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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 -
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 -
World Journal of Pediatrics : WJP Feb 2020Type I interferonopathy is a group of autoinflammatory disorders associated with prominent enhanced type I interferon signaling. The mechanisms are complex, and the... (Review)
Review
BACKGROUNDS
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.
DATA SOURCES
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.
Topics: Aortic Diseases; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Child; Dental Enamel Hypoplasia; Humans; Immunosuppressive Agents; Interferon Type I; Metacarpus; Muscular Diseases; Nervous System Malformations; Odontodysplasia; Osteoporosis; Phenotype; Protein Kinase Inhibitors; Reverse Transcriptase Inhibitors; Vascular Calcification
PubMed: 31377974
DOI: 10.1007/s12519-019-00273-z -
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 -
Oral Health & Preventive Dentistry Sep 2020Regional odontodysplasia (RO) is a rare dental anomaly affecting primary and/or permanent dentition, and leads to comprehensive treatment need. The purpose of this study... (Review)
Review
PURPOSE
Regional odontodysplasia (RO) is a rare dental anomaly affecting primary and/or permanent dentition, and leads to comprehensive treatment need. The purpose of this study was to present a larger consecutive sample with RO, discuss treatment strategies for patients with RO, and review the literature.
MATERIALS AND METHODS
A consecutive, retrospective sample of seven children with RO (6 males, 1 female) including all patients diagnosed with RO in the eastern part of Denmark was conducted over a period of 15 years. The evaluation included gender, localisation and treatment outcome. A review of the literature and cases published within the last 15 years was conducted.
RESULT
Referral age was 2-12 years (mean: 7.3 years). The gender ratio was 1:6 (female:male), and the right:left ratio was 3:4. 71% of the patients had RO in the mandible and 29% in the maxilla. 43% had RO in the permanent dentition, while both primary and permanent dentition were affected in 57%. Typically, RO affected incisors and canines. In some patients, RO also affected more distal tooth types. Treatment included early multiple extractions and subsequent combined orthodontics, surgery and prosthetics. A search on RO cases published within the last 15 years was conducted and included 44 cases. The review showed a male and maxillary preponderance. The most common treatment of RO is extraction.
CONCLUSION
Treatment of RO should take place in interdisciplinary, specialised teams, and individual treatment plans should be designed. Fewer but more extensive treatment sessions under general anesthaesia may minimise the burden of care for the patients.
Topics: Child; Dentition, Permanent; Female; Humans; Incisor; Male; Mandible; Odontodysplasia; Retrospective Studies
PubMed: 32895649
DOI: 10.3290/j.ohpd.a45070 -
Clinical Oral Investigations Nov 2019Tooth agenesis is one of the most common craniofacial developmental anomalies. In hypodontia, one to five teeth are missing, whereas oligodontia refers to the absence of...
OBJECTIVE
Tooth agenesis is one of the most common craniofacial developmental anomalies. In hypodontia, one to five teeth are missing, whereas oligodontia refers to the absence of at least six teeth, excluding the third molars. Mutations in several genes including MSX1, PAX9, AXIN2, and WNT10A have been shown to cause non-syndromic tooth agenesis. Regional odontodysplasia (RO), also known as "ghost teeth," is a rare developmental anomaly of tooth formation affecting both dentitions. Some possible causes of RO have been suggested, yet the etiology remains unknown. Because the phenotypes of both oligodontia and RO co-occur in one Finnish family, the aim here was to investigate the genetic etiology of the two conditions.
MATERIALS AND METHODS
A mutation screening of the genes MSX1, PAX9, AXIN2, and WNT10A was performed for the family members of a RO patient and family history of oligodontia.
RESULTS
An initiation codon mutation of the PAX9 gene was found in the proband and segregating with oligodontia in the family.
CONCLUSIONS
The etiology of regional odontodysplasia (RO) may be genetic and the same genes can be involved both in RO and tooth agenesis.
CLINICAL RELEVANCE
Our results give new insights into the etiology of regional odontodysplasia, yet further results are needed.
Topics: Anodontia; Codon, Initiator; Humans; MSX1 Transcription Factor; Mutation; Odontodysplasia; PAX9 Transcription Factor; Pedigree
PubMed: 30809714
DOI: 10.1007/s00784-019-02849-5 -
American Journal of Medical Genetics.... Oct 2021Singleton-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...
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.
Topics: Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aortic Diseases; CD56 Antigen; Dental Enamel Hypoplasia; Femur Head; Femur Head Necrosis; Humans; Interferons; Male; Metacarpus; Muscular Diseases; Odontodysplasia; Osteoporosis; Receptors, Cell Surface; Skin Abnormalities; Treatment Outcome; Vascular Calcification
PubMed: 34189824
DOI: 10.1002/ajmg.a.62395 -
International Journal of Clinical... 2023A rare dental developmental anomaly known as regional odontodysplasia (RO) manifests itself in hypoplastic and hypomineralized teeth with discolored yellow to brown...
UNLABELLED
A rare dental developmental anomaly known as regional odontodysplasia (RO) manifests itself in hypoplastic and hypomineralized teeth with discolored yellow to brown enamel. Radiographically, the affected tooth appears as a shell tooth with a large pulp chamber and a thin layer of teeth structure. The treatment plan is not well-established, and a multidisciplinary approach is often needed. However, a literature review revealed that most of the studies regarding RO are case reports, and more research, including epidemiological, genetic, and experimental studies, is needed to understand this condition better. Additionally, the cause of this anomaly is currently unknown. Removing the affected tooth is a controversial matter, and the treatment options should be chosen on an individual basis, considering the patient's goals for treatment. This report describes an uncommon case of an 8-year-old girl who has RO affecting the front teeth in the upper jaw and a long-standing infection caused by actinomycosis.
HOW TO CITE THIS ARTICLE
Helal N. Regional Odontodysplasia with Actinomycosis Infection: A Rare Case Report. Int J Clin Pediatr Dent 2023;16(1):190-197.
PubMed: 37020769
DOI: 10.5005/jp-journals-10005-2504 -
The Journal of Clinical Pediatric... Nov 2023Regional odontodysplasia (RO) is a rare non-hereditary dental anomaly associated with dysplasia. Its etiology remains unclear but is known to affect both the mesodermal...
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.
Topics: Humans; Odontodysplasia; Dentition, Permanent
PubMed: 37997252
DOI: 10.22514/jocpd.2023.094 -
The Journal of Clinical Pediatric... May 2024PHACES syndrome is an acronym for the syndromic presentation of Posterior fossa malformation, Hemangioma, Arterial anomalies, Coarctation of aorta/cardiac defects, Eye...
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.
Topics: Humans; Male; Aortic Coarctation; Odontodysplasia; Eye Abnormalities; Child, Preschool; Neurocutaneous Syndromes; Cranial Fossa, Posterior; Tooth Extraction
PubMed: 38755995
DOI: 10.22514/jocpd.2024.070