Biallelic mutations in RNASEH2B are classically associated with Aicardi–Goutières syndrome. However, heterozygous variants have recently been linked to monogenic systemic lupus erythematosus, expanding the clinical spectrum.
A 29-year-old male. At age 18, developed chronic severe thrombocytopenia refractory to steroids and rituximab, with multiple hospitalizations for trauma-related bleeding. Later presented with hypothyroidism and chondritis. Labs showed normal immunoglobulins, positive antinuclear antibodies (1:160), low B (260/mm3) and natural killer (NK) cells (58/mm3), high double negative T (DNT) cells (9%), altered T and B subpopulations (high central memory T and DR+ T cells, low switched B cells, and high transitional B cells). Treated with sirolimus and hydroxychloroquine with mild response. With subcutaneous immunoglobulin, achieved platelet and DNT normalization.
P2: 14-year-old male. At age 4, presented with urticaria and angioedema on hands, ears, and face, worsened by sun exposure, unresponsive to antihistamines or steroids. Immunologic workup showed no cytopenia, normal acute-phase markers, low IgG (<1/2 SD), normal IgA/IgM, normal complement (C3/C4), negative autoantibodies, and normal lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, CD56+).
P3: 27-year-old female. At age 25, presented two events of myopericarditis requiring hospitalization. Extensive cardiac workup confirmed elevated cardiac enzymes with normal imaging, and the patient responded to colchicine, nonsteroidal, anti-inflammatory drugs, and corticosteroids. Immunological studies showed normal immunoglobulins and complement, negative autoantibodies, and NK lymphopenia. All patients carried the heterozygous pathogenic variant RNASEH2B c.529G>A, p.(Ala177Thr). Interferon signature was performed in 2/3 patients and was markedly elevated in P1: 174.48 (cutoff 8.4) and IL-18 at 106.1 copies/ng (reference value <35); and P2: 28.2. P1 is currently on eltrombopag and in plan of starting baricitinib, P2 remains under expectant management, and P3 is receiving colchicine.
These cases highlight that patients with heterozygous variants in RNASEH2B developed clinical symptoms. The elevated interferon signature supports type I interferonopathy as a shared pathophysiological mechanism in these patients. Early recognition is crucial to diagnose and guide targeted treatment.
