GATA2 deficiency, a syndrome caused by heterozygous loss-of-function variants in the GATA2 gene, is characterized by immunodeficiency, bone marrow failure, and predisposition to myeloid neoplasms. Its clinical presentation is highly variable, making early diagnosis challenging. Although GATA2 deficiency has been linked to systemic inflammation, gastrointestinal involvement mimicking inflammatory bowel disease (IBD) is extremely rare. This report presented the case of two adolescent boys with no family history of novel heterozygous frameshift GATA2 variants. Notably, Patient 1 initially presented with clinical and endoscopic features strongly suggestive of Crohn's disease, including weight loss, perianal abscess, and characteristic intestinal ulcers, before developing acute myeloid leukemia with monosomy 7. This is a rare presentation of GATA2 deficiency manifesting initially with Crohn's disease-like symptoms. Patient 2 presented with intractable cutaneous warts and pancytopenia, later diagnosed as myelodysplastic syndrome with der(1;7)(q10;p10). Both patients harbored novel GATA2 frameshift variants predicted to eliminate the DNA-binding domain, suggesting a loss-of-function mechanism. These cases expand the phenotypic spectrum of GATA2 deficiency and highlight that atypical IBD-like symptoms, including Crohn's disease-like presentations, may cause an initial manifestation. GATA2 deficiency should be considered in patients with IBD-like symptoms, refractory skin disorders, and hematological abnormalities. Early genetic testing and family screening are essential to ensuring timely diagnosis and curative hematopoietic stem cell transplantation before progression to advanced myeloid disease.

The spectrum of myeloid disorders ranges from aplastic bone marrow failure characterized by an empty bone marrow completely lacking in hematopoiesis to acute myeloid leukemia in which the marrow space is replaced by undifferentiated leukemic blasts. Recent advances in the capacity to sequence bulk tumor population as well as at a single-cell level has provided significant insight into the stepwise process of transformation to acute myeloid leukemia. Using models of progression in the context of germ line predisposition (trisomy 21, GATA2 deficiency, and SAMD9/9L syndrome), premalignant states (clonal hematopoiesis and clonal cytopenia of unknown significance), and myelodysplastic syndrome, we review the mechanisms of progression focusing on the hierarchy of clonal mutation and potential roles of transcription factor alterations, splicing factor mutations, and the bone marrow environment in progression to acute myeloid leukemia. Despite major advances in our understanding, preventing the progression of these disorders or treating them at the acute leukemia phase remains a major area of unmet medical need.

Germline GATA2-deficiency usually manifests as immunodeficiencies and myeloid neoplasms and sometimes with dermatological diseases, including warts, panniculitis, and skin cancers. We report a 36-year-old woman with germline GATA2-deficiency who developed Merkel cell carcinoma followed by acute myeloid leukemia. Molecular analysis revealed a germline GATA2 S447R variant, not reported from the previous reported case, suggesting a potential association with Merkel cell carcinoma. This case broadens the spectrum of solid cancers linked to GATA2-deficiency, emphasizing the need for considering primary immunodeficiency in young patients with myeloid neoplasms or rare skin cancers, facilitating early detection and treatments.

GATA2 deficiency is an autosomal dominant disease that manifests with a range of clinical symptoms, including increased susceptibility to viral, bacterial, and fungal infections. Furthermore, the increased susceptibility to infections in GATA2 deficiency can trigger hemophagocytic lymphohistiocytosis (HLH) in these patients. Our systematic review evaluates reported cases of GATA2 deficiency and HLH in the literature. A systematic review of case reports was conducted following PRISMA 2020 guidelines, encompassing studies retrieved from Ovid MEDLINE ALL, Embase via Ovid SP, Scopus, Web of Science, and Google Scholar from inception until June 14, 2024. This review included studies reporting patients diagnosed with GATA2 deficiency or having a documented history of the condition, who subsequently developed or were concurrently diagnosed with HLH. Various study types were considered, such as case reports, case series, letters to editors, original articles, correspondences, and commentaries, without any restrictions on language. In our systematic review, 15 studies from 2016 to 2024 were analyzed, encompassing 23 patients with GATA2 deficiency and HLH. the mean (SD) age of patients was 23.48 (10.54) years, ranging from 7 to 57 years. These patients exhibited diverse genetic mutations and a spectrum of infections, particularly Mycobacterium avium (M. avium), Mycobacterium kansasii (M. kansasii), Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), herpes simplex virus (HSV), and influenza A, often leading to HLH. Family histories of GATA2-deficient patients with HLH occasionally reveal confirmed GATA2 mutations or suspicious cases among first-degree relatives. Hematopoietic stem cell transplantation (HSCT) was performed in 8 patients with GATA2 deficiency and HLH. Among them, 6 patients survived post-therapy, while 2 patients died following HSCT. Currently, 1 patient is being considered for HSCT. The overall mortality rate among GATA2 deficiency patients who experienced HLH was 39.13%. This systematic review highlights GATA2 deficiency's association with diverse infections triggering HLH, emphasizing early infection management to mitigate mortality risks. This comprehensive analysis contributes to scientific knowledge, offering important insights for clinicians and researchers in diagnosing and managing this rare condition.