Extreme hyperleukocytosis and blueberry muffin skin lesions as the initial presentation of neonatal leukemia: a case report

Abstract

Background

Neonatal leukemia is a rare and aggressive hematologic malignancy, accounting for less than 1% of pediatric leukemias. Mixed phenotype acute leukemia (MPAL) is particularly uncommon in this age group and poses significant diagnostic and therapeutic challenges. Hyperleukocytosis and leukostasis are life-threatening complications requiring urgent intervention.

Case presentation

We report the case of a 7-day-old male neonate, small for gestational age, who presented with extreme hyperleukocytosis (peak leukocyte count: 615,400/µL), severe anemia, thrombocytopenia, and generalized purpuric skin lesions consistent with blueberry muffin syndrome. The clinical course was complicated by coagulopathy and a high risk of tumor lysis syndrome. Cytoreductive management included manual partial exchange transfusion due to the unavailability of leukapheresis, achieving transient leukoreduction. Flow cytometry identified two abnormal populations: B-lineage blasts expressing CD19, CD79a, and cytoplasmic CD22, and a myeloid/monocytic population expressing myeloperoxidase (MPO), CD13, and CD33. Lineage assignment was established according to World Health Organization (WHO, 5th edition) and International Consensus Classification (ICC) lineage-defining criteria, confirming MPAL, B/myeloid subtype. Cytogenetic analysis revealed a karyotype 46,XY, add(19)(p13), while molecular testing for KMT2A rearrangements and other recurrent fusion genes was negative. Induction chemotherapy was initiated after initial stabilization; however, the patient died 45 days after diagnosis due to disease progression.

Conclusion

This case highlights the diagnostic complexity and aggressive clinical course of neonatal MPAL, particularly in the absence of KMT2A rearrangements, and emphasizes the biological heterogeneity of this entity. Strict application of WHO/ICC lineage-defining criteria is essential to ensure accurate classification. Exchange transfusion may serve as a feasible bridging cytoreductive strategy in neonates with life-threatening hyperleukocytosis when leukapheresis is not available, although its effects are temporary and do not replace definitive therapy. Early recognition, prompt supportive management, and improved molecular characterization are critical to optimizing outcomes in this rare and high-risk population.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12887-026-06995-0.

Introduction

Congenital leukemia is an extremely rare hematologic malignancy defined by its presence at birth, whereas neonatal leukemia refers to cases diagnosed within the first 28 days of life [1]. Together, these entities account for less than 1% of all pediatric leukemias, with an estimated incidence of 1 to 5 cases per million live births. Despite its low frequency, neonatal leukemia is clinically significant due to its aggressive course, high morbidity and mortality, and the considerable diagnostic and therapeutic challenges it poses during the neonatal period [2].

Neonatal leukemia has been associated with several chromosomal abnormalities, including trisomy 21, trisomy 9, trisomy 13, and Turner syndrome [1]. However, a substantial proportion of cases occur in the absence of identifiable cytogenetic alterations, reflecting the biological heterogeneity of the disease. At the molecular level, rearrangements involving the KMT2A gene represent the most frequently reported abnormalities in neonatal leukemia and are associated with an aggressive clinical phenotype and poor prognosis [3–5]. Nevertheless, some patients lack these recurrent alterations, suggesting the presence of alternative pathogenic mechanisms that remain incompletely understood.

Clinically, neonatal leukemia presents with variable and often nonspecific manifestations, including hepatosplenomegaly, respiratory distress, anemia, thrombocytopenia, and leukocytosis with circulating blasts [2]. These features may mimic severe neonatal infections such as sepsis, frequently leading to diagnostic delays. In cases not associated with Down syndrome, more severe systemic manifestations including pleural effusion, ascites, hepatic or renal failure, and metabolic acidosis have been described. In contrast, patients with Down syndrome may exhibit a broader clinical spectrum, ranging from asymptomatic presentations to multiorgan involvement, requiring careful hematologic follow-up [3].

Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by the co-expression of lineage-defining markers from more than one hematopoietic lineage. According to the World Health Organization (WHO, 5th edition) and the International Consensus Classification (ICC), MPAL accounts for approximately 2–3% of acute leukemias and represents a diagnostic and therapeutic challenge due to its biological complexity and lack of standardized treatment strategies [8, 9]. Its occurrence in the neonatal period is particularly uncommon, with limited data available in the literature.

One of the most severe complications of neonatal leukemia is hyperleukocytosis, defined as a leukocyte count exceeding 100,000/mm³, which constitutes an oncohematologic emergency [4]. This condition is associated with leukostasis due to microvascular obstruction by leukemic blasts, leading to tissue hypoxia and multiorgan dysfunction, particularly affecting the central nervous system and lungs [5]. Additionally, up to 50% of neonates may present with cutaneous involvement in the form of blueberry muffin lesions, characterized by diffuse bluish nodules, predominantly on the face and trunk [6]. Although nonspecific, this finding should prompt immediate hematologic evaluation.

Tumor lysis syndrome (TLS) is another potentially life-threatening complication that may occur spontaneously in neonatal leukemia, even prior to initiation of therapy, leading to severe metabolic disturbances and acute kidney injury [7]. Furthermore, coagulopathy, including disseminated intravascular coagulation, may contribute to early clinical deterioration.

Given its rapid progression, high risk of complications, and limited available evidence, neonatal leukemia requires early recognition and prompt multidisciplinary management. In this context, case reports remain essential to improve understanding of its clinical behavior. We present a case of neonatal mixed phenotype acute leukemia (MPAL), B/myeloid subtype, with an aggressive clinical course characterized by extreme hyperleukocytosis, blueberry muffin skin involvement, coagulopathy, and high risk of tumor lysis syndrome, in the absence of KMT2A rearrangement.

Case presentation

A 7-day-old male neonate, born at term (38 weeks of gestation), small for gestational age, and delivered vaginally, was referred to a tertiary care center due to extreme hyperleukocytosis associated with severe anemia, thrombocytopenia, and purpuric skin lesions, raising a high clinical suspicion of neonatal leukemia.

The patient was the first child of a 16-year-old primigravida mother with adequate prenatal care (six visits) and a history of urinary tract infection during the third trimester. The 18-year-old father had no relevant medical history. There was no family history of hematologic or oncologic diseases. At birth, the neonate weighed 2,460 g, measured 46 cm in length, and had a head circumference of 33 cm. Apgar scores were 6 at 1 min, 5 at 5 min, and 9 at 10 min.

From the immediate neonatal period, the patient exhibited generalized purpuric skin lesions consistent with blueberry muffin syndrome, marked pallor, and severe hematologic abnormalities (Fig. 1). During the first days of life, he developed mild respiratory distress requiring supplemental oxygen therapy. Initial laboratory evaluation revealed leukocytosis of 200,000/µL, hemoglobin of 6 g/dL, and a platelet count of 20,000/µL, prompting initiation of transfusional support and empirical antibiotic therapy (Table 1).

Fig. 1.

Diffuse purpuric cutaneous lesions consistent with blueberry muffin syndrome observed in the neonatal period. A-B Generalized purpuric lesion involving the face, trunk, and extremities, consistent with blueberry muffin lesions. C-E Close-up view of cutaneous lesions on the back, lower limb, and foot, showing multiple purplish macules and papules of variable size

Table 1.

Temporal evolution of key hematologic, coagulation, and metabolic parameters during hospitalization

Parameter	Day 1	Day 3	Day 5	Day 7	Day 9	Reference Range (Neonate)
White blood cells (×10³/µL)	> 200	↑	615.4	↓	↓	9–30
Circulating blasts (%)	~ 90	~ 90	~ 90	↓	↓	0
Hemoglobin (g/dL)	6.0	6.4	6.8	↑	↑	13–20
Platelets (×10³/µL)	20	12	↑	↑	↑	150–400
Lactate dehydrogenase (U/L)	763	↑	921	↓	↓	< 450
Uric acid (mg/dL)	↑	↓	↓	Normal	Normal	2.5–6.0
Calcium (mg/dL)	6.0	↓	↓	↑	↑	8.5–10.5
Prothrombin time (s)	20.0	↑	23.8	↓	↓	10–14
aPTT (s)	44.7	↑	49.0	↓	↓	25–40
Fibrinogen (mg/dL)	160	↓	53.8	↑	↑	150–400
Serum lactate (mmol/L)	4.2	↓	–	–	–	< 2.0

Upon admission to the referral center, the patient was hemodynamically stable and required oxygen via nasal cannula (FiO₂ 24–30%). Vital signs included a heart rate of 110–130 beats per minute, respiratory rate of 27–52 breaths per minute, oxygen saturation of 95–99%, and body temperature between 36.7 and 37.0 °C.

Physical examination revealed generalized pallor, disseminated purpuric lesions, capillary refill time < 2 s, and marked hepatosplenomegaly, with the spleen palpable to the left iliac fossa. Sacral hypertrichosis was noted, along with a right parietal cephalohematoma. Neurological examination showed an awake neonate with reduced reactivity to stimuli, preserved tone, and intact neonatal reflexes.

Laboratory investigations demonstrated extreme hyperleukocytosis, with a peak leukocyte count of 615,400/µL, severe anemia (hemoglobin 6.4–6.8 g/dL), and marked thrombocytopenia (12,000–63,000/µL). Peripheral blood smear revealed approximately 90% circulating blasts with high nuclear-to-cytoplasmic ratio, fine chromatin, and inconspicuous nucleoli.

Coagulation studies showed prolonged prothrombin time (20–21 s), prolonged activated partial thromboplastin time (44–49 s), elevated INR (~ 1.6), hypofibrinogenemia (nadir 129 mg/dL), and severe thrombocytopenia, consistent with a consumptive coagulopathy compatible with evolving disseminated intravascular coagulation (DIC).

Biochemical analysis revealed markedly elevated lactate dehydrogenase levels (763–783 U/L), significant hyperuricemia (up to 153 mg/L), hypocalcemia (6.0 mg/dL), electrolyte imbalances, and elevated lactate (4.2 mmol/L), indicating a high risk of tumor lysis syndrome (TLS).

Preventive management for TLS was initiated with intensive intravenous hyperhydration aimed at maintaining urine output > 3 mL/kg/h, along with allopurinol therapy from admission. Allopurinol was selected based on its availability, established safety profile, and broader experience in neonatal populations. Strict metabolic and renal monitoring was maintained, without requirement for renal replacement therapy.

Given the extreme hyperleukocytosis and risk of leukostasis, cytoreductive management was initiated. Due to the technical limitations of leukapheresis in neonates, a manual partial exchange transfusion (exanguinotransfusion) was performed as a leukoreductive strategy, achieving a transient reduction in leukocyte count and partial clinical stabilization.

Hematologic evaluation included multiparametric flow cytometry performed on peripheral blood, which identified two abnormal blast populations. The first corresponded to B-lineage blasts (58.76%) with a pro-B immunophenotype, expressing CD19, CD79a, and cytoplasmic CD22. The second corresponded to a myeloid/monocytic population (34.07%) with expression of myeloid markers, including myeloperoxidase (MPO), CD13, and CD33, and evidence of asynchronous maturation.

Importantly, lineage assignment was established based on lineage-defining markers in accordance with current WHO (5th edition) and International Consensus Classification (ICC) criteria. The expression of MPO confirmed myeloid lineage, while the presence of specific B-lineage markers supported lymphoid differentiation. Additional markers such as NG2 and CD15/CD65 were considered supportive but not determinant for lineage classification. These findings established the diagnosis of mixed phenotype acute leukemia (MPAL), B/myeloid subtype.

Cytogenetic analysis revealed a karyotype 46,XY, add(19)(p13) in all analyzed metaphases, indicating additional chromosomal material of unknown origin on chromosome 19p. Molecular studies were performed to exclude recurrent gene fusions associated with acute leukemia. Specifically, testing for KMT2A rearrangements (including KMT2A::AFF1) using FISH and/or RT-PCR was negative. Additional fusion transcripts, including ETV6::RUNX1, TCF3::PBX1, BCR::ABL1, and CBFB::MYH11, were also not detected.

Whole exome sequencing was not performed during the initial evaluation. Genetic assessment was limited to conventional cytogenetics and targeted molecular testing, which constitute the standard first-line diagnostic approach in this clinical context.

A multidisciplinary evaluation was conducted. Nephrology confirmed high risk for TLS and recommended continued hyperhydration and close monitoring. Genetic evaluation noted dysmorphic features, including sacral hypertrichosis, raising suspicion of a possible underlying genetic condition. Cardiology assessment revealed a structurally normal heart with preserved systolic and diastolic function.

After initial clinical stabilization, induction chemotherapy was initiated according to institutional protocol, including daunorubicin (30 mg/m²), vincristine (1.5 mg/m²), and cytarabine (75 mg/m²/day).

During the induction phase, the patient remained hemodynamically stable, without evidence of active bleeding or acute organ failure, under continuous clinical, hematologic, and metabolic monitoring.

The patient died 45 days after diagnosis due to disease progression despite initial stabilization.

Discussion

Neonatal leukemia is an extremely rare malignancy, with an estimated incidence of 1–5 cases per million live births, and is associated with high morbidity and mortality [8]. Mixed phenotype acute leukemia (MPAL) is an uncommon subtype characterized by the co-expression of lineage-defining markers from more than one hematopoietic lineage, reflecting its biological complexity [1, 2, 9].

Strict adherence to WHO and ICC criteria is essential to avoid overdiagnosis. In the present case, the diagnosis of MPAL B/myeloid subtype was established according to WHO-HEM5 and ICC criteria. B-lineage assignment was based on the expression of CD19 in combination with cytoplasmic CD79a, fulfilling lineage-defining criteria. The myeloid/monocytic component was supported by the presence of a clearly identifiable aberrant monocytic population expressing CD14 with maturation asynchrony. Importantly, markers such as NG2, CD15, and CD65 were not used as lineage-defining criteria but rather interpreted as supportive findings within the immunophenotypic context. Accurate lineage assignment is critical given its implications for prognosis and therapeutic decision-making [1, 2, 9].

Hyperleukocytosis, defined as a leukocyte count exceeding 100,000/µL, represents a hematologic emergency due to the risk of leukostasis, microvascular obstruction, and end-organ damage [10, 11]. The extreme leukocyte count observed in this case (> 600,000/µL) is highly unusual and reflects a substantial tumor burden. Such levels are associated with an increased risk of respiratory failure, neurological complications, renal impairment, and early mortality [11, 15].

Cutaneous involvement in the form of blueberry muffin lesions is a recognized manifestation of neonatal leukemia and may result from leukemic infiltration or extramedullary hematopoiesis [12]. Although nonspecific, its presence in association with cytopenias and circulating blasts should prompt early evaluation for hematologic malignancy.

From a molecular perspective, rearrangements involving KMT2A represent the most frequent genetic abnormalities in neonatal leukemia and are associated with an aggressive clinical course [3–5]. In this case, a targeted molecular panel did not identify KMT2A rearrangements or other recurrent gene fusions. Instead, cytogenetic analysis revealed a rare structural abnormality, add(19)(p13), which has not been widely reported in this context. This finding highlights the genomic heterogeneity of neonatal leukemia and suggests the presence of additional molecular alterations not detected by conventional assays [16]. However, cryptic KMT2A rearrangements cannot be completely excluded.

Tumor lysis syndrome (TLS) is a potentially life-threatening complication in patients with high tumor burden and may occur spontaneously in neonatal leukemia [6]. Its management includes aggressive hydration and uric acid-lowering therapy. Allopurinol was selected in this case due to its established safety profile and broader clinical experience in neonatal populations, whereas rasburicase use remains limited by safety concerns and insufficient evidence in this age group [6, 7].

Coagulopathy, including disseminated intravascular coagulation (DIC), is another severe complication associated with neonatal leukemia. The laboratory findings in this patient were consistent with a consumptive coagulopathy, likely driven by systemic activation of coagulation pathways and leukemic cell activity, contributing to an increased risk of bleeding and clinical deterioration [13].

Transient abnormal myelopoiesis (TAM) is an important differential diagnosis in neonates presenting with leukocytosis and circulating blasts, particularly in the context of Down syndrome. TAM is typically associated with trisomy 21 and megakaryoblastic proliferation, and may resolve spontaneously. In this case, the absence of trisomy 21, lack of megakaryoblastic immunophenotype, and aggressive clinical course argued against this diagnosis [14].

In cases of extreme hyperleukocytosis, leukoreductive strategies such as exchange transfusion may be considered, particularly when leukapheresis is not feasible in neonates. Exchange transfusion may reduce leukocyte burden and improve microcirculatory flow; however, it carries significant risks, including hemodynamic instability, electrolyte disturbances, and procedural complications. In this patient, manual partial exchange transfusion was performed as a leukoreductive strategy. This achieved a transient reduction in leukocyte count but did not replace definitive therapy [11, 15].

Whole exome sequencing was not performed, representing a limitation of this report. Advanced genomic techniques could provide additional insights into the molecular basis of cases lacking recurrent cytogenetic abnormalities [16, 17].

This case highlights the importance of early recognition of neonatal leukemia, particularly in the presence of extreme hyperleukocytosis and cutaneous manifestations. Prompt diagnosis and appropriate supportive management are essential to reduce life-threatening complications, although outcomes remain poor in severe presentations [8, 18–21].

Conclusions

Neonatal leukemia remains a rare but highly aggressive hematologic malignancy associated with significant diagnostic and therapeutic challenges during the neonatal period. This case illustrates an exceptionally severe presentation characterized by extreme hyperleukocytosis, blueberry muffin skin involvement, coagulopathy, and a high risk of spontaneous tumor lysis syndrome, reflecting an elevated tumor burden and aggressive disease biology. The presence of mixed phenotype acute leukemia with an uncommon cytogenetic abnormality further highlights the biological heterogeneity of neonatal leukemia. Early recognition of key warning signs, prompt initiation of supportive measures, and a coordinated multidisciplinary approach are essential to anticipate life-threatening complications and to optimize early management. Detailed case reports such as this one contribute valuable clinical insights that may aid clinicians in improving diagnostic suspicion and therapeutic decision-making in this highly vulnerable population.

Abbreviations

ALL

Acute lymphoblastic leukemia

AML

Acute myeloid leukemia

MPAL

Mixed phenotype acute leukemia

LDH

Lactate dehydrogenase

TLS

Tumor lysis syndrome

Authors’ contributions

MABO, MAMT, and JRAV collected the data, interpreted the clinical findings, and drafted the manuscript. ASO was involved in the clinical management of the patient and critically revised the manuscript, providing expert input in neonatal surgery. CZC, VRL contributed to conceptualization, methodology, supervision, formal analysis, literature review, manuscript writing, critical revision, and final approval of the manuscript. All authors read and approved the final manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

All data generated or analyzed during this study are included in this published article. Additional details are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with the ethical standards of the institutional and national research committees and with the Declaration of Helsinki. Written informed consent to participate was obtained from the patient’s legal guardians.

Consent for publication

Written informed consent was obtained from the patient’s legal guardians for the publication of clinical details and any accompanying images.

Competing interests

The authors declare no competing interests.