A Panoply of Rheumatological Manifestations in Patients with GATA2 Deficiency

Abstract

Purpose: To characterize rheumatological manifestations of GATA2 deficiency. Methods: Single-center, retrospective review of 157 patients with GATA2 deficiency. Disease course, laboratory results, and imaging findings were extracted. In-person rheumatological assessments were performed on selected, available patients. A literature search of four databases was conducted to identify additional cases. Results: Rheumatological findings were identified in 28 patients, out of 157 cases reviewed (17.8%). Twenty-two of those patients (78.6%) reported symptom onset prior to or in conjunction with the molecular diagnosis of GATA2 deficiency. Notable rheumatological manifestations included: piezogenic pedal papules (PPP), joint hyperextensibility, early onset osteoarthritis, ankylosing spondylitis, and seronegative erosive rheumatoid arthritis. in peripheral blood of patients with rheumatological manifestations and GATA2 deficiency, CD4+ CD3+ helper T cells and naïve CD3+ CD4+ CD62L+ CD45RA+ helper T cell subpopulation fractions were significantly lower, while CD8+ cytotoxic T cell fractions were significantly higher, compared to those without rheumatological manifestations and with GATA2 deficiency. No changes in CD19, CD3, or NK populations were observed. Conclusion: GATA2 deficiency is associated with a broad spectrum of rheumatological disease manifestations. Low total helper t lymphocyte proportions and low naïve helper t cell proportions are associated with those most at risk of overt rheumatological manifestations. Further, PPP and joint hyperextensibility may explain some of the nonimmunologically-mediated joint problems encountered in patients with GATA2 deficiency. This catalogue suggests that rheumatological manifestations and immune dysregulation are relatively common in GATA2 deficiency. GATA2 is a zinc finger transcription factor that plays a critical role in hematopoietic lineage commitment. Haploinsufficiency of GATA2 underlies five distinct syndromes: (1) Mono-cytopenia and non-tuberculous mycobacterial infection (MonoMAC); (2) Dendritic cell, monocyte, B, and natural killer lymphopenia (DCML); (3) Familial myelodysplasia (MDS)/acute myelogenous leukemia (AML); (4) Emberger syndrome (primary lymphedema with MDS); and (5) classical NK cell deficiency 1-3. The definitive treatment strategy for patients with GATA2 deficiency is nonmyeloablative hematopoietic stem cell transplantation, which has been shown to successfully reconstitute cell population deficiencies and reverse myelodysplastic and infectious phenotypes 4. While the myelodysplastic and infectious disease manifestations in patients with GATA2 deficiency have been well described, only a handful of case reports and case series 5-11 have reported rheumatological manifestations in patients with GATA2 deficiency. Specifically, erythema nodosum 6,7,10,12 , panniculitis 6,7,9,12-14 , primary biliary cirrhosis 6 , hemophagocytic lymphohistiocytosis-like disease 11 , and uncharacterized arthralgias 5,7,14 were previously

GATA 2 Deficiency: Focus on Immune System Impairment

“…Recently, rheumatological manifestations were found in 17.8% of patients in a study ( 38 ), and a correlation with a lower CD4:CD8 T cells ratio was found. Surprisingly, other than panniculitis, erythema nodosum, psoriasis and arthritis, non-immunologically mediated disorders such as piezogenic pedal papules and joint hyperextensibility were found in a significant number of patients, suggesting a role of GATA2 in collagen architecture.…”

Mesenchymal stem cells‐derived extracellular vesicles containing miR‐378a‐3p inhibit the occurrence of inflammatory bowel disease by targeting GATA2

“…An existing study investigated the role of GATA2 in IBD and determined that the GATA2 deficiency might influence the development of IBD. 28 Additionally, previous research identified that the transcription factor GATA2 serve as an inducer for the inflammatory reaction in colitis. 13 Furthermore, the current study demonstrated that the inhibition of GATA2 could contribute to downregulated AQP4 and blockade of PPAR‐α, thereby reducing the LPS‐induced apoptosis of M064 cells.…”

“…Initially, our findings elicited the elevation of GATA2 in the colon tissues of IBD patients and mice, and its silencing could reduce the LPS‐induced apoptosis of M064 cells. An existing study investigated the role of GATA2 in IBD and determined that the GATA2 deficiency might influence the development of IBD 28 . Additionally, previous research identified that the transcription factor GATA2 serve as an inducer for the inflammatory reaction in colitis 13 .…”

Dendritic cells in inborn errors of immunity

“…NADPH oxidase has shown to play an important role in regulating in antigen processing and cross presentation by DCs to antigen specific CD8+ T cells. Amogerina group (151)(152)(153), in both in vivo and in vitro using gp91phox deficient mice, demonstrated that DCs from gp91phox-mice were impaired in antigen degradation and MHC class I presentation to CD8+ T cells and activation of CD8+ T cells (148)(149)(150)156).…”

“…Clinical features include recurrent infection (especially atypical mycobacterial infections, EBV, Pneumocystis jirovecii and recurrent HPV-related warts) and hematological malignancies (MDS/AML), pulmonary alveolar proteinosis (PAP), lymphedema, and sensorineural deafness. Rheumatological manifestations have also been reported ( 150 ).…”