Severe Pulmonary Fibrosis as the First Manifestation of Interferonopathy (TMEM173 Mutation)

Abstract

We report three cases of pulmonary disease suggesting fibrosis in two familial and one sporadic case. Pulmonary symptoms were associated with various clinical features of systemic inflammation and vasculitis involving the skin, and appeared at different ages. A strong interferon signature was found in all three cases. Disease was not responsive to corticosteroids, and lung transplantation was considered for all three subjects at an early age. One of them underwent double-lung transplantation, but she immediately experienced a primary graft dysfunction and died soon after. Recognized causes of familial interstitial lung disease were all excluded. All three subjects had a mutation in the previously described autoinflammatory disease called SAVI (stimulator of interferon genes [STING]-associated vasculopathy with onset in infancy). These cases emphasize the need to consider this possibility in children and young adults with lung fibrosis after common causes have been ruled out.

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

“…In addition, evidence indicates that inflammatory disease can be caused by germline missense mutations in the coding region of the STING gene itself (V147L/M, N154S, V155M, C206Y, R281Q, R284G, and S102P/F279L), which exert a gain-of-func-tion phenotype referred to as STING-associated vasculopathy with onset in infancy (SAVI) (Clarke et al, 2016; Fre´mond et al, 2016; Jeremiah et al, 2014; Liu et al, 2014; Melki et al, 2017;Picard et al, 2016; Seo et al, 2017). This disease causes skin lesions, rashes, and interstitial lung disease in children.…”

Management of suspected monogenic lung fibrosis in a specialised centre

“…Hermansky-Pudlak syndrome (HPS) associates pulmonary fibrosis, oculocutaneous albinism and platelet abnormalities and is due to mutations in the HPS-1 to HPS-9 genes [94]. Gain-of-function mutations in TMEM173 encoding stimulator of interferon genes (STING) are associated with pulmonary fibrosis and various clinical features of systemic inflammation and vasculitis involving the skin in children and young adults with a strong serum interferon elevation [7,95]. Mutations in COPA (encoding coatomer subunit α) are associated with a syndrome of autoimmunity manifested by lung and joint disease [8].…”

“…Genetic studies of familial forms of ILD led to the discovery of mutations in genes implicated in telomere homeostasis (TERT, TERC, RTEL1, PARN, DKC1, TINF2 and NAF1) or surfactant homeostasis (SFTPC, ABCA3 and NFKX2-1) or associated with complex syndromes (COPA, TMEM173, HPS-1 to HPS-8, NF1, FAM111B, NDUFAF6 and GATA2) (table 1 and figure 1) [3][4][5][6][7][8][9][10][11]. International guidelines on clinical practice for ILD are needed, but here we describe our current practice with the disease.…”

Lung Involvement in Children with Hereditary Autoinflammatory Disorders

“…Picard et al reported three young patients with SAVI, two familial and one sporadic, all displaying pulmonary manifestations suggestive of lung fibrosis at disease onset: the disease was resistant to corticosteroids, and lung transplantation was considered at an early age [40]. As chronic interstitial lung disease in SAVI might be fatal, there is an urgent need for effective therapies in this condition: a clinical trial with baricitinib, a Janus kinase inhibitor that blocks the interferon signaling cascade, is currently in progress and recruiting patients ().…”