A Novel GATA2 Splice-Site Mutation Associated with Familial Myelodysplastic Syndrome

Introduction

GATA binding protein 2 (GATA2) deficiency is a rare inherited disorder caused by haploinsufficiency of the GATA2 transcription factor, which is essential for hematopoietic stem cell maintenance and the development of multiple immune and myeloid lineages. ¹ Since its initial description in 2011, the disorder has been associated with persistent monocytopenia, B- and Natural killer (NK)-cell lymphopenia, recurrent viral infections, bone marrow failure, myelodysplastic syndrome (MDS), and progression to acute myeloid leukemia (AML). ² Nonfunctional or insufficient GATA2 protein results in a broad spectrum of clinical manifestations, including immunodeficiency, hematological malignancies, pulmonary alveolar proteinosis, peripheral lymphedema, deafness, and various developmental malformations. Phenotypic expression can vary widely, even within families, often delaying diagnosis until hematological involvement becomes apparent. ³

Early recognition of characteristic features is therefore crucial to facilitate timely genetic testing, family screening, and consideration of hematopoietic stem cell transplantation (HSCT), the only curative therapy currently available. ⁴ In this context, we report a pediatric case of GATA2 deficiency with a novel splice-site variant and a consistent familial phenotype.

Case Presentation

An 11-year-old girl was referred for evaluation of suspected immunodeficiency due to extensive, treatment-resistant facial and palmar warts beginning at age 8. She had a history of recurrent respiratory infections and underwent tonsillectomy–adenoidectomy at age 6. At 9 years, she developed fever and pancytopenia following varicella infection. She had persistent high-grade fever, elevated ferritin levels, and bone marrow findings showing hypocellularity with multilineage dysplasia and hemophagocytic histiocytes, consistent with infection-associated secondary hemophagocytic lymphohistiocytosis. Ebstein Barr virus and cytomegalovirus (CMV) polymerase chain reaction tests were negative at that time. She was treated with corticosteroids, resulting in clinical and laboratory improvement, and the episode resolved without recurrence. She had not received varicella vaccination, as it was not part of the national immunization schedule in our country at that time.

Her father had a 10-year history of persistent leukopenia and recurrent viral warts, had been followed for MDS for approximately a decade, and developed AML during the last year of his life, ultimately dying at the age of 34 years during chemotherapy.

Upon presentation, the proband demonstrated normal growth, multiple cutaneous warts, and right-sided ptosis, without organomegaly or lymphadenopathy. Laboratory evaluation revealed leukopenia (lymphocytes 580/mm³, monocytes 10/mm³, neutrophils 520/mm³) and thrombocytopenia (25 × 10⁹/L). Immunoglobulin levels were normal. Flow cytometry showed an inverted CD4/CD8 ratio and markedly decreased B and NK cells. Imaging demonstrated fibrous dysplasia of the right maxillary sinus with orbital extension and early tracheal bifurcation.

Given persistent monocytopenia, profound lymphopenia, bone marrow dysplasia, and a strong family history of myeloid malignancy, and the presence of treatment-resistant extensive cutaneous warts, GATA2 deficiency was suspected. Genetic sequencing using the MiSeq Illumina platform identified a previously undescribed heterozygous splice-site variant, c.1017 + 1 G > A, in intron 4 of GATA2. This variant was absent from GnomAD, ESP, and 1,000 Genomes databases and was confirmed in stored DNA from her deceased father.

She received HPV vaccination, azithromycin prophylaxis, and intravenous immunoglobulin replacement. Due to underlying GATA2 deficiency and associated bone marrow abnormalities, the patient underwent allogeneic HSCT from a matched unrelated donor. The conditioning regimen consisted of fludarabine, treosulfan, and anti-thymocyte globulin, while graft-versus-host disease (GVHD) prophylaxis included cyclosporine and mycophenolate mofetil. In the post-transplant period, she developed severe steroid-refractory gastrointestinal GVHD complicated by thrombotic microangiopathy, CMV reactivation, and multiorgan failure, ultimately leading to death approximately 6 months after transplantation.

Discussion

GATA2 deficiency is a heterogeneous inherited disorder characterized by a wide range of clinical manifestations, including immunodeficiency, susceptibility to viral and non-tuberculous mycobacterial infections, progressive cytopenias, and an increased risk for MDS and AML. The immunological profile typically includes monocytopenia, reduced B, NK, and dendritic cells, and an inverted CD4/CD8 ratio. ⁵ The clinical and laboratory findings observed in our patient align closely with this well-recognized spectrum.

The proband’s presentation with refractory HPV-related warts, profound monocytopenia, B- and NK-cell lymphopenia, and bone marrow dysplasia is consistent with previously described features of GATA2 deficiency. The parallel clinical history in her father, who progressed from MDS to AML, reinforces the hereditary nature of the condition. Identification of a previously unreported heterozygous splice-site variant in GATA2 affecting both individuals further expands the mutational spectrum of the disorder. This variant is located in a known hotspot region where other splice-site mutations have been reported. The identification of the same variant in the affected father supports its clinical relevance and suggests familial segregation. Consistent with this, the variant is classified as likely pathogenic and is predicted to affect normal splicing. Splice-site variants are uncommon but may significantly alter protein function and are known to contribute to early or aggressive hematological presentation. ³

Immunoglobulin levels in GATA2 deficiency are often normal, though hypogammaglobulinemia may occur. Importantly, even patients with normal immunoglobulin levels may experience recurrent sinopulmonary infections, and some individuals benefit from immunoglobulin replacement therapy. Although standardized guidelines for infection prophylaxis have not been established, early HPV vaccination and azithromycin prophylaxis have been suggested to reduce infectious complications. Given that HPV-associated warts are frequently among the earliest manifestations and that HPV-related dysplasia has been reported in approximately one-third of affected individuals, regular dermatologic and gynecological evaluations are recommended for early detection of dysplastic or malignant lesions. ⁶

Radiological findings in our patient included fibrous dysplasia of the maxillary sinus and early tracheal bifurcation; ptosis was noted on physical examination. Although developmental anomalies have been reported in association with GATA2 deficiency, a direct causal relationship between these findings and GATA2 haploinsufficiency cannot be definitively established. ⁷ These features are therefore best considered additional clinical observations of uncertain significance rather than confirmed manifestations of the disease.

This case emphasizes the importance of early clinical recognition and genetic testing in children with unexplained cytopenias, persistent viral warts, or a family history of hematological malignancy. Previous studies have shown that GATA2 mutations may be present in pediatric MDS regardless of karyotype and are particularly enriched in cases involving monosomy 7 or trisomy 8. Early identification allows for closer surveillance, detection of cytogenetic evolution, and timely referral for HSCT—the only curative treatment currently available. ⁸ Additionally, screening of relatives is essential to prevent the inadvertent selection of affected family members as stem-cell donors.

Although functional assays to define the precise splicing effect were not performed and extended family testing was not feasible, the identification of a previously unreported GATA2 splice-site variant with confirmed familial segregation and a consistent clinical phenotype provides clinically meaningful molecular evidence. The comprehensive immunological, hematological, and clinical characterization further contributes to understanding genotype–phenotype relationships in GATA2 deficiency and may facilitate earlier recognition and management of similar cases. Collectively, these findings support the pathogenicity of this variant and underscore the clinical importance of integrating genetic and phenotypic data in GATA2 deficiency.

Authors’ Contributions

S.A. contributed to patient clinical evaluation, data collection, and drafting of the article. G.Y. performed genetic analysis, variant interpretation, and contributed to article revision. A.D.A. contributed to genetic testing, data interpretation, and critical revision of the article. S.O. contributed to hematological evaluation, bone marrow interpretation, and clinical data verification. F.C. was responsible for the hematopoietic stem cell transplantation process, including patient management and clinical follow-up, and contributed to data interpretation. S.G. was responsible for the hematopoietic stem cell transplantation process, including patient management and clinical follow-up, and contributed to data interpretation. O.K. contributed to clinical assessment and provided expert input on immunological findings. E.Y. assisted in clinical data collection and contributed to article drafting. A.K. supervised the clinical workup, contributed to study conception and article writing, and approved the final version.

Ethical Statement

Ethical approval was not required for this case report in accordance with institutional policies. Written informed consent for publication was obtained from the patient’s legal guardians.