etiology, assessing and discussing related clinical cases of this dental anomaly is crucial to guide professionals in improving its treatment and outcomes. This article aimed to report the case of a 9-year-old male patient who presented to our department with the main complaint of absent eruption of permanent left mandibular quadrant teeth. This is the first case reported in China from a patient with multiple cutaneous nevi on the face and neck, and based on the retrieved clinical and radiographic features, we described and discussed the treatment and etiology of RO.

Mandibular Regional Odontodysplasia in a Toddler.

Regional odontodysplasia (ROD) is a rare developmental anomaly with distinctive clinical, radiographical and histological findings, affecting both primary and permanent dentitions. The teeth with ROD have an atypical morphology and are usually discolored, with either delayed eruption or complete failure to erupt. Radiographically, the affected teeth have a "ghostly" appearance, with marked radiolucency and decreased radiodensity, showing a thin outline of enamel and dentin, which appear hypomineralized histologically, with poorly structured dentinal tubules and enamel prisms. Calcifications are frequently found in the pulp chambers of the affected teeth. This case report discusses a three-year-old girl who presented with ROD in her mandible as well as the clinical and radiographical features, and treatment of the condition.

Hereditary dentin defects with systemic diseases.

OBJECTIVE: This review aimed to summarize recent progress on syndromic dentin defects, promoting a better understanding of systemic diseases with dentin malformations, the molecules involved, and related mechanisms. SUBJECTS AND METHODS: References on genetic diseases with dentin malformations were obtained from various sources, including PubMed, OMIM, NCBI, and other websites. The clinical phenotypes and genetic backgrounds of these diseases were then summarized, analyzed, and compared. RESULTS: Over 10 systemic diseases, including osteogenesis imperfecta, hypophosphatemic rickets, vitamin D-dependent rickets, familial tumoral calcinosis, Ehlers-Danlos syndrome, Schimke immuno-osseous dysplasia, hypophosphatasia, Elsahy-Waters syndrome, Singleton-Merten syndrome, odontochondrodysplasia, and microcephalic osteodysplastic primordial dwarfism type II were examined. Most of these are bone disorders, and their pathogenic genes may regulate both dentin and bone development, involving extracellular matrix, cell differentiation, and metabolism of calcium, phosphorus, and vitamin D. The phenotypes of these syndromic dentin defects various with the involved genes, part of them are similar to dentinogenesis imperfecta or dentin dysplasia, while others only present one or two types of dentin abnormalities such as discoloration, irregular enlarged or obliterated pulp and canal, or root malformation. CONCLUSION: Some specific dentin defects associated with systemic diseases may serve as important phenotypes for dentists to diagnose. Furthermore, mechanistic studies on syndromic dentin defects may provide valuable insights into isolated dentin defects and general dentin development or mineralization.

Management of unerupted anterior teeth: an audit of treatment outcomes

Introduction: Anterior teeth are valuable for aesthetics, speech and mastication. Their absence, impaction, and/or delayed eruption reate significant distress often leading to early presentation to the dental office. This study presents an audit of the management of impacted anterior teeth that presented at a tertiary level dental clinic. The periodontal outcomes of the aligned teeth were also reported. Methods: This is an observational study spanning a nine-year period. Demographic data, clinical presentation, as well as post alignment dental and periodontal status of the impacted teeth were assessed. Data were analysed using the Statistical Package for Social Sciences (SPSS) version 26. Fisher's exact test and paired samples T-test were used for categorical and continuous variables respectively. Significance was set at P < 0.05. Results: Twenty-eight (1.76%) cases presented with failed eruption of 32 anterior teeth were observed during the period under review. Eight patients were treated by extraction, orthodontic treatment, and space closure or prosthetic replacement, with a mean treatment time of 2.83 ± 2.66 years. Thirteen patients completed treatment by orthodontic alignment with mean alignment time of 1.4 ± 1.5 years and treatment time of 3.6 ± 2.5 years. Average loss of root length observed was 1.5mm. There was significant difference in the post-operative root length of aligned teeth compared to their normal antimeres (p < 0.005). Conclusion: Patients with impacted anterior teeth presented later than was beneficial for spontaneous alignment of their teeth. The average 1.5mm loss of root length observed was not detrimental to the anatomical retention or function of the aligned teeth. There is need for more enlightenment with regards to early presentation for dental problems to avoid expensive and time-consuming treatments.

A loosened gating mechanism of RIG-I leads to autoimmune disorders.

DDX58 encodes RIG-I, a cytosolic RNA sensor that ensures immune surveillance of nonself RNAs. Individuals with RIG-IE510V and RIG-IQ517H mutations have increased susceptibility to Singleton-Merten syndrome (SMS) defects, resulting in tissue-specific (mild) and classic (severe) phenotypes. The coupling between RNA recognition and conformational changes is central to RIG-I RNA proofreading, but the molecular determinants leading to dissociated disease phenotypes remain unknown. Herein, we employed hydrogen/deuterium exchange mass spectrometry (HDX-MS) and single molecule magnetic tweezers (MT) to precisely examine how subtle conformational changes in the helicase insertion domain (HEL2i) promote impaired ATPase and erroneous RNA proofreading activities. We showed that the mutations cause a loosened latch-gate engagement in apo RIG-I, which in turn gradually dampens its self RNA (Cap2 moiety:m7G cap and N1-2-2'-O-methylation RNA) proofreading ability, leading to increased immunopathy. These results reveal HEL2i as a unique checkpoint directing two specialized functions, i.e. stabilizing the CARD2-HEL2i interface and gating the helicase from incoming self RNAs; thus, these findings add new insights into the role of HEL2i in the control of antiviral innate immunity and autoimmunity diseases.

Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report.

BACKGROUND: Singleton-Merten syndrome 1 (SGMRT1) is a rare type I interferonopathy caused by heterozygous mutations in the IFIH1 gene. IFIH1 encodes the pattern recognition receptor MDA5 which senses viral dsRNA and activates antiviral type I interferon (IFN) signaling. In SGMRT1, IFIH1 mutations confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation. CASE PRESENTATION: We report the case of a nine year old child who initially presented with a slowly progressive decline of gross motor skill development and muscular weakness. At the age of five years, he developed osteoporosis, acro-osteolysis, alveolar bone loss and severe psoriasis. Whole exome sequencing revealed a pathogenic de novo IFIH1 mutation, confirming the diagnosis of SGMRT1. Consistent with constitutive type I interferon activation, patient blood cells exhibited a strong IFN signature as shown by marked up-regulation of IFN-stimulated genes. The patient was started on the Janus kinase (JAK) inhibitor, ruxolitinib, which inhibits signaling at the IFN-α/ß receptor. Within days of treatment, psoriatic skin lesions resolved completely and the IFN signature normalized. Therapeutic efficacy was sustained and over the course muscular weakness, osteopenia and growth also improved. CONCLUSIONS: JAK inhibition represents a valuable therapeutic option for patients with SGMRT1. Our findings also highlight the potential of a patient-tailored therapeutic approach based on pathogenetic insight.

Regional Odontodysplasia: A Systematic Review of Case Reports.

Regional odontodysplasia is a rare developmental disorder characterised by hypoplasia and hypomineralisation of enamel and dentin. Our systematic review aimed to organise the knowledge on localisation, symptomatology and treatment methods in patients with regional odontodysplasia based on case reports published in the databases PubMed, Scopus and Web of Science. Case reports were described in 28 different countries, considering 180 patients (including 91 females). Regional odontodysplasia occurs mainly in both deciduous and permanent dentition (66.1%). The affected teeth were observed more frequently in the maxilla (70.0%), especially on the left side (45.6%). The most common reported symptoms were ghost teeth, poorly developed buds, yellowish-brown colour of crowns and delayed eruption of permanent teeth in affected quadrants. The most popular treatment method was surgical treatment (78.6%) with subsequent prosthetic therapy (34.6%). Based on the review of cases, pathognomonic clinical and radiological signs can be found, however, it is difficult to reach a consensus on the choice of treatment method.

A novel pathogenic variant p.Asp797Val in IFIH1 in a Japanese boy with overlapping Singleton-Merten syndrome and Aicardi-Goutières syndrome.

Pathogenic-activating variants of interferon induced with Helicase C domain 1 (IFIH1) cause Singleton-Merten (S-M) syndrome, which accompanies acro-osteolysis, loss of permanent teeth, and aortic calcification, as well as causing Aicardi-Goutières (A-G) syndrome, which shows progressive encephalopathy, spastic paraplegia, and calcification of basal ganglia. Recently, patients with overlapping syndromes presenting with features of S-M syndrome and A-G syndrome were reported. However, progression of clinical features of this condition has not been fully understood. We report a Japanese boy with a novel pathogenic IFIH1 variant who presented with clinical features of S-M syndrome and A-G syndrome.

DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation.

BACKGROUND: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2. METHODS: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed. RESULTS: We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin. CONCLUSIONS: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.

Computational Insights into the Structural Dynamics of MDA5 Variants Associated with Aicardi-Goutières Syndrome and Singleton-Merten Syndrome.

Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by IFIH1 in humans. Single nucleotide polymorphisms in the IFIH1 results in fatal genetic disorders such as Aicardi-Goutières syndrome and Singleton-Merten syndrome, and in increased risk of type I diabetes in humans. In this study, we chose four different amino acid substitutions of the MDA5 protein responsible for genetic disorders: MDA5L372F, MDA5A452T, MDA5R779H, and MDA5R822Q and analyzed their structural and functional relationships using molecular dynamic simulations. Our results suggest that the mutated complexes are relatively more stable than the wild-type MDA5. The radius of gyration, interaction energies, and intra-hydrogen bond analysis indicated the stability of mutated complexes over the wild type, especially MDA5L372F and MDA5R822Q. The dominant motions exhibited by the wild-type and mutant complexes varied significantly. Moreover, the betweenness centrality of the wild-type and mutant complexes showed shared residues for intra-signal propagation. The observed results indicate that the mutations lead to a gain of function, as reported in previous studies, due to increased interaction energies and stability between RNA and MDA5 in mutated complexes. These findings are expected to deepen our understanding of MDA5 variants and may assist in the development of relevant therapeutics against the disorders.

Singleton-Merten syndrome: A rare cause of femoral head necrosis.

Singleton-Merten syndrome (SMS) is a type I interferonopathy. In this report, we disclose the first-to the best of our knowledge-direct association of SMS with femoral head necrosis (FHN). The following case report presents the condition of a 38-year-old male suffering from SMS with FHN, characterized by acute symptoms and rapid disease progression. As per the recommendations of the Association Research Circulation Osseous (ARCO) and the S3-guidelines, we successfully treated the FHN with core decompression. Our histological results correlate with the changes described in medical literature in patients with SMS and MDA5-knockout in vivo experiments such as osteopenia, widened medullary cavity, and thin cortical bone. Moreover, the conducted immunohistochemistry shows strong CD56 positivity of the osteoblasts and osteocytes, as well as significant CD68 and CD163 positivity of the middle-sized osteoclasts. Collectively, these findings suggest an underlying syndrome in the FHN. A six-month post-operative follow-up revealed complete recovery with the absence of the initial symptoms and ability to resume normal daily activities. Taken together, our findings suggest that SMS is an additional cause of FHN in young adults. Early detection and adequate treatment using well-established joint-preserving techniques demonstrate a favorable improvement of the patient's clinical condition.

Description of four patients with TRIP11 variants expand the clinical spectrum of odontochondroplasia (ODCD) and demonstrate the existence of common variants.

More than two decades since the first clinical and radiological description of odontochondroplasia (ODCD) was reported, biallelic loss of function variants in the Thyroid hormone receptor interactor 11 gene (TRIP11) were identified, the same gene implicated in the lethal disorder achondrogenesis (ACG1A). Here we report the clinical and radiological follow-up of four ODCD patients, including two siblings and an adult who interestingly has the mildest form observed to date. Four TRIP11 variants were detected, two previously unreported. Subsequently, we review the clinical and radiological findings of the 14 reported ODCD patients. The majority of ODCD patients are compound heterozygotes for TRIP11 variants, 12/14 have a null allele and a splice variant whilst one is homozygous for an in-frame splicing variant, with the splice variants resulting in residual GMAP activity and hypothesized to explain why they have ODCD and not ACG1A. However, adult patient 4 has two potentially null alleles and it remains unknown why she has very mild clinical features. The c.586C>T; p.(Gln196*) variant, previously shown by mRNA studies to result in p.Val105_Gln196del, is the most frequent variant, present in seven individuals from four families, three from different regions of the world, suggesting that it may be a variant hotspot. Another variant, c.2993_2994del; p.(Lys998Serfs*5), has been observed in two individuals with a possible common ancestor. In summary, although there are clinical and radiological characteristics common to all individuals, we demonstrate that the clinical spectrum of TRIP11-associated dysplasias is even more diverse than previously described and that common genetic variants may exist.