Odontodysplasia is an uncommon dental developmental disorder associated with enamel, dentin, pulp abnormalities, and overall tooth morphology. The affected tooth is grossly abnormal in size and contour and is commonly associated with swelling of the affected area and failure of eruption. Histologically, the enamel and dentin are hypoplastic and hypomineralized. Odontodyplasia occurs most commonly in response to direct trauma to the developing tooth bud (enamel organ and dental follicle). Data on the prevalence and features of non-traumatic odontodysplasia are lacking. Medical records of dogs diagnosed with odontodysplasia were reviewed at the William R. Pritchard Veterinary Medical Teaching Hospital (VMTH), University of California, Davis, for 10 years (from 2013 to 2023). Dogs with a known history of facial trauma, persistent deciduous tooth or teeth over the region of odontodysplastic tooth or teeth, and endodontic disease of the persistent deciduous tooth or teeth were excluded from the study. Twenty-eight dogs were included in this retrospective study, representing an incidence of 1.4 per 100 dogs presenting over 10 years. Regional odontodysplasia (RO) was identified in twenty-two dogs, and generalized odontodysplasia (GO) was found in six dogs. Both comprehensive oral examination and diagnostic imaging were essential in diagnosing and assessing the presence of odontodysplasia. Awake oral examination failed to identify odontodysplasia in almost 70% of the RO cases. Secondary diseases or lesions in odontodysplastic teeth, such as periodontal disease, endodontal disease, and perio-endo lesions, were commonly seen and were particularly more frequently identified in strategic teeth (canine and carnassial teeth) than non-strategic ones. Similarities, such as female predilection, maxilla more commonly affected, and clinical signs, were observed between RO in dogs and those reported in people. The exact etiology of non-traumatic odontodysplasia remains elusive, and the condition may be of multifactorial causality.

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.
区域性牙发育不良（ROD）是一种局部乳恒牙发育异常，具有独特的鬼影样影像学表现，临床表现为牙齿萌出延迟、形态异常，牙周软组织反复肿胀等，对患者影响深远。本文报告1例因面部肿胀就诊的2岁患儿，通过病史、口腔检查、影像学及组织学检查，结合文献回顾，分析其病理特征、可能发病机制、多学科诊治特点，帮助临床医师深入了解这类罕见病，为进一步研究提供临床样本。.

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.

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.

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.
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.
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.
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.

Arterial calcification is a common phenomenon in the elderly, in patients with atherosclerosis or renal failure and in diabetes. However, when present in very young individuals, it is likely to be associated with an underlying hereditary disorder of arterial calcification. Here, we present an overview of the few monogenic disorders presenting with early-onset cardiovascular calcification. These disorders can be classified according to the function of the respective disease gene into (1) disorders caused by an altered purine and phosphate/pyrophosphate metabolism, (2) interferonopathies, and (3) Gaucher disease. The finding of arterial calcification in early life should alert the clinician and prompt further genetic work-up to define the underlying genetic defect, to establish the correct diagnosis, and to enable appropriate therapy.

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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.

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BACKGROUND: Type I interferonopathy is a group of autoinflammatory disorders associated with prominent enhanced type I interferon signaling. The mechanisms are complex, and the clinical phenotypes are diverse. This review briefly summarized the recent progresses of type I interferonopathy focusing on the clinical and molecular features, pathogeneses, diagnoses and potential therapies.
METHODS: Original research articles and literature reviews published in PubMed-indexed journals.
RESULTS: Type I interferonopathies include Aicardi-Goutières syndrome, spondyloenchondro-dysplasia with immune dysregulation, stimulator of interferon genes-associated vasculopathy with onset in infancy, X-linked reticulate pigmentary disorder, ubiquitin-specific peptidase 18 deficiency, chronic atypical neutrophilic dermatitis with lipodystrophy, and Singleton-Merten syndrome originally. Other disorders including interferon-stimulated gene 15 deficiency and DNAse II deficiency are believed to be interferonopathies as well. Intracranial calcification, skin vasculopathy, interstitial lung disease, failure to thrive, skeletal development problems and autoimmune features are common. Abnormal responses to nucleic acid stimuli and defective regulation of protein degradation are main mechanisms in disease pathogenesis. First generation Janus kinase inhibitors including baricitinib, tofacitinib and ruxolitinib are useful for disease control. Reverse transcriptase inhibitors seem to be another option for Aicardi-Goutières syndrome.
CONCLUSIONS: Tremendous progress has been made for the discovery of type I interferonopathies and responsible genes. Janus kinase inhibitors and other agents have potential therapeutic roles. Future basic, translational and clinical studies towards disease monitoring and powerful therapies are warranted.