Nuclear factor of activated T cells 2 (NFATC2), also known as NFAT1, is a critical calcium/calcineurin-dependent transcription factor essential for immune homeostasis. Human inborn errors of immunity (IEIs) due to biallelic NFATC2 mutations are exceedingly rare, with only two distinct phenotypes previously described a syndromic disorder of joint contractures, osteochondromas, and B cell malignancy (JCOSL) from a homozygous C-terminal frameshift mutation, and a severe immunodeficiency with EBV-associated lymphoproliferation from a homozygous N-terminal deletion. The full spectrum of disease remains to be defined.
We report a 12-year-old female with a severe, early-onset immunodeficiency characterized by recurrent sinopulmonary infections, bloody diarrhea, chronic lung disease, and profound failure to thrive (body mass index 12). Immunological workup revealed anemia and thrombocytosis, as well as pan-hypogammaglobulinemia, with reduced CD4+ and CD8+ T cells. Whole exome sequencing identified two novel, ultra-rare, highly conserved heterozygous missense variants in NFATC2, located in exons 3 and 8 (Gly408Arg/Arg646Gln).
The clinical and immunological phenotype of our patient closely resembles the previously reported case with a homozygous N-terminal deletion, but contrasts sharply with the JCOSL phenotype. The variants in our patient are predicted to affect two critical functional domains: the N-terminal regulatory NFAT homology region (NHR) and the C-terminal DNA-binding REL homology region (RHR). The combined impact of these two mutations may result in a profound loss of NFATC2 function, disrupting T cell and B cell development and homeostasis, leading to a combined immunodeficiency. Chronic lung and gastrointestinal diseases are likely a consequence of both impaired pathogen clearance and underlying immune dysregulation. This case of compound heterozygous NFATC2 deficiency expands the genetic and clinical spectrum of a rare IEI, reinforcing the emerging genotype–phenotype correlation: variants affecting the N-terminal and DNA-binding domains result in severe immunodeficiency. It highlights the necessity of considering NFATC2 in the differential diagnosis of complex CVID-like presentations with multi-organ involvement.
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