Sting-Associated Vasculopathy, Infantile-Onset

A number sign (#) is used with this entry because of evidence that STING-associated vasculopathy with onset in infancy (SAVI) is caused by heterozygous mutation in the STING gene (TMEM173; 612374) on chromosome 5q31.

Description

STING-associated vasculopathy with onset in infancy is an autoinflammatory vasculopathy causing severe skin lesions, particularly affecting the face, ears, nose, and digits, and resulting in ulceration, eschar formation, necrosis, and, in some cases, amputation. Many patients have interstitial lung disease. Tissue biopsy and laboratory findings show a hyperinflammatory state, with evidence of increased beta-interferon (IFNB1; 147640) signaling (summary by Liu et al., 2014).

Clinical Features

Liu et al. (2014) reported 6 unrelated children with an inflammatory vasculopathy. Four patients presented within the first 8 weeks of life with skin lesions on the extremities, including telangiectatic, pustular, or blistering rashes on the cheeks, nose, fingers, toes, and soles; 2 patients presented with tachypnea in the perinatal period. All eventually developed severe skin lesions that extended to the pinnae of the ears and sites on the limbs. The acral skin lesions, which worsened in the winter, developed into painful, ulcerative lesions with eschar formation and tissue infarction, necessitating amputation of digits and causing scarring of the ear cartilage and perforation of the nasal septum. Other features included livedo reticularis, Raynaud phenomenon, nail bed capillary tortuosity, and recurrent low-grade fever flares. Five patients had radiographic evidence of interstitial lung disease and adenopathy, 3 of whom were clinically affected and showed lung fibrosis. Two patients developed myositis and joint stiffness. Lesional skin biopsies showed marked vascular inflammation limited to capillaries, as well as microthrombosis. There was evidence of IgM and C3 deposition in scattered vessels, consistent with immune complex deposition. The patients had chronic anemia, thrombocytosis, T-cell lymphopenia with normal B cells, hypergammaglobulinemia, and leukopenia. Five patients had variable or transient autoantibody titers, including antinuclear, antiphospholipid, and anticardiolipin antibodies. Immunosuppressant therapy was ineffective. All patients had failure to thrive, and 2 died in their teenage years of pulmonary complications. Cognition was normal. Postmortem examination of 1 patient showed widespread vasculopathy of the systemic and pulmonary vasculature. Laboratory studies were consistent with systemic inflammation, including increased erythrocyte sedimentation rate and C-reactive protein. Peripheral blood showed a strong transcriptional interferon-response-gene signature and increased levels of interferon-induced cytokines.

Jeremiah et al. (2014) reported a family of mixed European descent in which 4 individuals had a complex systemic inflammatory syndrome variably associated with pulmonary fibrosis and autoimmunity. The proband presented at age 2 years with recurrent febrile illnesses, intermittent malar rash, failure to thrive, and interstitial lung disease. Lung biopsy showed macrophagic alveolitis, follicular hyperplasia, B-cell germinal centers, and interstitial fibrosis. Laboratory studies showed antinuclear autoantibodies. Antiinflammatory treatment was ineffective. The proband's father and paternal uncle, who were monozygotic twins, had experienced failure to thrive since childhood, with recurrent febrile attacks during adolescence, malar rash, interstitial lung disease, and polyarthralgia and polyarthritis associated with antinuclear antibodies and rheumatoid factor. The uncle of the proband died at age 29 years of fulminant necrotizing fasciitis. The paternal grandfather of the proband had long-lasting intermittent arthralgia and chronic low weight, but no interstitial lung disease. All 4 individuals had increased erythrocyte sedimentation rate and C-reactive protein (CRP; 123260).

Inheritance

The transmission pattern of SAVI in the family reported by Jeremiah et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 6 unrelated patients with SAVI, Liu et al. (2014) identified 3 different de novo heterozygous missense mutations in the TMEM173 gene (612374.0001-612374.0003). The mutation in the first patient was found by whole-exome sequencing, and mutations in the subsequent patients were found by Sanger sequencing. One of the patients was somatic mosaic for the mutation. Studies in patient cells as well as transfection studies in HEK293T cells indicated that the mutations resulted in a gain of function, with constitutive STAT1 (600555) phosphorylation and activation and increased IFNB1 activity. In vitro experiments using patient cells showed that inhibition of JAK1 (147795) resulted in decreased IFNB1 transcription and blockage of some interferon-response genes.

In 3 affected members of a 3-generation family of mixed European descent with SAVI, Jeremiah et al. (2014) identified a heterozygous missense mutation in the STING gene (V155M; 612374.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional expression assays showed that the mutation caused constitutive activation of the IFNB1 promoter, even in the absence of stimulation. Confocal microscopy of patient fibroblasts showed that mutant STING was present mainly in the Golgi and in perinuclear punctiform vesicles, suggestive of activation, whereas wildtype STING was uniformly expressed in the cytoplasm of control cells. Patient samples showed increased type 1 interferon activity and overexpression of downstream genes.