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Rheumatology (Oxford, England) Feb 2019Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many... (Review)
Review
Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others. JAKs are the key initiating players of the JAK/STAT pathway. Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus. A class of drugs-called JAK inhibitors or JAKinibs-that block one or more JAKs has been developed in the last decade, and now numbers >20 members. Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond. In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA.
Topics: Alopecia Areata; Aortic Diseases; Arthritis, Psoriatic; Arthritis, Rheumatoid; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Chilblains; Cytokines; Dental Enamel Hypoplasia; Dermatitis, Atopic; Giant Cell Arteritis; Humans; Immunologic Deficiency Syndromes; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Lupus Erythematosus, Cutaneous; Metacarpus; Muscular Diseases; Nervous System Malformations; Odontodysplasia; Osteoporosis; Psoriasis; Spondylarthropathies; Uveitis; Vascular Calcification
PubMed: 30806709
DOI: 10.1093/rheumatology/key276 -
Arteriosclerosis, Thrombosis, and... Jan 2021Arterial calcification is a common phenomenon in the elderly, in patients with atherosclerosis or renal failure and in diabetes. However, when present in very young... (Review)
Review
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.
Topics: Animals; Aortic Diseases; Arteries; Dental Enamel Hypoplasia; Gaucher Disease; Genetic Predisposition to Disease; Heredity; Humans; Metabolism, Inborn Errors; Metacarpus; Muscular Diseases; Odontodysplasia; Osteogenesis; Osteoporosis; Phenotype; Risk Assessment; Risk Factors; Vascular Calcification
PubMed: 33176451
DOI: 10.1161/ATVBAHA.120.315577 -
Frontiers in Physiology 2015The most common root malformations in humans arise from either developmental disorders of the root alone or disorders of radicular development as part of a general tooth... (Review)
Review
The most common root malformations in humans arise from either developmental disorders of the root alone or disorders of radicular development as part of a general tooth dysplasia. The aim of this review is to relate the characteristics of these root malformations to potentially disrupted processes involved in radicular morphogenesis. Radicular morphogenesis proceeds under the control of Hertwig's epithelial root sheath (HERS) which determines the number, length, and shape of the root, induces the formation of radicular dentin, and participates in the development of root cementum. Formation of HERS at the transition from crown to root development appears to be very insensitive to adverse effects, with the result that rootless teeth are extremely rare. In contrast, shortened roots as a consequence of impaired or prematurely halted apical growth of HERS constitute the most prevalent radicular dysplasia which occurs due to trauma and unknown reasons as well as in association with dentin disorders. While odontoblast differentiation inevitably stops when growth of HERS is arrested, it seems to be unaffected even in cases of severe dentin dysplasias such as regional odontodysplasia and dentin dysplasia type I. As a result radicular dentin formation is at least initiated and progresses for a limited time. The only condition affecting cementogenesis is hypophosphatasia which disrupts the formation of acellular cementum through an inhibition of mineralization. A process particularly susceptible to adverse effects appears to be the formation of the furcation in multirooted teeth. Impairment or disruption of this process entails taurodontism, single-rooted posterior teeth, and misshapen furcations. Thus, even though many characteristics of human root malformations can be related to disorders of specific processes involved in radicular morphogenesis, precise inferences as to the pathogenesis of these dysplasias are hampered by the still limited knowledge on root formation.
PubMed: 26578979
DOI: 10.3389/fphys.2015.00307 -
International Journal of Environmental... Feb 2022Regional odontodysplasia is a rare developmental disorder characterised by hypoplasia and hypomineralisation of enamel and dentin. Our systematic review aimed to... (Review)
Review
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.
Topics: Bibliometrics; Dentition, Permanent; Female; Humans; Maxilla; Odontodysplasia; Radiography; Tooth, Deciduous
PubMed: 35162705
DOI: 10.3390/ijerph19031683 -
Pediatric Rheumatology Online Journal Jun 2016Defective regulation of type I interferon response is associated with severe inflammatory phenotypes and autoimmunity. Type I interferonopathies are a clinically... (Review)
Review
Defective regulation of type I interferon response is associated with severe inflammatory phenotypes and autoimmunity. Type I interferonopathies are a clinically heterogenic group of Mendelian diseases with a constitutive activation of this pathway that might present as atypical, severe, early onset rheumatic diseases. Skin vasculopathy with chilblains and livedo reticularis, interstitial lung disease, and panniculitis are common. Recent studies have implicated abnormal responses to nucleic acid stimuli or defective regulation of downstream effector molecules in disease pathogenesis. As observed for IL1-β and autoinflammatory diseases, knowledge of the defects responsible for type I interferonopathies will likely promote the development of targeted therapy.
Topics: Aortic Diseases; Arthritis, Juvenile; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Dental Enamel Hypoplasia; Homozygote; Humans; Interferon Type I; Lupus Erythematosus, Systemic; Metacarpus; Muscular Diseases; Mutation; Nervous System Malformations; Odontodysplasia; Osteochondrodysplasias; Osteoporosis; Proteome; Rare Diseases; Signal Transduction; Vascular Calcification
PubMed: 27260006
DOI: 10.1186/s12969-016-0094-4 -
The Saudi Dental Journal Jul 2019Regional odontodysplasia (RO) is a localized developmental anomaly involving both dentitions. The characteristic clinical findings are soft discolored several contiguous... (Review)
Review
BACKGROUND AND OBJECTIVE
Regional odontodysplasia (RO) is a localized developmental anomaly involving both dentitions. The characteristic clinical findings are soft discolored several contiguous teeth with atypical morphology associated with swelling or abscess formation. Radiographic images of the involved teeth show a ghost-like appearance because enamel and dentin are hypoplastic and hypocalcified. Although RO is known for more than seven decades, the literature on RO is mostly limited to case reports.The objective of this investigation was to provide an updated review of the literature with regards to clinical presentation and epidemiology of RO. Because of its rarity, retrospective analysis of the published reports across the world is considered one of the most appropriate available methods to analyze epidemiological and clinical data of RO. This review was reported and conducted according to the PRISMA guidelines.
RESULTS
Between 1953 and 2017, 161 cases were reported in literatures written in English. At the time of diagnosis, the age of the patients ranged between 1 and 25 years. There was slight female predilection with a ratio of 1.37: 1. When examined collectively, the maxilla was commonly affected compared to the mandible. RO occurred in both dentitions in 75 reported cases. While it affects the deciduous teeth alone in 19.3% and the permanent teeth in 34.2% of the cases. Failure of tooth eruption was the most common presenting finding (41.6%) followed by swelling of the affected area (32.3%).
CONCLUSION
Although RO was first described almost 80 years ago and the total subsequent case reports were over 160 cases, there is no consensus on its pathogenesis and how it should be treated. The descriptive nature of the examined case reports reveals the limited information on this condition. Further experimental and genetic studies are needed.
PubMed: 31337932
DOI: 10.1016/j.sdentj.2019.04.012 -
Head and Neck Pathology Mar 2020Regional odontodysplasia (RO) is a rare dental anomaly of unknown etiology that can affect both deciduous and permanent dentition. RO is characterized by severe...
Regional odontodysplasia (RO) is a rare dental anomaly of unknown etiology that can affect both deciduous and permanent dentition. RO is characterized by severe hypoplasia of enamel and dentin, and teeth affected are friable and more susceptible to caries and fractures. Most of the lesions occur in the anterior maxilla and correlation with clinical and radiographic features is essential to provide a correct diagnosis. The major criteria for diagnosis are predominantly based on radiography, which shows presence of large pulp chambers and a marked reduction in the radiopacity of enamel and dentin, making the distinction between these mineralized structures difficult. Early diagnosis is important to minimize future sequels and allow preventive or conservative treatment. The therapeutic approach of the RO should be based on the degree of severity of the anomaly and in the individual functional and aesthetic needs of each case. A classic case of RO affecting the maxilla is exemplified in this Sine Qua Non Radiology-Pathology article.
Topics: Child; Female; Humans; Maxilla; Odontodysplasia
PubMed: 30900210
DOI: 10.1007/s12105-019-01031-3 -
Journal of Medical Genetics Mar 2022Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic...
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 (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 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 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.
Topics: DEAD Box Protein 58; Exanthema; Glaucoma, Open-Angle; Humans; Interferons; Metacarpus; Odontodysplasia; Receptors, Immunologic
PubMed: 33495304
DOI: 10.1136/jmedgenet-2020-107447 -
Nucleic Acids Research Jun 2022DDX58 encodes RIG-I, a cytosolic RNA sensor that ensures immune surveillance of nonself RNAs. Individuals with RIG-IE510V and RIG-IQ517H mutations have increased...
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.
Topics: Autoimmune Diseases; DEAD Box Protein 58; DEAD-box RNA Helicases; Humans; Immunity, Innate; Metacarpus; Odontodysplasia; RNA
PubMed: 35580046
DOI: 10.1093/nar/gkac361 -
Hua Xi Kou Qiang Yi Xue Za Zhi = Huaxi... Feb 2024Regional odontodysplasia (ROD) is a localized developmental anomaly involving deciduous and permanent dentition, with a significant impact on patients. The affected... (Review)
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.
Topics: Humans; Child, Preschool; Odontodysplasia; Cellulitis; Face; Dentition, Permanent; Radiography
PubMed: 38475960
DOI: 10.7518/hxkq.2024.2023247