Singleton-Merten Syndrome Research Articles

Prosthetic rehabilitation in a patient with Singleton Merten syndrome and acrylic resin hypersensitivity

Singleton Merten Syndrome is a rare disease characterized by the presence of the dental dysplasia phenotype, calcifications in the aorta, progressive wear and loss of bone protein (osteoporosis) in the hands and feet. Patients have muscle weakness, poor motor development, abnormal dentition, deformities of thefeet and hands, and skin lesions. Objective: This report describes the maxillomandibular rehabilitation of a patient with Singleton Merten Syndrome and an allergic reaction to the acrylic resin through maxillary overdenture and mandibular partial removable denture. Case report: Female patient, 18 years old, with clinical characteristics of Singleton Merten Syndrome and allergic reaction to acrylic resin, with complaints of loss of function and esthetics dueto the absence of several teeth, but with the presence of unerupted maxillary and mandibular tooth buds. Maxillary overdenture and mandibular removable partial denture were made of polyethylene. Conclusion: The rehabilitation treatment with maxillary overdenture and mandibular partial removable denture provided better facial muscle support, restoring masticatory function and facial esthetics. With this treatment, it was possible to reestablish patient’s satisfactionand self-esteem due to the correct construction of the prostheses, and minimize hypersensitivity reactions in the oral mucosa, which allowed the use of these prostheses by the patient without any complications.

RIG-I-Like Receptor Signaling in Singleton-Merten Syndrome.

Singleton-Merten syndrome (SMS) is an autosomal dominant, multi-system innate immune disorder characterized by early and severe aortic and valvular calcification, dental and skeletal abnormalities, psoriasis, glaucoma, and other varying clinical findings. Recently we identified a specific gain-of-function mutation in IFIH1, interferon induced with helicase C domain 1, segregated with this disease. SMS disease without hallmark dental anomalies, termed atypical SMS, has recently been reported caused by variants in DDX58, DEXD/H-box helicase 58. IFIH1 and DDX58 encode retinoic acid-inducible gene I (RIG-I)-like receptors family members melanoma differentiation-associated gene 5 and RIG-I, respectively. These cytosolic pattern recognition receptors function in viral RNA detection initiating an innate immune response through independent pathways that promote type I and type III interferon expression and proinflammatory cytokines. In this review, we focus on SMS as an innate immune disorder summarizing clinical features, molecular aspects of the pathogenetic pathway and discussing underlying mechanisms of the disease.

Musculoskeletal Disease in MDA5-Related Type I Interferonopathy: A Mendelian Mimic of Jaccoud's Arthropathy.

To define the molecular basis of a multisystem phenotype with progressive musculoskeletal disease of the hands and feet, including camptodactyly, subluxation, and tendon rupture, reminiscent of Jaccoud's arthropathy. We identified 2 families segregating an autosomal-dominant phenotype encompassing musculoskeletal disease and variable additional features, including psoriasis, dental abnormalities, cardiac valve involvement, glaucoma, and basal ganglia calcification. We measured the expression of interferon (IFN)-stimulated genes in the peripheral blood and skin, and undertook targeted Sanger sequencing of the IFIH1 gene encoding the cytosolic double-stranded RNA (dsRNA) sensor melanoma differentiation-associated protein 5 (MDA-5). We also assessed the functional consequences of IFIH1 gene variants using an in vitro IFNβ reporter assay in HEK 293T cells. We recorded an up-regulation of type I IFN-induced gene transcripts in all 5 patients tested and identified a heterozygous gain-of-function mutation in IFIH1 in each family, resulting in different substitutions of the threonine residue at position 331 of MDA-5. Both of these variants were associated with increased IFNβ expression in the absence of exogenous dsRNA ligand, consistent with constitutive activation of MDA-5. These cases highlight the significant musculoskeletal involvement that can be associated with mutations in MDA-5, and emphasize the value of testing for up-regulation of IFN signaling as a marker of the underlying molecular lesion. Our data indicate that both Singleton-Merten syndrome and neuroinflammation described in the context of MDA-5 gain-of-function constitute part of the same type I interferonopathy disease spectrum, and provide possible novel insight into the pathology of Jaccoud's arthropathy.

Prosthetic rehabilitation in a patient with Singleton Merten syndrome and acrylic resin hypersensitivity

Singleton Merten Syndrome is a rare disease characterized by the presence of the dental dysplasia phenotype, calcifications in the aorta, progressive wear and loss of bone protein (osteoporosis) in the hands and feet. Patients have muscle weakness, poor motor development, abnormal dentition, deformities of the feet and hands, and skin lesions. Objective: This report describes the maxillomandibular rehabilitation of a patient with Singleton Merten Syndrome and an allergic reaction to the acrylic resin through maxillary overdenture and mandibular partial removable denture. Case report: Female patient, 18 years old, with clinical characteristics of Singleton Merten Syndrome and allergic reaction to acrylic resin, with complaints of loss of function and esthetics due to the absence of several teeth, but with the presence of unerupted maxillary and mandibular tooth buds. Maxillary overdenture and mandibular removable partial denture were made of polyethylene. Conclusion: The rehabilitation treatment with maxillary overdenture and mandibular partial removable denture provided better facial muscle support, restoring masticatory function and facial esthetics. With this treatment, it was possible to reestablish patient’s satisfaction and self-esteem due to the correct construction of the prostheses, and minimize hypersensitivity reactions in the oral mucosa, which allowed the use of these prostheses by the patient without any complications.

Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts.

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. 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.

Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity.

Singleton-Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton-Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation-Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton-Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton-Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal.

ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA.

The cytosolic antiviral innate immune sensor RIG-I distinguishes 5' tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) and increased interferon levels, suggesting misregulated signaling by RIG-I. Here we report that SMS mutations phenocopy a mutation that allows ATP binding but prevents hydrolysis. ATPase deficient RIG-I constitutively signals through endogenous RNA and co-purifies with self-RNA even from virus infected cells. Biochemical studies and cryo-electron microscopy identify a 60S ribosomal expansion segment as a dominant self-RNA that is stably bound by ATPase deficient RIG-I. ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5' triphosphate dsRNA. Our results indicate that ATP-hydrolysis prevents recognition of self-RNA and suggest that SMS mutations lead to unintentional signaling through prolonged RNA binding.

Interféronopathies de type I

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.

Long term clinical outcome of dental implants placed in a patient with Singleton–Merten syndrome

PatientsSingleton–Merten syndrome is an extremely rare autosomal dominant condition with less than 10 reported cases in the literature. It is characterized by abnormal aortic calcifications and dental abnormalities. The goal of this case report is to discuss the abnormal oral clinical features and the modified treatment protocol that was used in order to achieve osseointegration of dental implants in a patient having abnormal bone density and bone turnover associated with Singleton–Merten Syndrome. DiscussionFollowing extraction of the remaining teeth, titanium implants (Friadent GmbH, Mannheim, Germany and Straumann®, Basel, Switzerland) were placed in the upper and lower jaw of the patient. The upper jaw which was treated with dental implants, received a bar supported implant retained prosthesis and the lower jaw an implant retained telescopic prosthesis. The patient was regularly followed up for the past 13 years during which, clinical and radiological evaluation of osseointegration was undertaken. All the loaded implants showed clinical and radiographic evidence of osseointegration. With a follow up of 13 years after insertion of the first implant, the patient reported functioning well with no complications. ConclusionThe treatment with dental implants in the extremely rare Singleton–Merten syndrome patients is a reasonable treatment option to rehabilitate maxillofacial aesthetics and establish normal function of the jaws.

Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome

Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.

A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome

Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated protein 5 [MDA5]) in four SMS subjects from two families and a simplex case. IFIH1 has been linked to a number of autoimmune disorders, including Aicardi-Goutières syndrome. Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues. Invitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction. Interferon signature genes were upregulated in SMS individuals' blood and dental cells. Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption.

Singleton-Merten Syndrome: a rare autoimmune disorder caused by a specific IFIH1 mutation

s of the 51st Workshop for Pediatric Research 51st Workshop for Pediatric Research Gottingen, Germany 16-17 April 2015 This supplement has not been sponsored. Meeting abstracts Meeting abstract Singleton-Merten Syndrome (SMS) is a rare autosomal-dominant disorder characterized by a variety of symptoms including extreme calcifications of the ascending aorta and cardiac valves, dental anomalies (early onset periodontitis, root resorption), psoriasis and widened medullary cavities of the phalanges with focal osteoporosis. Employing whole exome sequencing of five SMS individuals of three families we identified the missense mutation, c.2465G>A (p.Arg822Gln) in the interferon induced with helicase C domain 1 (IFIH1) gene. Additional Sanger sequencing confirmed co-segregation of the mutation with the disorder. IFIH1, encoding melanoma differentiation-associated protein 5 (MDA5), is a member of the RIG-I-like receptor family and functions as a cytoplasmic pattern recognition receptor recognizing viral double stranded RNA (dsRNA). Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues including heart, skin and cartilage. Functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction after polyinosinic:polycytidylic acid (poly (I:C)) stimulation in vitro. This indicates that SMS-MDA5 is hyperactive to non-self dsRNA. According to additional in vitro studies, interferon signature genes including SIGLEC1 were upregulated in blood and dental cells derived from SMS individuals. Taken together, our data demonstrate that the MDA5 gain-of-function mutation p.Arg822Gln causes the autosomal dominant disorder SMS through dysregulation of the human innate immune response.

Establishment of Singleton-Merten Syndrome pulp cells: evidence of mineralization dysregulation

Singleton-Merten syndrome (SMS) is a rare disease with a phenotype of dental dysplasia. Currently, the underlying mechanism of this disease is unknown. In order to investigate the functional mechanism of the SMS tooth phenotypes, we isolated dental pulp tissue and established SMS primary pulp cells. These cells exhibited normal morphology and could be maintained in culture. Their ability to express alkaline phosphatase and mineralize was confirmed by in vitro staining. A comparative osteogenesis polymerase chain reaction array analysis was performed revealing 22 genes up-regulated and 8 genes down-regulated greater than 2-fold in SMS versus unaffected pulp cells. Down-regulated genes included ALP, IGF2, TGFBR2 and COL1A1. Collagen type I was reduced in SMS cells as shown by Western blot analysis. Furthermore, matrix metallopeptidase 13 was found to be dramatically increased in SMS pulp cells. Our findings suggest that dentin mineralization is dysregulated in SMS and may contribute to the root phenotype found in this disease.

Singleton–Merten syndrome: An autosomal dominant disorder with variable expression

In 1973, Singleton and Merten described two females with abnormal dentition, unique radiographic changes especially of the hands, and severe calcification and intimal weakening of the aortic arch and valve. Since then three additional cases with similar features have been reported and the diagnosis was suggested in another three individuals. We present an update of one case and the detailed clinical phenotype of six other cases with Singleton-Merten syndrome. The occurrence of the disorder in six members of two families and vertical male-to-male transmission indicate an autosomal dominant pattern of inheritance. Variability in phenotype, also within a single family, is significant. Core manifestations are marked aortic calcification, dental anomalies (delayed eruption and immature root formation of primarily the anterior permanent teeth, and early loss of permanent teeth due to short roots, acute root resorption, high caries, and aggressive alveolar bone loss), osteopenia and acro-osteolysis, and to a lesser extend also glaucoma, psoriasis, muscle weakness, and joint laxity. Additional clinical characteristics described here include particular facial characteristics (high anterior hairline, broad forehead, smooth philtrum, thin upper vermillion) and abnormal joint and muscle ligaments. The cause and pathogenesis of this syndrome remain unknown. © 2013 Wiley Periodicals, Inc.

Psoriatic arthritis or could it be Singleton-Merten syndrome?

Aims To describe Singleton-Merten Syndrome as an unusual cause of arthritis associated with a psoriasiform rash. Methods Case report. Results We present this case of a girl who at 11 months suffered from discrete red scaly areas on the trunk, limbs and scalp. She was given a diagnosis of psoriasis which remained poorly controlled throughout childhood, despite phototherapy and methotrexate treatment. In infancy, slow gross motor development was noted and felt to be related to hypermobility. She also began complaining of morning stiffness and pain in her hands and knees. The ESR was slightly raised at 17 but all other investigations were negative including ANA, rheumatoid factor and HLA-B27. X-rays showed osteopenic bones but no joint erosion. A diagnosis of psoriatic arthritis was made and although wheelchair bound, she never had significant joint inflammation. Dental concerns also emerged with delayed eruption and very malformed teeth with short roots. She was of proportional short stature with height at the 3rd centile at 10 years. At 11 years a systolic murmur was first heard although she had no cardiac symptoms. An echocardiograph revealed a moderately stenosed valve which rapidly progressed with syncopal episodes 18 months later. At this point the ejection fraction was 21% and a computed tomography scan revealed calcification of the aortic arch to the transverse arch. She had an aortic root replacement with pulmonary autograft. Around this time, she had repeat X-rays which were felt to not be typical of psoriatic arthritis. Instead they showed acro-osteolysis with periarticular osteopaenia, and medullary widening. Subsequently given her other clinical features, Singleton-Merten Syndrome was diagnosed. Conclusions Singleton-Merten Syndrome is a rare autosomal dominant multisystem condition with less than 10 cases reported in the literature. It is thought to be due to abnormal calcium deposition although its genetic basis is not known. Manifestations include aortic valve calcification, osteoporosis with widened medullary cavities, muscle weakness, short stature, psoriasiform eruptions, glaucoma and dentin dysplasia. Rheumatologists commonly treat arthropathies and therefore although this is a rare cause we hope to highlight awareness of this syndrome.

Double valve endocarditis in Singleton-Merten syndrom, a case report of a very rare disease

Introduction: Singleton-Merten syndrome is an extremely rare multisystem disorder, the major characteristics of which are tooth abnormalities (dental dysplasia), calcifications in the aorta and aortic and mitral valves. Singleton-Merten syndrome is present as a result of a random mutation or an autosomal dominant pattern of inheritance. Only 6 patients were reported in the litterature world wide. Deaths was reported to be between 4 and 18 years. Classic radiologic findings were first described by Dr. Edward Singleton and Dr. David Merten in 1973.

A Syndrome of Widened Medullary Cavities of Bone, Aortic Calcification, Abnormal Dentition, and Muscular Weakness (The Singleton—Merten Syndrome)

Two patients with clinical and radiological features similar to those of Singleton and Merten's patients are described. These patients exhibit features of a unique clinical syndrome of unknown etiology: generalized muscular weakness with secondary hip and foot deformities, progressive calcification of the thoracic aorta beginning in childhood, calcific aortic stenosis leading to heart failure, dysplasia of the teeth, poor physical development, osteoporosis, expanded medullary cavities of the metacarpal and metatarsal bones, and chronic psoriaform skin lesions.