Case report: Pneumocystis jirovecii pneumonia in a severe case of Aicardi-Goutières syndrome with an IFIH1 gain-of-function mutation mimicking combined immunodeficiency

Abstract

Aicardi-Goutières syndrome (AGS) is a genetically determined early-onset progressive encephalopathy caused by mutations leading to overexpression of type I interferon (IFN) and resulting in various clinical phenotypes. A gain-of-function (GOF) mutation in the IFIH1 gene is associated with robust production of type I IFN and activation of the Janus kinase (JAK) signal transducer and activator of the transcription (STAT) pathway, which can cause AGS type 7. We detail the clinical case of an infant who initially presented with Pneumocystis jirovecii pneumonia (PCP), had recurrent respiratory infections, and was later treated with a JAK inhibitor, baricitinib, because of a genetically confirmed GOF mutation in the IFIH1 gene. This spectrum of IFIH1 GOF mutations with overlapping features of hyperinflammation and severe opportunistic infection, which mimics combined immunodeficiency (CID), has not been described before. In this case, therapy with baricitinib effectively blocked IFN-α activation and reduced STAT1 signaling but had no effect on the progression of the neurological disease.

Keywords: Aicardi–Goutières syndrome (AGS); IFIH1 gene; Janus kinase inhibitor; combined immune deficiency; interferonopathy.

Figure 1

Initial brain MRI scans (T2 sagittal and axial plane). (A) Normal thickness of pons and midbrain. (A, B) Higher T2 signal of the frontal white matter.

Figure 2

(A): Total STAT1 levels in CD4+ T lymphocytes from the patient on indicated time points and healthy controls. (B) Phosphorylated STAT1 (pSTAT1) levels in unstimulated whole-blood CD4+ T lymphocytes and on interferon (IFN)-α induction. (C) Basal (unstimulated) pSTAT1 levels and pSTAT1 levels on stimulation with IFN-α for 15 minutes in CD4+ T lymphocytes from the patient before treatment and after 3 months of baricitinib, and from healthy controls. Values in (A) and (C) for healthy controls (n=3) are the mean ± SD. MFI, median fluorescence intensity; HC, healthy controls.

Figure 3

(A) Follow-up brain MRI scans (T2 sagittal and axial plane) after 1 year: severe atrophy of midbrain compared with initial MRI. (B) Severe reduction of brain volume and abnormal signal of the white matter—leucoencephalopathy.