Discussion
This report shares the clinical course of a patient with CN-SGD caused by compound heterozygous mutations within the SMARCD2 gene. The clinical characteristics and bone marrow findings of our patient align with the previously described phenotype except she had normal growth and neuro-development. Unlike previously reported cases, our patient developed clinical findings like Bechet disease and post-infectious glomerulonephritis. Our patient showed evidence of early myelofibrosis at the age of 6-years, even before commencement of TPO-mimetic therapy. As expected, the myelofibrosis worsened after commencement of Romiplostim but reduced within 3-months after discontinuation of Romiplostim.9,10
Table 1 summarizes the previously mutations within SMARCD2 in five cases with CN-SGD. The two heterozygous novel variants that were identified in our case are considered pathogenic as both sequence changes create a premature translational stop signal in the gene that result in an absent or disrupted protein product. Both variants in the gnomAD population database (https://gnomad.broadinstitute.org/) and had not been reported in the literature in individuals with -related conditions. The molecular mechanisms contributing to of SMRACD2related SCN and immune deficiency are well characterized.2,3 SMARCD2 -deficient bone marrow-derived CD34+ cells have impaired in vitro expansion and differentiation toward the neutrophilic lineage causing SCN.3 Furthermore, the SMARCD2 -deficient neutrophils are shown to have sub-optimal phagocytic activity due to severely impaired chemotactic response which in turn causes abnormal disaggregation, locomotion, and defective in-vitro-killing of Staphylococcus aureus, lack lactoferrin leading to susceptibility towards infection.2,4 Interestingly,SMARCD2 -deficient neutrophils show normal levels of myeloperoxidase and normal oxidative burst response. Furthermore, The phenotype of CN-SGD caused by SMARCD2 1 is similar to that caused by five-base pair deletion within the second exon of the CEBPε (CCAAT/enhancer binding protein epsilon) gene.11 The SMARCD2 gene product functions as a controller of early myeloid–erythroid progenitor cellular differentiation via interaction with transcription factorCEBPε. 1 As a result, mutations within these two genes lead to similar downstream effects and cause clinically similar phenotypes.12 Unlike patients with CEBPεdeficiency, most of the reported patients who had SMARCD2deficiency showed evidence of myelodys­plasia. Therefore, it is critical to identify the underlying molecular events to better characterize the outcome in children with CN-SGD. These differences can be attributed to the role of SMARCD2 in controlling early stage differentiation of HSCs toward neutrophil granulocytes, while CEPBε controls terminal dif­ferentiation of neutrophils.13
Our patient’s clinical course was altered after addition of Romiplostim, TPO-RA. The rationale behind using Romiplostim in this desperate clinical setting deserves discussion. Thrombopoietin and TPO-RA induce hematopoietic stem and progenitor cells (HSPCs) through binding with the receptor c-mpl 14 and regulate hematopoiesis through its pleotropic actions.15 These findings led to clinical trials evaluating TPO-RA as a therapeutic option for SAA with encouraging outcomes.5,7,16-18 The dosing regimen in SAA was higher than immune thrombocytopenic purpura and ranged from 5 to20 mcg/kg/dose.19 We hypothesized that Romiplostim will help induce HSPCs and provide synergistic effect to G-CSF, a lineage-specific chemokine.20 An attempt to reduce G-CSF dose immediately dropped our patient’s ANC which indirectly provides evidence that Romiplostim helped induce proliferation of HSPCs, yet higher dose of G-CSF was needed for subsequent maturation of granulopoiesis. While we do not have mechanistic data to support our hypothesis, it is possible that Romiplostim may offer a synergistic therapeutic benefit to children with SCN/CN-SGD who are resistant to G-CSF. Clearly caution needs to be applied prior to using combination therapy as it may increase risk of progression towards MDS/leukemia. In conclusion, we share the clinical course of a patient with CN-SGD caused by novel heterozygous mutations within SMRCD2 and short-term benefit of combination therapy with G-CSF and Romiplostim.