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Case Reports
. 2019 Jan;39(1):75-80.
doi: 10.1007/s10875-018-0572-1. Epub 2018 Dec 20.

DDX58 and Classic Singleton-Merten Syndrome

Carlos R Ferreira  1 , Yanick J Crow  2   3 , William A Gahl  4 , Pamela J Gardner  5 , Raphaela Goldbach-Mansky  6 , Sun Hur  7 , Adriana Almeida de Jesús  6 , Michele Nehrebecky  8 , Ji Woo Park  9 , Tracy A Briggs  10   11
Affiliations
Case Reports

DDX58 and Classic Singleton-Merten Syndrome

Carlos R Ferreira et al. J Clin Immunol. 2019 Jan.

Abstract

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.

Keywords: Interferonopathy; Singleton-Merten syndrome; retinoic acid-inducible gene I; type I interferon.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Clinical manifestations of SMS in the family. a A pacemaker generator, sternotomy wires, and a prosthetic mitral valve are present. b Calcification of the abdominal aorta is observed and the lumbar vertebral bodies show low bone mineral density. c Joint deformities are evident due to metacarpophalangeal joint subluxation. d Calcification is seen at the insertion of the Achilles tendon and the plantar fascia. e Toenails are hypoplastic and subcutaneous calcium deposition is evident over the fourth toe
Fig. 2
Fig. 2
Dental manifestations of SMS. Clinical photography of maxillary a and mandibular b teeth showing failure of eruption of many permanent teeth. A dental panoramic radiograph c confirmed that most of these permanent teeth were impacted in the bone. d Anterior periapical radiograph showing very short roots. e Periapical view of upper left quadrant teeth revealing absent periodontal ligament space consistent with ankylosis
Fig. 3
Fig. 3
Type I interferon induction is associated with a Gln517His heterozygous DDX58 variant. a Interferon-beta luciferase assay following transient transfection of HEK293 cells demonstrated significantly elevated basal and poly I:C stimulated interferon induction in both the Gln517His mutant and the previously described Glu373Ala mutant relative to WT expression. b Gene expression of selected 28 interferon-stimulated genes (ISGs) was assayed, and an IFN-score was calculated. Mean and SD of the IFN score are depicted in parenthesis for each group of individuals. HC: healthy controls; NOMID: neonatal-onset multisystem inflammatory disease; CANDLE: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; SAVI: STING-associated vasculopathy with onset in infancy; 4088: proband’s son; 4089: proband
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