GATA2 Deficiency Masquerading as WHIM Syndrome Led to Monosomy 7 MDS in a Teenager

An 18-year-old woman whose years of unexplained low blood counts were initially mistaken for a rare immunodeficiency called WHIM syndrome has been diagnosed with GATA2 deficiency, a hereditary bone marrow failure disorder, and has since developed myelodysplastic syndrome (MDS) associated with monosomy 7, one of the most ominous chromosomal losses in pediatric blood malignancy. The case, reported in Clinical Case Reports, traces a five-year diagnostic journey that began with growth retardation and profound cytopenias at age 13 and ended with a genetic finding that reshaped her entire clinical outlook.

The patient was born prematurely at 34 weeks of gestation to consanguineous parents, weighing 1900 grams. Her early medical history already pointed toward a multisystem disorder: cochlear implantation at age 3 for sensorineural hearing loss and surgical repair of an atrial septal defect, a congenital hole in the wall separating the heart’s upper chambers, at age 4. When she reached the endocrinology clinic at age 13 with growth retardation, weighing 33.7 kilograms and standing 135.5 centimeters tall, laboratory testing revealed the full hematologic picture: anemia with a hemoglobin of 9.1 g/dL, thrombocytopenia with platelets at 130 × 10⁹/L, and leukopenia with a white blood cell count of just 1 × 10⁹/L.

What made those numbers clinically alarming was the pattern beneath them. Her peripheral blood smear showed marked monocytopenia, with monocytes essentially absent at 0%, alongside left-shifted granulopoiesis and toxic granulation. Follow-up testing confirmed persistent pancytopenia, with hemoglobin falling to 8.3 g/dL, white blood cells at 0.78 × 10⁹/L, and platelets at 128 × 10⁹/L. A reticulocyte count of 3.24% was inappropriately low for the degree of anemia, and iron studies showing serum iron below 10 μg/dL with a transferrin saturation of 3% pointed to impaired marrow production rather than iron deficiency alone. A FANCA assay came back weakly positive, raising the possibility of Fanconi anemia, though bone marrow examination revealed a hypocellular marrow with erythroid hyperplasia and a myeloid-to-erythroid ratio of approximately 1:2, without morphologic evidence of MDS, increased blasts, or hematologic malignancy at that time. Cytogenetic analysis was not performed during that initial evaluation.

Beyond the blood counts, the physical examination and history built a distinctive syndromic profile. She had severe progressive vision impairment over the preceding month, with a refractive error ranging from −7 to −9 diopters, numerous warts on her lower extremities, and multiple oral aphthous ulcers that had partially resolved by the time of evaluation. Her abdomen was soft and nontender, but she had mild hepatomegaly with the liver palpable 2 centimeters below the costal margin and splenomegaly with the spleen extending 6 centimeters below the costal margin, confirmed by abdominal ultrasonography showing dimensions of 52 × 135 millimeters with normal echogenicity. Flow cytometry of peripheral blood lymphocyte subsets revealed profound depletion of CD19+ B cells to below 1%, with relative T-cell predominance, a finding that provided significant context for the eventual identification of the GATA2 mutation.

Given the combination of hearing loss, vision impairment, multiple lower-extremity warts, anemia, pancytopenia, splenomegaly, bronchopneumonia, an abdominal lipoma, immunodeficiency, and the history of atrial septal defect, clinicians initially suspected WHIM syndrome, a rare autosomal dominant immunodeficiency named for its cardinal features: warts, hypogammaglobulinemia, infections, and myelokathexis. During that period she was managed with monthly intravenous immunoglobulin at a dose of 10 grams and prophylactic antimicrobial therapy including acyclovir and co-trimoxazole. The diagnostic uncertainty persisted until whole-exome sequencing performed at age 16, using DNA extracted from peripheral blood, identified a heterozygous likely pathogenic frameshift variant in GATA2: Chr3:128200674 G>GT, NM_032638, ENST00000341105.2, Exon 5, c.1130dup, p.Tyr377*. The laboratory classified the variant as likely pathogenic under American College of Medical Genetics and Genomics criteria, noting that it introduces a premature termination codon and is predicted to result in loss of GATA2 function. Crucially, no pathogenic or likely pathogenic variants were found in CXCR4 or CXCR2, the genes most commonly implicated in WHIM syndrome, making that molecular diagnosis far less likely.

GATA2 encodes a zinc finger-containing transcription factor that serves as a pivotal regulator of hematopoiesis, with essential functions in hematopoietic stem cell homeostasis and lymphocyte lineage development. Individuals harboring GATA2 mutations exhibit a broad spectrum of clinical abnormalities, including cytopenias affecting B-cell, natural killer cell, lymphocyte, and monocyte subsets, heightened susceptibility to infections due to immunodeficiency, pulmonary alveolar proteinosis, and pulmonary hypertension. The disorder may present with severe bone marrow failure, diverse immunodeficiency phenotypes, or syndromic congenital anomalies, and because of incomplete or partial penetrance it can remain entirely asymptomatic in a small proportion of mutation carriers. The revised 2016 World Health Organization classification of hematopoietic tumors formally recognized the spectrum as a distinct category of myeloid neoplasms with germline GATA2 mutations, encompassing MonoMac syndrome, characterized by monocytopenia and susceptibility to mycobacterial infections; Emberger syndrome, marked by myelodysplasia and lymphedema; and DCML deficiency, affecting dendritic cells, monocytes, B-lymphocytes, and NK-lymphocytes. Patients with GATA2 deficiency face a high predisposition to familial and primary pediatric forms of MDS and acute myeloid leukemia, with a median age at onset of 17 years.

At the molecular level, GATA2 is critically involved in early embryonic hematopoietic specification through the endothelial-to-hematopoietic transition, and postnatally it is highly expressed in hematopoietic stem cells and early progenitors, promoting myeloid-erythroid differentiation. Maintaining stem cell survival, self-renewal, and differentiation in adult hematopoiesis requires GATA2 to interact with a variety of transcriptional regulators, so interruption of these processes in GATA2 deficiency significantly increases the risk of hematopoietic dysfunction and confers a strong predisposition to MDS and AML. The variant identified in this patient, c.1130dup, is a frameshift mutation introducing a premature termination codon, predicted to result in nonsense-mediated mRNA decay and consequent loss of function, placing it in the category of null variants that induce GATA2 haploinsufficiency through complete or near-complete loss of protein function.

The clonal evolution that clinicians feared materialized at age 18. Cytogenetic evaluation using GTG-banding at 400–450 band resolution across twenty metaphase spreads demonstrated monosomy 7 in all examined abnormal metaphases: two metaphases showed isolated monosomy 7, while the remaining 18 harbored monosomy 7 together with an additional marker chromosome. Fluorescence in situ hybridization using an MDS probe panel revealed a 7q22 (RELN) deletion in 87 of 125 interphase nuclei, or 71%, with no abnormalities detected by the remaining probes targeting SEMA5A, EGR1, D7Z1, D8Z1, and PTPRT. Bone marrow flow cytometric analysis showed a distribution of approximately 40% mature lymphoid cells, 40% mature myeloid cells, and 20% monocytes, with CD19+ B cells remaining below 1%, consistent with the earlier peripheral blood immunophenotyping. Morphologic evaluation showed pancytopenia with dysplastic changes involving both erythroid and myeloid lineages, confirming the diagnosis of MDS.

Monosomy 7 is the most frequently encountered clonal cytogenetic abnormality in GATA2-deficient individuals who develop myeloid neoplasms, reported in close to half of all such cases. When present alongside a 7q17 deletion or the unbalanced translocation der(1;7)(q10;p10), monosomy 7 consistently produces monoallelic loss of 7q, a genetic feature that confers a poor prognosis. Focusing specifically on pediatric MDS with monosomy 7, germline GATA2 mutations are identifiable in 37% of affected children, and that percentage rises dramatically in the adolescent subgroup, in whom GATA2 deficiency underlies 72% of monosomy 7 cases. This epidemiologic context makes the molecular diagnosis in this patient not merely descriptive but prognostically decisive, since it identifies the underlying germline driver of the clonal abnormality rather than treating the chromosomal loss as an isolated event.

Following the MDS diagnosis, azacitidine therapy was initiated at a dose of 100 milligrams daily for five consecutive days in monthly cycles as disease-directed therapy while the patient awaits allogeneic hematopoietic stem cell transplantation, which to date constitutes the sole curative intervention available for GATA2 deficiency. For individuals deemed high-risk, there is broad agreement that the most favorable window for preemptive transplantation falls within the hypocellular phase of MDS, before the emergence of serious sequelae such as opportunistic infections or transformation to MDS with excess blasts or AML. The patient remained under ongoing azacitidine treatment, and formal assessment of hematologic response was pending completion of further treatment at the time of reporting. The case authors note that the prolonged interval between initial presentation and eventual diagnosis, driven in part by family circumstances and financial limitations that interrupted follow-up, illustrates the dynamic nature of GATA2 deficiency and underscores the importance of repeated hematologic, cytogenetic, and molecular evaluation in patients with unexplained cytopenias, even when initial marrow findings are nondiagnostic. A limitation acknowledged in the report is that variant allele frequencies were not provided and no non-hematopoietic tissue was available for independent confirmation of germline status, so although the clinical phenotype strongly supports GATA2 deficiency, the germline origin of the identified variant could not be independently confirmed, and the available data do not permit definitive assignment of the additional variants detected by whole-exome sequencing as germline or somatic.

Subject of Research: A case report of GATA2 deficiency presenting with a WHIM-like phenotype and subsequent monosomy 7-associated myelodysplastic syndrome in an adolescent female

Article Title: GATA2 Deficiency Presenting With a WHIM‐Like Phenotype and Subsequent Development of Monosomy 7‐Associated Myelodysplastic Syndrome in an Adolescent Female: A Case Report

Article References: Eghbali, A., Poortavakol, M., & Mirmohammadi, H. S. (2026). GATA2 Deficiency Presenting With a WHIM ‐Like Phenotype and Subsequent Development of Monosomy 7‐Associated Myelodysplastic Syndrome in an Adolescent Female: A Case Report. Clinical Case Reports, 14(11), Article e73869. https://doi.org/10.1002/ccr3.73869

Image Credits: AI Generated

DOI: 10.1002/ccr3.73869

Keywords: GATA2 deficiency, WHIM syndrome, myelodysplastic syndrome, monosomy 7, bone marrow failure, whole-exome sequencing, cytopenia, monocytopenia, azacitidine, hematopoietic stem cell transplantation, immunodeficiency, case report