Aicardi goutières syndrome is associated with pulmonary hypertension

Abstract

While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney p < .001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney p < .0001). We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH.

Keywords: Aicardi Goutières Syndrome; Interferons; Pulmonary hypertension.

Figure 1:. Genetics and IFN scores in individuals with AGS.

(A). The distribution of molecular results is shown. (B). Cardiac evaluation within the AGS cohort is shown by genotype (white=ECHO unavailable or not done; grey=no PH detected; black=PH present). (C). IFN signaling gene (ISG) scores were calculated and an IFN signature was derived for all AGS affected individuals in the MDBP registry for whom blood samples were available (180 AGS samples and 104 control samples). Across all genotypes of AGS, ISG scores were significantly increased compared to control samples (by Mann-Whitney all p<0.0001 except for RNASEH2A, p=0.001). (D) Individuals with IFIH1 variants had higher ISGs compared to other AGS genotypes (Mann-Whitney all p<0.0001).

Figure 2:. Pathology features consistent with pulmonary hypertension.

H+E stained sections of both small and large arteries show marked muscular hypertrophy (A, B), marked cellular intimal proliferation (C) leading to complete luminal occlusion (D). Also noted was concentric intimal fibrosis (E) and intraluminal thrombus formation (F). H+E sections showed histologic features consistent with severe pulmonary hypertension including plexiform (*) and dilation (arrow) lesions associated with markedly remodeled pulmonary arteries (PA) (G, H, I). Open intrapulmonary bronchopulmonary anastomoses (K) that bridge the pulmonary arteries and bronchial arteries (BA), along with marked BA remodeling and occlusions (J) are present (Br: bronchiole). Microscopic examination of the lungs included elastin [Verhoeff-van Gieson (VVG), L] stained sections showing marked pulmonary artery remodeling. Immunohistochemistry on lung sections revealed fibrointimal proliferation with infiltration of macrophages (CD163⁺, M) and tunica medical thickening [smooth muscle actin (SMA)⁺, N]. Gross examination of the heart showing dilatation of the right ventricle (O).