Introduction

GATA2 deficiency is a rare genetic disorder characterized by immune system dysfunction, myelodysplastic syndrome (MDS), lung disease, and vascular and lymphatic problems [1]. It results from mutations in the GATA2 gene, which encodes a critical nuclear transcription factor involved in hematopoiesis and the maintenance of hematopoietic stem cells, ultimately playing a pivotal role in immune system function and the differentiation of progenitor cells [2]. GATA2 deficiency is an autosomal dominant disorder with incomplete penetrance, meaning that individuals with the mutation may not always display symptoms [3].

The GATA2 gene, a pivotal regulator of hematopoiesis and immune system function, plays an indispensable role in maintaining the delicate balance of the human body’s blood-forming and immune processes [4]. Its absence or malfunction can result in a rare and complex genetic disorder known as GATA2 deficiency. This case report is dedicated to the exploration of the GATA2 gene’s critical functions, the consequences of its deficiency, and the ensuing clinical challenges faced by individuals affected by this condition.

GATA2, as a nuclear transcription factor, orchestrates the development and differentiation of hematopoietic stem cells, ultimately influencing the formation of diverse blood cell types and the functionality of the immune system [4]. In the context of GATA2 deficiency, the ramifications are profound, encompassing early-onset immunodeficiency, myelodysplastic syndrome (MDS), lung diseases, and a range of vascular and lymphatic complications [1]. The clinical spectrum of GATA2 deficiency is as broad as its impact, presenting unique diagnostic complexities and emphasizing the critical importance of early recognition for effective management [5]. This case report will provide a comprehensive account of a 55-year-old female patient affected by GATA2 deficiency, highlighting the clinical manifestations, diagnostic challenges, and therapeutic approaches in the context of this enigmatic disorder.

This case report underscores the diagnostic challenges posed by the highly variable nature of GATA2 deficiency and emphasizes the significance of early diagnosis. In the subsequent sections, we will comprehensively outline the clinical journey and diagnostic challenges encountered by this patient, highlighting the importance of a timely and accurate diagnosis in the management of GATA2 deficiency.

Case presentation

A 55-year-old female with a medical history of gastroesophageal reflux disease (GERD) and Meckel’s diverticulum presented with a series of perplexing symptoms that unfolded over several months. In November 2020, she initially complained of myalgias, which, by early December 2020, had progressed to include new onset fevers, chills, anemia, and shortness of breath. Although her symptoms bore resemblance to a viral illness, particularly the rapidly spreading SARS-CoV‑2, official testing for COVID-19 returned negative results. The patient’s symptoms, however, did not wane, and she returned to the Emergency Department (ED) after a few weeks, adding a concerning 40-pound weight loss over one month to her complaints. This complex clinical presentation prompted healthcare providers to initiate a differential diagnosis, considering Adult Stills Disease versus Mixed Connective Tissue Disease as potential culprits for her symptoms. Prednisone therapy was commenced, resulting in an initial improvement, but the patient later experienced a recurrence of symptoms, necessitating further evaluation. In March 2021, her condition took a more severe turn, culminating in her readmission to the hospital. Notably, chest imaging revealed increasing alveolar nodular opacities and enlarged mediastinal lymph nodes, contrasting with the previous imaging from January 2021. This imaging raised concern and prompted further investigation into her condition.

Microbiological findings during her hospitalization included sputum cultures that grew Aspergillus fumigatus, indicating a fungal infection. To explore this further, a bone marrow biopsy (BMB) was conducted, alongside a bronchoalveolar lavage. Although the initial smear from the lavage showed no presence of acid-fast bacilli (AFB), biopsy pathology unveiled the existence of intra-alveolar eosinophilic proteinaceous material and AFB within macrophages. As a result, the patient was discharged and prescribed voriconazole while initiating a prednisone taper in an attempt to manage her symptoms and the identified fungal infection.

Despite initial treatment, the patient’s symptoms remained unyielding, and further examination revealed numerous AFB in the bone marrow, coupled with a diagnosis of refractory anemia, a trisomy 8 mutation, and disseminated Mycobacterium avium complex (MAC) infection. The bone marrow aspirate morphology and biopsy revealed dysplastic features (hypogranular neutrophils, megaloblastic erythropoiesis), increased blasts, and abnormal megakaryocytes. The biopsy provided additional insights, demonstrating increased cellularity, dysplastic changes in multiple cell lineages, and evidence of ineffective hematopoiesis, including ringed sideroblasts and abnormal localization of immature precursors within the bone marrow microenvironment. These detailed assessments, coupled with cytogenetic analysis showing trisomy 8, confirmed the diagnosis of myelodysplastic syndrome (MDS).

In diagnosing refractory anemia, the bone marrow smears were scrutinized for distinct dysplastic features. Notably, dysplastic erythrocytes characterized by megaloblastic changes, irregular nuclear contours, and abnormal nuclear-cytoplasmic ratios were observed. Additionally, dysplastic megakaryocytes exhibiting abnormal nuclear lobulation and cytoplasmic vacuolation were noted, consistent with the diagnosis. These morphological abnormalities, in conjunction with other diagnostic criteria, supported the diagnosis of refractory anemia. Subsequently, she was readmitted to the hospital, where treatment began with RIPE therapy (RIF/INH/PZA/EMP), which was later altered to RIPE with azithromycin following negative GeneXpert testing for Mycobacterium tuberculosis (Mtb).

In April 2021, the patient’s clinical journey took another significant turn, marked by abdominal pain and shortness of breath. It was during this period that the possibility of myelodysplastic syndrome (MDS) and GATA2 deficiency was introduced as a potential diagnosis. Recognizing the intricacies of the case and the need for specialized care, the decision was made to transfer the patient to the National Institutes of Health (NIH), where her ultimate diagnosis of GATA2 deficiency was confirmed. This chronological narrative offers a comprehensive insight into the unfolding clinical presentation of a patient whose path to diagnosis and management was marked by complexity and challenges, ultimately leading to the discovery of GATA2 deficiency as the underlying cause of her symptoms. The patient’s diagnostic journey is depicted in two tables: Table 1 presents a detailed overview of immunological tests, while Table 2 provides microbiology findings, both at different time points.

Table 1 Summary of immunological tests conducted on the patient, including the date of completion, patient values, and normal reference ranges
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Table 2 Microbiology findings from diagnostic tests performed on the patient, including cerebrospinal fluid analysis and other relevant microbiological assessments. The table includes dates of completion, patient values, and normal reference ranges
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Table 1 provides a summary of immunological tests conducted on the patient, including the date of completion, patient values, and normal reference ranges. These tests assess various aspects of the immune system, such as antibody levels and autoimmune markers.

Table 2 presents microbiology findings from diagnostic tests performed on the patient, including cerebrospinal fluid analysis and other relevant microbiological assessments. The table includes dates of completion, patient values, and normal reference ranges (Fig. 1).

Fig. 1
figure 1

The chronological progression of the patient’s clinical journey, highlighting key events and milestones from the onset of symptoms to the confirmation of GATA2 deficiency as the underlying diagnosis. This visual representation offers an overview of the complex and evolving nature of the patient’s presentation, providing context for the subsequent discussions on diagnostic challenges, management strategies, and the importance of early recognition of GATA2 deficiency

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Discussion

GATA2 deficiency and its clinical manifestations

GATA2 deficiency, a rare genetic disorder, results from mutations in the GATA2 gene, a key regulator of hematopoiesis and immune system function [1]. GATA2 is crucial for maintaining hematopoietic stem cells and guiding the differentiation of progenitor cells, ultimately shaping the immune system and blood cell production [4]. In the absence or malfunction of GATA2, patients may experience a spectrum of clinical manifestations, including early-onset immunodeficiency, myelodysplastic syndrome (MDS), lung diseases, and a range of vascular and lymphatic complications [1]. These diverse presentations stem from the disruption of hematopoiesis, immune system function, and the overall homeostasis of the body.

Diagnostic challenges

This case underscores the formidable diagnostic challenges posed by GATA2 deficiency. The initial presentation of myalgias and subsequent evolution into a complex syndrome of symptoms resembling viral illness, combined with a negative SARS-CoV‑2 test, exemplify the elusive nature of this disorder. Furthermore, the patient’s recurrent admissions and the initiation of prednisone therapy illustrate the diagnostic ambiguity associated with GATA2 deficiency, as its clinical features often overlap with other conditions, in this case, Adult Stills Disease and Mixed Connective Tissue Disease. This diagnostic uncertainty underscores the need for heightened awareness among healthcare providers and the importance of considering GATA2 deficiency as a differential diagnosis in patients with compatible clinical features.

Pulmonary involvement

A distinctive feature of GATA2 deficiency is pulmonary pathology, often presenting as Pulmonary Alveolar Proteinosis (PAP) and Pulmonary Arterial Hypertension (PAH) [6]. In this case, the patient’s chest imaging revealed alveolar nodular opacities and enlarged mediastinal lymph nodes. These findings are in line with the documented pulmonary complications seen in GATA2 deficiency and highlight the importance of thorough evaluation when patients present with respiratory symptoms.

Hematologic abnormalities

The patient’s clinical journey was marked by profound cytopenias, which is a common consequence of GATA2 deficiency [7]. These hematologic abnormalities can eventually progress to MDS [1], as seen in this case. Additionally, isolated trisomy 8, which was observed in this patient, is associated with myeloid neoplasia in GATA2 deficiency [8], further emphasizing the heterogeneity of this disorder and the need for thorough hematologic evaluation.

Importance of early diagnosis

Early diagnosis of GATA2 deficiency is critical, as it allows for optimal disease management and the prevention of severe complications. In this case, the delay in diagnosis and the recurrent admissions illustrate the potential consequences of delayed recognition. Furthermore, the highly variable nature of GATA2 deficiency, with symptoms typically not presenting at birth but developing over time, underscores the need for a high index of suspicion in patients with compatible clinical features.

The role of specialized centers

The patient’s transfer to the National Institutes of Health (NIH) underscores the significance of specialized centers in the diagnosis and management of complex and rare disorders like GATA2 deficiency. Such centers have the expertise and resources required to provide precise diagnoses and tailored treatment plans for patients with elusive conditions.

The case highlights the complexities of GATA2 deficiency and the need for a multidisciplinary approach to patient care, ultimately improving the outcomes for individuals affected by this rare genetic disorder.

Further management

GATA2 deficiency is typically diagnosed through genetic testing to identify mutations in the GATA2 gene. Specifically, next-generation sequencing (NGS) may be employed to identify GATA2 gene mutations, contributing to a comprehensive diagnostic approach. Once diagnosed, management of GATA2 deficiency often involves a multidisciplinary approach, including hematologists, immunologists, and infectious disease specialists. Treatment strategies aim to address specific manifestations of the disorder, such as immunodeficiency, myelodysplastic syndrome (MDS), and pulmonary complications. Common therapeutic interventions may include hematopoietic stem cell transplantation (HSCT), considered the only curative treatment for GATA2 deficiency, particularly in cases of severe immunodeficiency or MDS. Additionally, immunoglobulin replacement therapy (intravenous or subcutaneous) may be administered to manage recurrent infections associated with immunodeficiency. Supportive care is crucial, with regular monitoring of blood counts, immunologic parameters, and pulmonary function for early detection and management of complications. Prophylactic antibiotics such as trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones (e.g., ciprofloxacin), and macrolides (e.g., azithromycin) may be prescribed to prevent opportunistic bacterial infections. Antifungal agents such as fluconazole, itraconazole, or voriconazole may also be used to mitigate the risk of fungal infections, given the increased susceptibility observed in patients with GATA2 deficiency. These prophylactic measures aim to minimize the occurrence of infectious complications and improve overall patient outcomes by reducing the risk of severe bacterial and fungal infections in immunocompromised individuals. Pulmonary interventions may be necessary for addressing complications such as pulmonary alveolar proteinosis (PAP), involving supportive measures like oxygen therapy and pulmonary lavage, along with targeted therapies to address underlying pathophysiology. Overall, the management of GATA2 deficiency requires individualized treatment plans tailored to the patient’s specific clinical presentation and needs.

In addition to patient management, screening of relatives for GATA2 deficiency should include genetic testing, specifically sequencing of the GATA2 gene, to identify carriers of the mutation. This screening may also encompass immunological and hematological evaluations to assess potential manifestations of the disorder in asymptomatic relatives. Early detection and intervention in asymptomatic relatives can facilitate proactive management and improve outcomes.

Limitations

This case report has several inherent limitations that warrant consideration. First and foremost, it is based on a single-patient case, which limits the generalizability of the findings to a broader population. The unique clinical presentation and course of GATA2 deficiency can vary significantly among affected individuals, and the experiences of this patient may not fully represent the diversity of this rare disorder. Additionally, the retrospective nature of the case report relies on historical medical records, which may introduce limitations in terms of data completeness, accuracy, and potential recall bias. The availability and accessibility of past medical records from different healthcare institutions may also affect the comprehensiveness of the case report. Furthermore, the decision to transfer the patient to a specialized center may introduce a selection bias, as these centers often handle more complex and severe cases. Lastly, the report provides limited information about long-term outcomes and the patient’s perspective, areas that could contribute to a more comprehensive understanding of GATA2 deficiency. These limitations underscore the need for continued research and documentation of cases to gain a more holistic perspective of this intricate genetic disorder.

Conclusions

In conclusion, GATA2 deficiency, resulting from mutations in the GATA2 gene, is a rare and intricate genetic disorder that profoundly impacts hematopoiesis, immune system regulation, and overall well-being. This case report provides a valuable insight into the clinical complexities and diagnostic challenges associated with GATA2 deficiency, highlighting its diverse manifestations, diagnostic ambiguity, and the imperative need for early recognition. Looking ahead, the future of GATA2 deficiency lies in enhanced awareness, early diagnosis, and specialized care. Continued research and documentation of cases will contribute to a more comprehensive understanding of the disorder and lead to improved outcomes.