Rare monogenic germline variants in genes coding for immune system proteins often result in extreme and deadly phenotypes. JAK3 is a tyrosine kinase involved in cell growth, development, and differentiation, which mediates essential signaling in hematopoiesis and immunity. Autosomal recessive JAK3 deficiency causes severe combined immunodeficiency that manifests early after birth and usually results in death from infection within the first two years of life. Gain-of-function (GOF) variants in immune system genes may present at a later age with hyperinflammation, autoimmunity, and lymphoproliferation.
A 19-year-old male was hospitalized for a history of fever of unknown origin. On physical examination, he had a disseminated rash with ulcers and hepatosplenomegaly. He also developed severe ulcerative colitis. Two years later, he died of intestinal perforation, with final diagnoses of T/NK cell liver lymphoma, inflammatory bowel disease (IBD), and ulcerative-necrotizing vasculitis.
Epstein–Barr virus (EBV) serology was IgG positive to EA and EBNA, with a viral count of 1,000,000 copies. A liver biopsy found acute inflammation with necrosis and eosinophilia. The routine immunological workup was essentially normal, except for NK cell predominance: 75% of lymphocytes were CD56+.
Whole-exome sequencing analysis identified a heterozygous germline missense variant (MAB 0.52, DP 71x) in exon 17 of JAK3 (c.2395C>T, p.Arg799Cys), located in a linker between the pseudokinase and kinase domains; exceedingly rare (gnomADe MAF 0.00005), possibly deleterious (CADD 24.9), and highly conserved across species (GERP++RS 5.11).
In 2020, Lesmana and colleagues reported a mother and son with NK cell lymphoproliferation, lymphadenopathy, splenomegaly, and autoimmunity, including common-variable immunodeficiency, psoriasis, vasculitis, and autoimmune cytopenia. The immunological workup in the son revealed hypogammaglobulinemia, expanded NK cells between 40 and 60% of total lymphocytes, and decreased FOXP3 expression with low B cells. A novel germline heterozygous variant in JAK3 (Q507P) was identified at another linker domain and characterized as GOF with constitutive phosphorylation. Several other GOF somatic variants have been found in hematologic malignancies and chronic lymphoproliferative disorder of NK cells (CLDNK).
This case highlights EBV susceptibility and IBD as previously unrecognized features of JAK3-GOF. Next, we want to perform directed mutagenesis and functional validation assay to characterize this variant.
