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Pediatric Rheumatology Online Journal Apr 2022Singleton-Merten syndrome 1 (SGMRT1) is a rare type I interferonopathy caused by heterozygous mutations in the IFIH1 gene. IFIH1 encodes the pattern recognition receptor...
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/β 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.
Topics: Aortic Diseases; Child; Child, Preschool; Dental Enamel Hypoplasia; Humans; Interferon Type I; Interferon-Induced Helicase, IFIH1; Male; Metacarpus; Muscle Weakness; Muscular Diseases; Nitriles; Odontodysplasia; Osteoporosis; Pyrazoles; Pyrimidines; Vascular Calcification
PubMed: 35410415
DOI: 10.1186/s12969-022-00686-7 -
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 -
Journal of Veterinary Dentistry Jun 2021As part of an annual wellness evaluation, we performed oral and dental examination under general anesthesia in 7 zoo Bolivian squirrel monkeys aged 10 and 15 years, and...
As part of an annual wellness evaluation, we performed oral and dental examination under general anesthesia in 7 zoo Bolivian squirrel monkeys aged 10 and 15 years, and 8 zoo black-tufted marmosets aged between 1 and 7 years. No oral discomfort was observed in any animal prior to the procedure. Apart from dilacerated roots of second mandibular incisor teeth in Bolivian squirrel monkeys and one case of presumably odontodysplasia in a black-tufted marmoset, no major variations in number and shape of the present teeth and roots were revealed. All 15 animals had gingivitis, but periodontitis was only diagnosed in 3 black-tufted marmosets. Most commonly diagnosed dental pathology in Bolivian squirrel monkeys was attrition/abrasion, affecting 11.9% of all teeth, followed by caries, which was only diagnosed in older animals. Altogether 8 fractured teeth were diagnosed in Bolivian squirrel monkeys only, with root fracture being the most common type, followed by complicated crown fracture and complicated crown-root fracture. Radiographic signs of endodontic disease were found in 10 teeth in Bolivian squirrel monkeys and in one nonvital tooth with intact crown in a black-tufted marmoset. We associated high occurrence of caries in the older Bolivian squirrel monkeys with their diet and saliva characteristics of these animals. Lack of any periodontitis in Bolivian squirrel monkeys may partially be attributed to limitations of radiography technique, although squirrel monkeys appear to be far less susceptible to naturally occurring periodontitis than marmosets.
Topics: Animals; Callithrix; Saimiri
PubMed: 34821512
DOI: 10.1177/08987564211041781 -
American Journal of Medical Genetics.... Jan 2022Pathogenic-activating variants of interferon induced with Helicase C domain 1 (IFIH1) cause Singleton-Merten (S-M) syndrome, which accompanies acro-osteolysis, loss of...
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.
Topics: Aortic Diseases; Autoimmune Diseases of the Nervous System; Dental Enamel Hypoplasia; Humans; Interferon-Induced Helicase, IFIH1; Interferons; Japan; Male; Metacarpus; Muscular Diseases; Nervous System Malformations; Odontodysplasia; Osteoporosis; Vascular Calcification
PubMed: 34453469
DOI: 10.1002/ajmg.a.62478 -
Biomolecules Aug 2021Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by in humans. Single nucleotide polymorphisms in the...
Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by in humans. Single nucleotide polymorphisms in the 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: MDA5, MDA5, MDA5, and MDA5 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 MDA5 and MDA5. 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.
Topics: Aortic Diseases; Autoimmune Diseases of the Nervous System; Computational Biology; Dental Enamel Hypoplasia; Humans; Hydrogen Bonding; Interferon-Induced Helicase, IFIH1; Metacarpus; Molecular Conformation; Molecular Dynamics Simulation; Muscular Diseases; Mutant Proteins; Mutation; Mutation, Missense; Nervous System Malformations; Odontodysplasia; Osteoporosis; Phenotype; Principal Component Analysis; RNA; Thermodynamics; Vascular Calcification
PubMed: 34439917
DOI: 10.3390/biom11081251 -
American Journal of Orthodontics and... Sep 2021One of the most challenging problems for orthodontists is that of multiple missing maxillary teeth in a growing patient. In many patients, a good treatment option is...
One of the most challenging problems for orthodontists is that of multiple missing maxillary teeth in a growing patient. In many patients, a good treatment option is autotransplantation. This case report describes the multidisciplinary treatment of an 11-year-old girl with regional odontodysplasia affecting the maxillary right and left central incisors, and congenitally missing maxillary left lateral incisor and canine. Autotransplantation of the mandibular second premolars to the affected area was combined with orthodontic space closure, and the transplanted premolars were reshaped and restored with a resin composite to be in line with the left central and lateral incisors. After completion of the orthodontic treatment, gingivectomy was performed to obtain an even gingival contour and symmetrical gingival tissue. Space closure of the maxillary anterior teeth was achieved. Autotransplantation enabled the patient to retain her natural teeth rather than having a prosthesis or dental implant. The autotransplanted tooth allows for alveolar bone growth in synchrony with neighboring teeth and the formation of normal interdental papilla while adapting to functional stimuli and confers a high survival rate in the long term.
Topics: Anodontia; Bicuspid; Child; Female; Humans; Incisor; Maxilla; Orthodontic Space Closure
PubMed: 34334269
DOI: 10.1016/j.ajodo.2020.06.035 -
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 -
European Journal of Medical Genetics May 2021More than two decades since the first clinical and radiological description of odontochondroplasia (ODCD) was reported, biallelic loss of function variants in the...
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.
Topics: Adult; Child; Cytoskeletal Proteins; Female; Humans; Loss of Function Mutation; Male; Odontodysplasia; Osteochondrodysplasias; Phenotype
PubMed: 33746040
DOI: 10.1016/j.ejmg.2021.104198 -
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 -
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