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.

Figure 1

Select abnormalities observed in our Natural History of Disease GATA2 deficiency cohort. (A) CT imaging showing sacroiliac irregularity and periarticular sclerosis compatible with sacroiliitis in a 30-year-old male. (B) Small juxta-articular erosions involving the distal interphalangeal joints bilaterally, mild-moderate degenerative changes of the radiocarpal joints bilaterally, and tiny juxta-articular erosions involving the proximal interphalangeal joints on the left in a 53-year-old female. (C) X-ray imaging showing atraumatic fusion of three thoracic vertebrae in a 20-year-old female. (D) Patellofemoral joint x-ray showing spurs and washed out periarticular osteopenia in a 46-year-old male; knee aspiration yielded 60,000 WBCs and no organism or acute gout crystals. (E,F) Piezogenic pedal papules observed with weight-bearing, but not when elevated in a 22-year-old female.

Figure 2

Immune and MSK dysregulation in patients with GATA2 deficiency. Summary of previously published infectious, myelodysplastic, and rheumatological disease manifestations observed in patients with GATA2 deficiency, as well as rheumatological manifestations described herein for the first time (indicated with an asterisk*). MDS - familial myelodysplasia, AML - acute myelogenous leukemia, AVN – avascular necrosis, MSK - musculoskeletal, HLH/MAS - hemophagocytic lymphohistiocytosis/macrophage activation syndrome, HSV – herpes simplex virus, PAP – pulmonary alveolar proteinosis, NTM – nontuberculous mycobacteria, RA – rheumatoid arthritis, JIA – juvenile idiopathic arthritis.

Figure 3

Lymphocyte phenotyping from peripheral blood of patients with GATA2 deficiency. (A) CD4+ CD3+ helper T cells proportions. (B) CD8+/CD3+ cytotoxic T cell proportions. (C) CD3+ CD4+ CD62L+ CD45RA+ True Negative naïve helper T cell subset proportions. (D) CD3+ CD4+ CD62L− CD45RA− Effector Memory helper T cell subset proportions. (E) CD19+ B cells proportions. (F) CD3+ T cell proportions. (G) CD16+ and/or CD56+ NK cell proportions. (H) CD16+ and/or CD56+, CD3+ NK T cell proportions. (I) CD3+ CD8+ CD62L+ CD45RA+ Naïve cytotoxic T cell subset proportions. Box-whisker plot indicates the 10–90% distribution, with outliers identified as scatter dots. *p < 0.05 Mann-Whitney U test. Rheumatologic group (n = 25 of 28 patients) and non-rheumatologic group (n = 95 of 129 patients).

Figure 4

Flow-diagram of literature review. Records were included if they described GATA2 pathology in patients or direct mechanisms in animal models, and were related to inflammation, bone disease, muscle disease, fractures, spondyloarthropathies, rheumatoid arthritis, and other rheumatological manifestations. Only human studies identified are summarized in Supplemental Table 2.