NCKAP1L encodes hematopoietic protein-1 (HEM1), a component of the WASp family verproline-homologous protein (WAVE) actin regulatory complex, activated downstream of multiple immune receptors. HEM1 deficiency disrupts WAVE-mediated regulation of F-actin polymerization and actin capping in neutrophils and lymphocytes, resulting in impaired immune synapse formation, cell migration, and phagocytosis, and excessive cytokine release due to dysregulated granule exocytosis (1, 2). HEM1 deficiency also impacts mTORC2 signaling, T cell proliferation, and other T cell effector functions (3, 4). Thus, the totality of HEM1 deficiency is impaired specific immunity, in addition to nonspecific immune system hyperactivation.
Biallelic loss-of-function NCKAP1L variants, including the homozygous c.1076C>T (p.P359L) variant, were first described in 2020 and cause an inborn error of immunity marked by early-onset infection susceptibility, autoimmunity, and excessive inflammation (4). Only nine patients from seven kindreds with HEM1 deficiency have been reported (1, 3–5).
We describe two previously unreported patients and provide updated clinical information on two previously published patients, all homozygous for NCKAP1L c.1076C>T (p.P359L) (4, 6), comparing their features with prior cases. Three patients presented in early life with severe bacterial and viral infections accompanied by excessive inflammatory responses resembling hemophagocytic lymphohistiocytosis (HLH), but with uncharacteristic leukocytosis, and improving spontaneously without targeted immunosuppression. One fetus was identified at 25 weeks’ gestation with hydrops, including cardiomegaly, pleural effusion, ascites, echogenic bowel, and Doppler findings consistent with severe anemia; subsequent imaging revealed hepatosplenomegaly, and fetal demise occurred at 31 weeks.
While hydrops fetalis has not been previously reported, it is noteworthy that the older sister of the two patients reported by Salzer et al. (3) died shortly after birth of unknown cause.
Over time, the three surviving patients experienced fewer infections, even without prophylaxis, but experienced lymphoproliferative, atopic, and immune-mediated organ disease, without classical autoimmunity. Three of the four patients are alive at ages 4–17 years and receive supportive care or immunomodulation; none have undergone hematopoietic stem cell transplantation.
This report expands the clinical and immunologic spectrum of HEM1-associated immune actinopathy and increases the total number of reported cases to 12. The shared homozygous c.1076C>T variant among unrelated Ojibway Indigenous Canadian families suggests a possible founder effect.
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