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.