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Current Osteoporosis Reports Aug 2017We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve... (Review)
Review
PURPOSE OF REVIEW
We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease.
RECENT FINDINGS
Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.
Topics: Abnormalities, Multiple; Aortic Diseases; Basal Ganglia Diseases; Calcinosis; Cartilage Diseases; Dental Enamel Hypoplasia; Diphosphates; Enzyme Replacement Therapy; Gaucher Disease; Hand Deformities, Congenital; Humans; Hyperostosis, Cortical, Congenital; Hyperphosphatemia; Interferons; Metacarpus; Muscular Diseases; Odontodysplasia; Osteoporosis; Phosphates; Progeria; Pseudoxanthoma Elasticum; Pulmonary Valve Stenosis; Vascular Calcification
PubMed: 28585220
DOI: 10.1007/s11914-017-0370-3 -
Journal of Dentistry For Children... Jan 2023Regional odontodysplasia (ROD) is a rare developmental anomaly with distinctive clinical, radiographical and histological findings, affecting both primary and permanent...
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.
Topics: Humans; Female; Child, Preschool; Odontodysplasia; Dentition, Permanent; Tooth, Deciduous; Dental Enamel; Mandible
PubMed: 37106528
DOI: No ID Found -
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 -
Journal of Dentistry For Children... May 2018Regional odontodysplasia is a non-hereditary development dental anomaly involving epithelial and mesenchymal-derived dental tissues. The condition affects both primary...
Regional odontodysplasia is a non-hereditary development dental anomaly involving epithelial and mesenchymal-derived dental tissues. The condition affects both primary and permanent teeth. Clinically, affected teeth are hypoplastic, soft upon probing, have a yellow-brown discoloration and present high susceptibility to caries. Radiographically, the teeth show enlarged pulp chambers, open apices and no clear differentiation between enamel and dentin. The reduced radiopacity of the enamel and dentin gave rise to the term ghost teeth. We present the case of a three-year-old boy diagnosed with regional odontodysplasia involving more than one quadrant, showing facial asymmetry and missing primary and permanent teeth.
Topics: Child, Preschool; Denture, Partial, Removable; Facial Asymmetry; Humans; Male; Odontodysplasia
PubMed: 30345960
DOI: No ID Found -
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 -
Annales de Dermatologie Et de... Nov 2015Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date,...
Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date, interferonopathies include Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, PRoteasome-associated auto-inflammatory syndrome (PRAAS) and Singleton-Merten syndrome. These diseases present phenotypic overlap including cutaneous features like chilblain lupus, that can be inaugural or present within the first months of life. This novel set of inborn errors of immunity is evolving rapidly, with recognition of new diseases and genes. Recent and improved understanding of the physiopathology of overexpression of type I interferons has allowed the development of targeted therapies, currently being evaluated, like Janus-kinases or reverse transcriptase inhibitors.
Topics: Aortic Diseases; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Chilblains; Dental Enamel Hypoplasia; Humans; Interferon Type I; Janus Kinases; Lupus Erythematosus, Cutaneous; Metacarpus; Muscular Diseases; Nervous System Malformations; Odontodysplasia; Osteochondrodysplasias; Osteoporosis; Proteasome Endopeptidase Complex; Reverse Transcriptase Inhibitors; Skin; Syndrome; Treatment Outcome; Vascular Calcification
PubMed: 26363997
DOI: 10.1016/j.annder.2015.06.018 -
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 -
Journal of Clinical Immunology Jan 2019Singleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy....
PURPOSE
Singleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy. Pathogenic variants in IFIH1 have previously been associated with the classic Singleton-Merten syndrome, while variants in DDX58 has been described in association with a milder phenotype, which is suggested to have a better prognosis. We studied a family with severe, "classic" Singleton-Merten syndrome.
METHODS
We undertook clinical phenotyping, next-generation sequencing, and functional studies of type I interferon production in patient whole blood and assessed the type I interferon promoter activity in HEK293 cells transfected with wild-type or mutant DDX58 stimulated with Poly I:C.
RESULTS
We demonstrate a DDX58 autosomal dominant gain-of-function mutation, with constitutive upregulation of type I interferon.
CONCLUSIONS
DDX58 mutations may be associated with the classic features of Singleton-Merten syndrome including dental dysplasia, tendon rupture, and severe cardiac sequela.
Topics: Adult; Aortic Diseases; Cell Line; DEAD Box Protein 58; Dental Enamel Hypoplasia; Female; Gain of Function Mutation; HEK293 Cells; Humans; Interferon Type I; Male; Metacarpus; Middle Aged; Muscular Diseases; Odontodysplasia; Osteoporosis; Phenotype; Promoter Regions, Genetic; Receptors, Immunologic; Vascular Calcification
PubMed: 30574673
DOI: 10.1007/s10875-018-0572-1 -
Journal of the American Dental... Feb 2018Segmental odontomaxillary dysplasia (SOD) is a characteristic developmental abnormality that demonstrates posterior maxillary enlargement, dental abnormalities, altered...
BACKGROUND AND OVERVIEW
Segmental odontomaxillary dysplasia (SOD) is a characteristic developmental abnormality that demonstrates posterior maxillary enlargement, dental abnormalities, altered bone trabeculation, and possible cutaneous findings. Only 62 cases have been reported in the English-language literature.
CASE DESCRIPTION
The authors described 3 newly diagnosed cases of SOD, all found in the left posterior maxilla in adolescent female patients; they reviewed the literature to elucidate this rare entity.
CONCLUSIONS AND PRACTICAL IMPLICATIONS
Because of the complexity and variety of associated dental and craniofacial features, patients with SOD may seek diagnosis from various dental and medical providers. The signs of SOD are characteristic, yet the condition is largely underrecognized among health care professionals, which may lead to unnecessary treatment.
Topics: Adolescent; Child; Developmental Disabilities; Female; Humans; Maxilla; Odontodysplasia
PubMed: 29389339
DOI: 10.1016/j.adaj.2017.08.007