Primary immune regulatory disorder (PIRD) is a subset of inborn errors of immunity (IEIs) caused by disruption of genes involved in regulating the immune response. PIRDs are predominantly characterized by dysregulated immune activation that leads to organ damage, but may also include susceptibility to infections due to the intrinsic immune gene defect. We identified a novel PIRD in six children from four unrelated families from different ancestries presenting with severe infant-onset hemolytic anemia, life-threatening inflammatory lung disease, and severe pulmonary infections. All but one patient succumbed to disease.
Exome sequencing revealed biallelic coding variants in PTPN6, which encodes SHP1, a protein phosphatase primarily expressed in hematopoietic cells that functions as a critical negative regulator of both adaptive and innate immune signaling. All SHP1 variants are absent from gnomAD and are predicted to be damaging by multiple prediction algorithms (Combined Annotation Dependent Depletion [CADD], Rare Exome Variant Ensemble Learner [REVEL], and AlphaMissense). The variants are all clustered within the SHP1 phosphatase domain, which mediates the removal of phosphate groups from signaling proteins. Functional studies demonstrate that these variants destabilize SHP1 protein levels and markedly reduce or abolish the SHP1 phosphatase activity. These mutant SHP1 proteins also fail to appropriately downregulate ERK signaling following cell stimulation. Bulk RNA sequencing (RNA-seq) from one affected patient showed profoundly heightened inflammatory gene signatures, placing this individual as an outlier relative to a pediatric septic shock cohort, particularly within IL-6/STAT3, TNFα/NFkB, and general inflammatory pathways. These findings parallel phenotypes observed in SHP1-deficient mouse models, which also develop hyperinflammatory disease and anemia due to loss of SHP1-mediated negative regulation.
Collectively, these clinical and experimental data establish PTPN6 loss-of-function as the cause of a severe, newly recognized PIRD characterized by infant-onset severe anemia and life-threatening inflammatory pulmonary disease. Data from SHP1-deficient mice suggest SYK inhibition can prevent the development of inflammatory disease, suggesting potential therapeutic benefit with SYK inhibitors such as fostamatinib. Ongoing studies aim to further define the immunologic consequences of SHP1 deficiency and evaluate targeted therapeutic strategies for patients with this newly recognized disorder.
