Name: ARPC1B deficiency | Acronym: IMD71
Alt. names: Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia

Gene: ARPC1B | MOI: Autosomal recessive | Mechanism of action: Loss of Function

No. of cases in DB: 39 | First reported in: 2017

Last updated on: 2023-10-22 21:36:50 by Xiao P. Peng

OMIM: 617718

Orphanet: -

MONDO: 0060583

DOID: 0112004

ClinGen: Definitive (2020-07-22)

Kahr et al. (2017) first identified three individuals from two families with homozygous mutations in ARPC1B who presented early in life with failure to thrive, recurrent invasive infections, microthrombocytopenia, eosinophilia, small vessel vasculitis, eczema, inflammatory bowel disease (IBD) often with GI bleeding, and other findings reminiscent of immunoactinopathies like Wiskott-Aldrich syndrome (WAS) (PMID: 28368018). The authors showed that these mutations resulted in ARPC1B loss of function and defective Arp2/3 actin filament branching, leading to abnormally shaped platelets, decreased platelet dense granules and defective platelet spreading with prominent filopodia but limited lammellipodia. The phenotypic spectrum was subsequently expanded by identification of at least 24 additional pediatric and young adult patients (PMID: 27965109, 29127144, 30771411, 30254128, 32499645). In addition to severe eczema, vasculitis, IBD, cytopenias, and recurrent bacterial and viral infections predominantly involving the skin, GI and sinorespiratory tracts, some patients showed additional immune dysregulatory and autoinflammatory findings such as recurrent fevers, arthritis, lymphadenopathy, and hepatosplenomegaly. Additional immunophenotypic abnormalities commonly seen in patients include elevated inflammatory markers, lymphocytosis, increased numbers of circulating B cells with increased levels of isotype-switched immunoglobulins, and elevated levels of auto-antibodies such as ANA and ANCA. Though the initial patients did not show overt T cell lymphopenia, subsequent patients had both quantitative and qualitative T cell defects, including regulatory T cell dysfunction, as well as evidence of both dysfunction and migration abnormalities in NK cells. One patient developed HPV-associated cervical and vulval intraepithelial dysplasia grade 3 and anaplastic large cell lymphoma, suggesting the potential for increased malignancy risk like for WAS (PMID: 32499645).

Most patients received antibiotic prophylaxis and some received antifungal prophylaxis if affected by recurrent fungal infections. Patients' autoinflammatory features did not seem to respond to TNF inhibition, but did respond to steroids, mofetil mycophenolate and sirolimus (PMID: 30771411). A recent small cohort study of patients with ARPC1B mutations receiving allogeneic hematopoietic stem cell transplantation (HSCT) found that most tolerated transplant conditioning, with a high rate of engraftment, and subsequent resolution of immunodeficiency, autoinflammation, and autoimmunity (PMID: 35767111). Indeed, successful immune-mediated symptomatic resolution with sustained donor chimerism and excellent survival was seen in 6 of 7 patients, though the single patient who only achieved mixed chimerism with prevalence of T-cells from the donor also remained alive and symptom-free. Active infections and clinically significant comorbidities at the time of transplant were the main contributors to acute post-transplant morbidity and mortality. Of note, cells from all tested ARPC1B patients exhibit increased radiosensitivity to ionizing radiation, although to a lower level than those observed in patients with ataxia telangiectasia or other DNA damage checkpoint mutations, as well as presumably double-strand break repair defects (PMID: 35967303).