Two novel kindreds with autosomal recessive STAT2 deficiency

STAT2 is a transcription factor in the type I/III interferon (IFN) antiviral response. Autosomal recessive STAT2 deficiency, reported in 12 kindreds from nine countries, underlies severe viral infections and hyperinflammation. We report three patients from two kindreds from Portugal and Algeria, respectively, with novel homozygous STAT2 mutations. The three patients developed complications following live attenuated measles-mumps-rubella (MMR) vaccine, including hemophagocytic lymphohistiocytosis (HLH) in one patient, who responded to treatment with intravenous immunoglobulins (IVIG), steroids, and ruxolitinib (JAK-STAT inhibitor). The patients are now 36, 33, and 3 years old and healthy on prophylaxis with cotrimoxazole and itraconazole (P1), cotrimoxazole (P2), or IVIG (P3). The STAT2 K490Qfs*41 and c.941+1G>T mutant alleles do not encode detectable and functional STAT2 proteins, and the patients' primary cells do not respond to type I IFNs. STAT2 deficiency should be considered in patients with severe adverse reactions to MMR vaccination, and the use of targeted anti-inflammatory drugs like ruxolitinib should be further explored to control hyperinflammation.