Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
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.

PubMed Disclaimer

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
See this image and copyright information in PMC

References

    1. Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, Rice GI, Erlandsen H, Kehl HG, Thiele H, Nürnberg P, Höhne W, Crow YJ, Feigenbaum A, Hennekam RC. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015;96(2):275–282. doi: 10.1016/j.ajhg.2014.12.014. - DOI - PMC - PubMed
    1. Rice GI, Del Toro Duany Y, Jenkinson EM, et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. 2014;46(5):503–509. doi: 10.1038/ng.2933. - DOI - PMC - PubMed
    1. Oda H, Nakagawa K, Abe J, Awaya T, Funabiki M, Hijikata A, Nishikomori R, Funatsuka M, Ohshima Y, Sugawara Y, Yasumi T, Kato H, Shirai T, Ohara O, Fujita T, Heike T. Aicardi-Goutières syndrome is caused by IFIH1 mutations. Am J Hum Genet. 2014;95(1):121–125. doi: 10.1016/j.ajhg.2014.06.007. - DOI - PMC - PubMed
    1. de Carvalho LM, Ngoumou G, Park JW, Ehmke N, Deigendesch N, Kitabayashi N, Melki I, Souza FFL, Tzschach A, Nogueira-Barbosa MH, Ferriani V, Louzada-Junior P, Marques W, Jr, Lourenço CM, Horn D, Kallinich T, Stenzel W, Hur S, Rice GI, Crow YJ. Musculoskeletal disease in MDA5-related type I interferonopathy: a Mendelian mimic of Jaccoud’s arthropathy. Arthritis Rheumatol. 2017;69(10):2081–2091. doi: 10.1002/art.40179. - DOI - PMC - PubMed
    1. Bursztejn AC, Briggs TA, del Toro Duany Y, Anderson BH, O’Sullivan J, Williams SG, Bodemer C, Fraitag S, Gebhard F, Leheup B, Lemelle I, Oojageer A, Raffo E, Schmitt E, Rice GI, Hur S, Crow YJ. Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutières and Singleton-Merten syndromes. Br J Dermatol. 2015;173(6):1505–1513. doi: 10.1111/bjd.14073. - DOI - PMC - PubMed

Publication types

MeSH terms

Supplementary concepts