- Somatic mosaicism causing autoinflammatory diseases is increasingly recognized, but the onset and mechanisms of clonal expansion remain enigmatic.
Case
A patient underwent surgical resection and chemotherapy for Ewing’s sarcoma at 15 years of age. Five years later, after a primary Epstein–Barr virus infection, persistent mildly elevated levels of C-reactive protein without symptoms were noted. Three years later, chronic headache, myalgia, diarrhea, and low-grade to spiking fevers developed, and she had episodes of urticaria, arthritis, or pleuropericarditis that occasionally resulted in hospitalization.
Diagnosis
An autoinflammatory disease due to somatic mosaicism in NLRC4 (p.Val341Leu) was confirmed via exome sequencing. Treatment with canakinumab, an interleukin-1–blocking agent, was initiated, with rapid resolution of inflammation and symptoms.
Genetic Findings
Exome sequencing revealed an additional acquired myeloid driver variant in TET2 (p.Ile1226Metfs*2) with an evolution in variant allele fraction similar to that of the NLRC4 variant. By genotyping individual white cells, both pathogenic variants occurred in the same cell, consistent with their parallel variant allele fractions over time.
Conclusions
A hematopoietic stem and progenitor cell acquired both the passenger NLRC4 and driver TET2 pathogenic variants, resulting in clonal hematopoiesis, skewed myelomonocytic differentiation, and progressive NLRC4 inflammasome–driven autoinflammation. These data are consistent with a synergy between inflammation and myeloid-predominant clonal expansion and observations in Tet2-deficient mouse models and humans with hematoinflammatory disorders.
De Langhe, E., Van Loo, S., Malengier-Devlies, B., Metzemaekers, M., Staels, F., Vandenhaute, J., Berghen, N., Sciot, R., Corveleyn, A., Tšuiko, O., Gouwy, M., Lenaerts, J., Verschueren, P., Wouters, C. H., Proost, P., Matthys, P., Legius, E., & Schrijvers, R. (2023). TET2-Driver and NLRC4-Passenger Variants in Adult-Onset Autoinflammation. New England Journal of Medicine, 388(17), 1626-1629.