Singleton Merten Syndrome (SMS) is a rare autosomal dominant disorder caused by IFIH1 or DDX58 mutations, characterized by chronic inflammation leading to vascular calcifications, valvular disease, musculoskeletal abnormalities, dental dysplasia, skin findings like psoriasis and glaucoma. We report an 8-year-old boy with a DDX58 mutation associated SMS who presented with difficulty walking and ankle pain, found to have extensive aortoiliac and mesenteric artery narrowing. Advanced imaging with computed tomography (CT) and cinematic rendering provided detailed vascular mapping, underscoring the importance of radiologic evaluation in detecting and evaluating the extent of vascular involvement in SMS.

Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-β-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-β on TM cells. Our study is the first to demonstrate that IFN-β significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-β remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-β-induced autophagy in TM cells, we performed microarray analysis in IFN-β-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-β-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-β. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-β, which elevates IOP by modulating autophagy through RSAD2 in TM cells.

This review aimed to summarize recent progress on syndromic dentin defects, promoting a better understanding of systemic diseases with dentin malformations, the molecules involved, and related mechanisms. References on genetic diseases with dentin malformations were obtained from various sources, including PubMed, OMIM, NCBI, and other websites. The clinical phenotypes and genetic backgrounds of these diseases were then summarized, analyzed, and compared. Over 10 systemic diseases, including osteogenesis imperfecta, hypophosphatemic rickets, vitamin D-dependent rickets, familial tumoral calcinosis, Ehlers-Danlos syndrome, Schimke immuno-osseous dysplasia, hypophosphatasia, Elsahy-Waters syndrome, Singleton-Merten syndrome, odontochondrodysplasia, and microcephalic osteodysplastic primordial dwarfism type II were examined. Most of these are bone disorders, and their pathogenic genes may regulate both dentin and bone development, involving extracellular matrix, cell differentiation, and metabolism of calcium, phosphorus, and vitamin D. The phenotypes of these syndromic dentin defects various with the involved genes, part of them are similar to dentinogenesis imperfecta or dentin dysplasia, while others only present one or two types of dentin abnormalities such as discoloration, irregular enlarged or obliterated pulp and canal, or root malformation. Some specific dentin defects associated with systemic diseases may serve as important phenotypes for dentists to diagnose. Furthermore, mechanistic studies on syndromic dentin defects may provide valuable insights into isolated dentin defects and general dentin development or mineralization.

Singleton Merten syndrome (SMS) is one of the rarest multisystem genetic disorders that had been recognized in only a few cases. Patients who have this syndrome often present with calcification of the aorta and heart valves, dental dysplasia, joint calcification, distinct facial features, and growth and developmental delay. Other physical findings usually associated with SMS may include glaucoma, skeletal abnormalities including tendon rupture, muscle weakness, and arthropathy. In individuals with SMS, autoimmune diseases like psoriasis and systemic lupus erythematosus (SLE) can occur. In this case, we report a pre-term baby girl that developed congenital aortic calcification, renal hypertension, dental anomalies, multiple joint calcifications, atypical facial features, mild mental retardation, and developmental delay. At 17 years, the patient developed SLE based on positive antinuclear antibody (ANA) with clinical and immunological features like fever, malar rash, pericardial effusion, proteinuria, high ANA concentration, high anti-double-stranded DNA, low C4 complement, and presence of anti-Smith antibodies.

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 DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2. 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. We have identified a novel DDX58 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 DDX58 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. 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.