The type I interferonopathies comprise a recently recognized group of mendelian diseases characterized by an upregulation of type I interferon signaling. These monogenic phenotypes include classic Aicardi-Goutières syndrome and syndromic forms of systemic lupus erythematosus, including familial chilblain lupus and spondyloenchondrodysplasia. Dermatologic features provide a major diagnostic clue to this disease grouping, as exemplified by the recently described stimulator of interferon genes–associated vasculopathy with onset in infancy (SAVI) caused by gain-of-function mutations in TMEM173.
We describe a male child who, from the age of 2 months, had significant cutaneous disease that manifested as red violaceous plaques of the cheeks, nose, ears, fingers, and toes that progressed to gangrenous necrosis. In addition to his severe cutaneous vasculopathy, he experienced recurrent fevers, interstitial lung disease, and failure to thrive. His clinical syndrome was refractory to multiple immunosuppressive therapies. Evidence of marked upregulation of type I interferon signaling was observed in peripheral blood, and genetic testing identified a de novo germline mutation in TMEM173, confirming a diagnosis of SAVI 7 years after the onset of his disease.
Conclusions and Relevance
This observational report describes a new case of SAVI, a recently defined monogenic inflammatory phenotype, that exemplifies an emerging group of disorders related to primary upregulation of type I interferon signaling.
The type I interferonopathies are a newly considered group of monogenic inflammatory diseases that share a common pathogenesis related to an upregulation of type I interferon signaling.1 This group of conditions includes Aicardi-Goutières syndrome, familial chilblain lupus, spondyloenchondysplasia, and the phenotypes associated with mutations in PSMB8. Stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy (SAVI) is a recently described type I interferonopathy with early-onset inflammation manifesting as cutaneous vasculopathy and pulmonary inflammation.2,3 We describe a new case of SAVI, highlighting the differential diagnosis with childhood granulomatosis with polyangiitis (GPA; previously known as Wegener granulomatosis).
This male child was born at 38 weeks of gestation after a normal pregnancy with intrauterine growth restriction. His birth weight was 2700 g, length was 45 cm, and head circumference was 32 cm (all under the fifth percentile). Cutaneous features developed at approximately 8 weeks of age, with purple-red infiltrated and telangiectatic plaques, and sometimes with pustula that affected the cheeks, helix and lobule of the ears, tip of the nose, and dorsal side of the hands, fingers, and toes. He was also noted to have a reticulated patterning of the limbs. Rapid development of large eschars and secondary painful crusts on the cheeks and the tip of the helix were observed (Figure 1). These features worsened every winter according to cold exposure, with 3 to 4 cutaneous flare-ups per year associated with high temperatures that lasted approximately 7 to 10 days. Three histologic analyses of the telangiectatic plaques (3-mm biopsy specimens) revealed rare epidermal apoptotic keratinocytes and perivascular lymphocytic and neutrophilic infiltrates with nuclear dust (leukocytoclasia) throughout the entire dermis without damage to the vessel wall, fibrinoid necrosis, and thrombi. The results of direct immunofluorescence of lesional skin were negative. At the age of 3 months, he was also noted to be tachypneic. High-resolution computed tomography of the chest revealed interstitial lung disease characterized by diffuse ground glass and reticular opacities with an upper left and lower lung predominance. Bronchoalveolar lavage revealed an inflammatory infiltrate with a large amount of lymphocytes. Routine laboratory examination revealed a normal white blood cell count, hemoglobin level, platelet count, and renal and hepatic function. The erythrocyte sedimentation rate varied from 40 to 67 mm/h (reference range, <20 mm/h), whereas the C-reactive protein level was normal or slightly increased. Lactate dehydrogenase was consistently increased, with levels fluctuating from 549 to 1124 U/L (reference range, 170-450 U/L) (to convert to microkatals, multiply by 0.0167). The results of tests for circulating antinuclear rheumatoid factor, cryoglobulin, cryofibrinogen, cold agglutinins, IgG and IgM antibodies for cardiolipin, β2-glycoprotein I, and lupus anticoagulant were negative. Nontyped antineutrophil cytoplasmic antibodies (ANCA) test results were positive, with levels varying from 1/200 to 1/400 (reference range, <1/100). Considering the clinical presentation of cutaneous inflammatory and necrotic lesions, interstitial lung disease, and the positive ANCA titer results, a diagnosis of childhood protracted superficial GPA was suspected.
A and B, At 5 months of age, erythematous and violaceous infiltrated plaques that affected the cheeks with central cutaneous ulcerations and eschars, the tip of the nose, the helix and lobule of the ears, and the dorsal side of the hands and fingers. C, A reticulate and inflammatory livedo of the limbs, predominating around the knees, was also noted.
He was initially treated with a methylprednisolone bolus, 1.73 g/m2 for 3 days, followed by oral prednisone, 2 mg/kg with gradual diminution of dose, acetylsalicylic acid (100 mg/d), clopidogrel bisulfate (2 mg/d), and nifedipine (10 mg/d). One month later, computed tomography of the lung revealed improvement with a regression of the ground glass opacification. However, his cutaneous features worsened, leading to partial amputation of the helix and profound ulcerations of the cheeks (which were prominent by 5 months of age). Thus, intravenous immunoglobulins (6 infusions of 1 g/kg per month) were given but with little apparent clinical effect. Mycophenolate mofetil (700 mg/m2 twice a day during a 4-year period) and hydroxychloroquine (50 mg in 6.5-mg/kg daily dosages) were then introduced. With this regimen, his lung involvement seemed stable, but he continued to experience recurrent episodes of skin necrosis. At 17 months of age, severe gangrene of the right fourth finger necessitated surgical amputation, leading to a trial of 4 consecutive rituximab infusions every week (375 mg/m2) with prophylactic pentamidine aerosols. Despite this, acute exacerbations with fever and skin damage occurred every winter, although his radiologic pulmonary features remained stable. Treatment with colchicine (1 mg/d for 12 months), methotrexate (0.8 mg/kg per week for 8 months), and chloroquine (50 mg/d in 4-mg/kg daily dosages for 30 months) were considered ineffective. Because of poor growth, with weight and height below the fifth percentile, and despite a normal growth hormone level (insulinlike growth factor 1134 ng/mL [to convert to nanomoles per liter, multiply by 0.131]), somatropin growth hormone treatment was introduced at 6 years of age. Oral prednisone resulted in partial remission of his cutaneous lesions, with corticosteroid dependence estimated at 7.5 mg/d (0.5 mg/kg daily). However, this did not prevent the further development of erythema and necrotic lesions of acral areas, particularly during the winter. Over time there was an evolution of telangiectasia on the nose, cheeks, chin, and perilabial region, with violaceous scaling and atrophic plaques on the hands and feet located predominantly on the toes and lateral sides with nail dystrophy (Figure 2). Nasal septum perforation occurred at 6 years of age. Histologic analysis of a nasal septum biopsy was unhelpful, revealing only a nonspecific polymorphic inflammatory infiltrate without perivascular distribution and an absence of vasculitis or granulomatosis. At this point, his pulmonary lesions remained stable from a radiologic perspective. No pulmonary biopsy was ever performed.
A-C, Facial telangiectatic lesions on the nose, cheeks, chin, and perilabial area associated with violaceous, scaling, and atrophic plaques on the hands and feet (predominantly on the toes and lateral sides). D, Severe nail dystrophy was also present.
Considering the possibility of a type I interferonopathy, we recorded an increase of interferon alfa activity in the serum (19 IU/L; reference range, <2 IU/L), and a significant overexpression of interferon-stimulated genes, a so-called interferon signature, was observed in peripheral blood (Figure 3). After the initial description of SAVI, genetic analyses confirmed a heterozygous somatic mutation (c.439G>A, p.V147M) in exon 5 of TMEM173, the gene encoding STING. This mutation occurred de novo; accordingly, neither parent had an interferon signature.
Quantitative reverse transcription–polymerase chain reaction of a panel of 6 interferon stimulated genes (ISGs) in whole blood measured in the proband and his parents compared with healthy controls. The relative quantification (RQ) value is equal to 2-ΔΔCt, with −ΔΔCt ± SDs (ie, the normalized fold change relative to a calibrator). Each value is derived from 3 technical replicates. Numbers in parentheses refer to decimalized age in years at sampling followed by the interferon score (IS) calculated from the median fold change in the RQ value for the panel of 6 ISGs.
SAVI is a newly described autoinflammatory disease that occurs due to heterozygous mutations of TMEM173, encoding STING. SAVI-related TMEM173 mutations confer a gain of function on STING, leading to a chronic induction of type I interferon signaling. This clinical syndrome was initially described in a series of 6 cases characterized by systemic inflammation with fever, clinical features of cutaneous vasculitis and microthrombotic angiopathy, and interstitial lung disease.2 Considering the clinical features previously reported and those described here, we provisionally suggest that 3 consecutive and intricately linked evolutive phases of SAVI can be distinguished. Cutaneous lesions typically begin in the neonatal period or shortly thereafter (<6 months of age), which can be reminiscent of chilblains, being characterized by erythematous to red-purple, sometimes purpuric, plaques present on acral areas, including the fingers, toes, tip of nose, cheeks, and ears (helix and lobule). Telangiectasia, pustules, finger swelling, acral or limb livedo reticularis, and tachypnea are variably associated. At this time, the presence of low-grade fever and systemic biological inflammation with increased levels of acute-phase reactant proteins (erythrocyte sedimentation rate and C-reactive protein) can be seen. Subsequently, these cutaneous lesions progress, with flare-ups worsened by cold weather, the development of punched-out skin ulcerations of variable sizes, eschars, and digital gangrene, which can lead to surgical amputation. This cold sensitivity, mentioned in the original series and highly reminiscent of the chilblains seen in Aicardi-Goutières syndrome and familial chilblain lupus, was striking in our case, with a seasonal rhythmicity and absence of cutaneous flare-ups and fever episodes during the warmer months. The last, more chronic stage is marked by the progressive development of atrophic and depigmented scars with telangiectasia of the extremities and nail alterations, including nail plate disruption, onycholysis, and severe onychodystrophy, resulting in partial or complete destruction of the nail plates.
The results of histologic analyses of lesional skin biopsy specimens were poorly contributive in our case, indicating nonspecific dermal perivascular inflammation with karyorrhexis in the absence of vasculitis or microthrombotic vascular changes. This finding could be due to the small size of the biopsy specimens taken and the disease stage at the time of examination.
In the context of skin inflammatory and necrotic lesions that primarily affected acral areas with systemic inflammation, several differential diagnoses could be evoked, including childhood-specific necrotizing vasculitis, antiphospholipid syndrome, cryoglobulinemic vasculitis, and thrombotic vasculopathy associated with cryofibrinogenemia. In our case, the association of the skin lesions with interstitial lung disease; positive titers of ANCA, although not typed; and subsequent nasal-septum perforation led us to consider the diagnosis of childhood limited and/or protracted superficial GPA.4,5 Nevertheless, some clinical and biological data appeared discordant with this diagnosis, including the extreme rarity of perinatal-onset GPA, the absence of other skin lesions encountered during childhood GPA (eg, vesicles and bullae, erythema nodosum, and pyoderma gangrenosum–like lesions), the absence of histologic granulomatous inflammation in skin or nasal biopsy specimens, and negativity of myeloperoxidase- and proteinase 3–specific ANCA.6 However, the presence or absence of specific ANCA does not appear to be a formal discriminating criterion between SAVI and GPA because cytoplasmic ANCA positivity was reported, albeit transiently and at low titer, in 2 of 6 cases of SAVI.2
The pulmonary manifestations observed in our case were consistent with the previously described cases of SAVI but differed in the absence of paratracheal adenopathy. Of interest, an improvement of the imaging features of interstitial lung disease on computed tomography was observed after treatment with methylprednisolone pulses and mycophenolate mofetil, although this treatment regimen failed to halt the progression of our patient’s skin lesions. Other treatments, including intravenous immunoglobulins, methotrexate, rituximab, colchicine, antimalarials, low-dose acetylsalicylic acid, clopidogrel, and nifedipine, were all considered ineffective, as previously reported.2
Clinical cutaneous phenotypic overlap between SAVI and the other interferonopathies is of particular interest from a pathophysiologic point of view. All these disorders, including familial chilblain lupus7; Aicardi-Goutières syndrome,1,8 where skin lesions can be particularly prominent in the context of SAMHD1 mutations; spondyloenchondysplasia9; and PSMB8-related disease,10,11 can demonstrate the early onset of chilblainlike lesions, acral vasculitis, and gangrene with varying degrees of severity (Table). Although no simplistic pathogenic explanation can be provided at this time, the direct effect of interferon alfa could account for the development of cold-sensitive skin lesions in areas of low flow and distal circulation, such as the fingers, toes, nose, and ears. Of note, interferon therapy has been previously associated with skin inflammatory and ischemic complications, including cutaneous digital necrosis, vasculitis-like syndrome, Raynaud phenomenon,12 and atrophie blanche.13,14 A direct vasoconstrictive effect and increased procoagulant activity induced by the local hyperproduction of interferon in endothelial cells14 could account for the vascular damage observed in SAVI. Similarly, interstitial pneumonitis, with radiologic anomalies close to SAVI pulmonary-related disease, has been reported after interferon therapy.15 The pulmonary tropism of SAVI presumably relates to the expression of STING in alveolar macrophages and pneumocytes.2,3
In the context of early-onset chilblains and acral vasculitis or gangrene, we suggest searching for increased interferon alfa activity in serum and interferon-stimulated gene transcripts in peripheral whole blood (a so-called type I interferon signature) to determine a diagnosis of a type I interferonopathy.
Accepted for Publication: January 30, 2015.
Corresponding Author: Yanick J. Crow, MD, PhD, Institut Imagine, Laboratory of Neurogenetics and Neuroinflammation, Necker Hospital for Sick Children, 24 Boulevard du Montparnasse, Third Floor, Room 309, 75015 Paris, France (email@example.com).
Published Online: May 20, 2015. doi:10.1001/jamadermatol.2015.0251.
Author Contributions: Drs Bessis and Crow had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Munoz, Rieux-Laucat, Crow, Bessis.
Acquisition, analysis, or interpretation of data: Munoz, Rodière, Jeremiah, Oojageer, Rice, Rozenberg, Crow, Bessis.
Drafting of the manuscript: Munoz, Jeremiah, Rieux-Laucat, Crow, Bessis.
Critical revision of the manuscript for important intellectual content: Munoz, Rodière, Oojageer, Rice, Rozenberg, Crow, Bessis.
Obtained funding: Crow, Bessis.
Administrative, technical, or material support: Munoz, Jeremiah, Oojageer, Rice, Rozenberg.
Study supervision: Rodière, Rieux-Laucat, Crow.
Conflict of Interest Disclosures: None reported.
Funding/Support: Ms Jeremiah reported having received support from the Fondation Arthritis, Paris, France. Dr Crow reported having received support from fellowship GA 309449 from the European Research Council and a state subsidy managed by the National Research Agency (France) under the Investments for the Future program (reference ANR-10-IAHU-01).
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We are indebted to the family for their permission to publish this report.
Munoz J, Rodière M, Jeremiah N, Rieux-Laucat F, Oojageer A, Rice GI, Rozenberg F, Crow YJ, Bessis D. Stimulator of Interferon Genes–Associated Vasculopathy With Onset in Infancy A Mimic of Childhood Granulomatosis With Polyangiitis. JAMA Dermatol. 2015;151(8):872-877. doi:10.1001/jamadermatol.2015.0251