Compound Heterozygous NFATC2 Variants in Adult Patients with Severe Atopy, Immune Dysregulation, and Recurrent Infection

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Introduction NFATC2 encodes the nuclear factor of activated T cells 2, a transcription factor essential for T cell activation, cytokine gene expression, and the maintenance of immune tolerance. Germline variants in NFATC2 have recently been implicated in a spectrum of inborn error of immunity (IEI) marked by combined immunodeficiency and immune dysregulation. Case Presentations We report two unrelated patients with recurrent and severe infections, atopy, and autoimmunity. Patient 1 A 21-year-old female presented with a history of viral meningitis, severe atopic dermatitis, asthma, and multiple recurrent infections. Immunological workup revealed markedly elevated serum IgE levels (5,780 IU/mL) and a reduced circulating Th17 cells. Genetic testing identified compound heterozygous variants in NFATC2 : c.677T>A (p.Leu226His) and c.1952G>A (p.Arg651His), affecting conserved regions involved in DNA binding and transcriptional activity. Patient 2 A 62-year-old woman with a history of recurrent otitis media and cutaneous abscesses since childhood, as well as bone marrow dysplasia and autoimmune hypothyroidism. Immunological evaluation revealed persistently elevated serum IgM levels, decreased naïve B cell counts, and the presence of antineutrophil cytoplasmic antibodies (ANCA). Genetic analysis revealed compound heterozygous variants c.1282G>C (p.Gly428Arg) and c.2462G>A (p.Arg821His), also located in functional domains of NFATC2. Discussion Both cases demonstrate overlapping features with immune dysregulation and susceptibility to infections, consistent with impaired NFATC2 function. The identified compound heterozygous variants in NFATC2 affect highly conserved residues located within functional domains involved in DNA binding and transcriptional activation, and are predicted to impair protein function. Although functional validation is pending, the consistency between the immunophenotypes and the known biology of NFATC2 strongly supports their pathogenicity. Conclusion Compound heterozygous NFATC2 variants may underlie a distinct IEI phenotype. Early recognition is essential to guide immunologic assessment, genetic counseling, and consideration of targeted therapies.

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