What are the causes of pancytopenia in children?

Causes of Pancytopenia in Children

Pancytopenia in children is most commonly caused by bone marrow disorders—including inherited bone marrow failure syndromes, aplastic anemia, megaloblastic anemia, and hematological malignancies—followed by infections and peripheral destruction mechanisms, with the specific etiology varying significantly by age and geographic region. 1, 2, 3

Primary Etiological Categories

Inherited Bone Marrow Failure Syndromes (Critical in Pediatrics)

Inherited bone marrow failure syndromes are clinically important causes of pancytopenia specifically in children and must be systematically excluded before labeling a case as acquired aplastic anemia. 4, 5, 6

The major inherited syndromes include:

• Fanconi anemia presents with short stature, skeletal anomalies (absent thumbs, radial hypoplasia), café-au-lait spots, renal malformations, and progressive bone marrow failure typically manifesting between ages 5-10 years, with high risk for AML/MDS evolution 7
• Dyskeratosis congenita manifests with the classic triad of nail dystrophy, lacy reticular skin pigmentation, and oral leukoplakia, plus bone marrow failure, pulmonary fibrosis, and predisposition to AML/MDS 7
• Diamond-Blackfan anemia presents in infancy with macrocytic anemia, short stature, craniofacial abnormalities (cleft palate, hypertelorism), thumb anomalies, and congenital heart defects, with later risk of MDS/AML 7
• Shwachman-Diamond syndrome is characterized by exocrine pancreatic insufficiency with steatorrhea and failure to thrive, skeletal abnormalities, short stature, neutropenia progressing to pancytopenia, and 10-20% risk of MDS/AML 7
• Severe congenital neutropenia presents in infancy with absolute neutrophil counts <0.5 × 10⁹/L, recurrent life-threatening infections, and 11% cumulative risk of MDS/AML at median age 16.2 years 7
• SAMD9/SAMD9L-associated syndromes account for 8-18% of childhood MDS cases, presenting with cytopenias, immunodeficiency, growth restriction, adrenal hypoplasia, and developmental delay 7, 1

Inherited disorders should be suspected when thrombocytopenia has been present since early life, a positive family history exists, or characteristic physical features are present. 7

Acquired Bone Marrow Disorders

• Aplastic anemia accounts for approximately 20% of pediatric pancytopenia cases and presents with bone marrow hypocellularity affecting all three cell lines 3, 5
• Myelodysplastic syndromes are characterized by ineffective hematopoiesis, dysplastic changes in ≥10% of cells in one or more lineages, and account for 10.7% of pancytopenia cases 1
• Acute leukemias (ALL, AML) and myelodysplastic syndrome together account for 21% of pediatric pancytopenia presentations, with blasts on peripheral smear mandating immediate bone marrow examination 3, 1

Nutritional Deficiencies

Megaloblastic anemia is the single most common etiological factor in many pediatric series, accounting for 28.4% of cases, and responds rapidly to vitamin B12 or folate replacement. 3

• Vitamin B12 and folate deficiency cause macrocytic anemia with hypersegmented neutrophils on peripheral smear and should be tested before initiating treatment 1
• Severe iron deficiency can contribute to pancytopenia, particularly in regions with high prevalence of nutritional deficiencies 2

Infectious Causes

Infections account for 21% of pediatric pancytopenia cases, with enteric fever (typhoid) being the most common infectious etiology in endemic regions, occurring in 30% of infection-related cases. 3

Additional infectious causes include:

• Malaria causes pancytopenia through hemolysis, splenic sequestration, and bone marrow suppression 3
• Kala-azar (visceral leishmaniasis) presents with fever, hepatosplenomegaly, and pancytopenia 3
• HIV infection causes pancytopenia through direct marrow suppression, opportunistic infections, and medication effects 2, 1
• Hepatitis C can cause cytopenias and should be tested in all cases 1
• Brucellosis commonly presents with mild transaminitis and pancytopenia, with bone marrow culture having the highest diagnostic sensitivity 1
• Ehrlichiosis causes pancytopenia with leukopenia and thrombocytopenia, with children under 10 years having the highest case-fatality rate 1
• Hemophagocytic lymphohistiocytosis presents with pancytopenia, fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and markedly elevated ferritin (often >10,000 ng/mL) 1
• Cytomegalovirus can cause post-transfusion mononucleosis syndrome with high fever, pancytopenia, and atypical lymphocytosis 1
• Parvovirus B19 should be tested in cases showing hypoplastic bone marrow pattern 1

Autoimmune and Immunodeficiency Disorders

• Systemic lupus erythematosus causes immune-mediated cytopenias with positive ANA and anti-dsDNA antibodies 7
• Autoimmune lymphoproliferative syndrome (ALPS) presents with chronic lymphadenopathy, splenomegaly, multilineage cytopenias, and requires FAS gene mutation testing for confirmation 7, 1
• Common variable immunodeficiency is associated with recurrent infections, abnormal serum immunoglobulin levels, and cytopenias 1

Hematologic Malignancies with Infiltration

• Non-Hodgkin lymphoma requires excisional lymph node biopsy with immunophenotyping and cytogenetics; fine-needle aspiration alone is insufficient 1
• Brain tumors account for 13.2% of children presenting with intraparenchymal hemorrhage and pancytopenia, typically highly malignant histological types 7

Peripheral Destruction and Sequestration

• Hypersplenism with sequestration is a common cause of hematologic abnormalities, often more frequent than bone marrow involvement in conditions like sarcoidosis 1
• Immune thrombocytopenia can present with isolated thrombocytopenia but splenomegaly occurs in <3% of true ITP cases; its presence mandates evaluation for secondary causes 7

Drug-Induced and Toxic Causes

• Methotrexate can rarely cause pancytopenia even with low-dose weekly therapy, particularly in patients with impaired renal function or concomitant sulfonamide medications, typically 4-6 weeks after dose increases 1
• Chemotherapy agents cause pancytopenia through direct bone marrow suppression and mucosal barrier disruption 1
• Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-L1) cause immune-related hematological toxicity in <5% of patients but with significant mortality risk 7, 1

Coagulation and Hematologic Disorders

• Thrombocytopenia from various causes (isoimmune, chemotherapy-induced, thrombocytopenia-absent radius syndrome) occurred in 11.8% of one pediatric series 7
• Hemophilia and other coagulation deficiencies (factors VIII, XIII, protein C/S deficiency) can present with intracranial hemorrhage and cytopenias, with severity correlating with bleeding risk 7
• Sickle cell disease can cause intracranial hemorrhage with pancytopenia, particularly from hemorrhagic infarction 7

Diagnostic Algorithm

Initial Laboratory Evaluation

Every child with pancytopenia requires a complete blood count with differential, reticulocyte count, and peripheral blood smear reviewed by a hematopathologist to exclude pseudothrombocytopenia and identify blasts, dysplasia, or schistocytes. 1, 7

• Repeat the CBC in a heparin or citrate tube to exclude EDTA-dependent pseudothrombocytopenia, which occurs in approximately 0.1% of cases 1
• Reticulocyte count helps differentiate between production defects (low reticulocyte count) and peripheral destruction (elevated reticulocyte count) 1
• Lactate dehydrogenase, haptoglobin, indirect bilirubin, and direct antiglobulin test assess for hemolysis and ineffective hematopoiesis 1

Mandatory Screening Tests

• HIV and hepatitis C testing is recommended in all pediatric patients with pancytopenia, as these infections commonly cause secondary cytopenias 1
• Vitamin B12, folate, and iron studies should be obtained prior to bone marrow examination, as megaloblastic anemia is a common reversible cause 1, 3
• Antinuclear antibody and anti-dsDNA testing when systemic symptoms suggest autoimmune disease 7
• Serum immunoglobulins (IgG, IgA, IgM) to identify immunodeficiency syndromes 7

Indications for Bone Marrow Examination

Bone marrow aspiration and biopsy with cytogenetic analysis is mandatory in any child with pancytopenia who has:

• Age >60 years (though rare in pediatrics, this applies to adolescents approaching adulthood) 1
• Abnormalities beyond isolated thrombocytopenia on blood count or smear 7
• Systemic features such as bone pain, fever, night sweats, or weight loss 1
• Hepatosplenomegaly or unexplained lymphadenopathy 7
• Blasts identified on peripheral smear (requires same-day bone marrow evaluation) 1
• No improvement after 3-6 months of observation or minimal response to first-line therapies 7
• Unclear diagnosis after initial laboratory work-up 1

Bone marrow examination should include aspirate, biopsy, flow cytometry, and cytogenetic analysis (minimum 15 metaphases) to detect clonal abnormalities and chromosomal changes diagnostic of MDS. 1, 7

Specialized Testing for Inherited Syndromes

• Chromosome breakage testing (DEB or MMC test) is diagnostic for Fanconi anemia and should be performed in any child with unexplained pancytopenia, especially with physical anomalies 7, 5
• Telomere length measurement by flow-FISH is diagnostic for dyskeratosis congenita 7
• Paroxysmal nocturnal hemoglobinuria (PNH) screening by flow cytometry should be performed in suspected aplastic anemia 1
• HLA-DR15 testing identifies aplastic anemia patients most likely to respond to immunosuppressive therapy 1

Critical Pitfalls to Avoid

• Do not attribute pancytopenia with splenomegaly to immune thrombocytopenia, as splenomegaly occurs in <3% of true ITP and mandates evaluation for lymphoproliferative, myeloproliferative, or autoimmune disorders 7
• Do not delay peripheral smear review while awaiting additional tests; early detection of blasts prevents tumor lysis syndrome and leukostasis 1
• Do not assume reactive cytopenias in the presence of hepatosplenomegaly, lymphadenopathy, or persistent symptoms without complete evaluation 1
• Do not miss inherited bone marrow failure syndromes by failing to obtain detailed family history and examine for subtle physical findings (short stature, thumb abnormalities, skin pigmentation, nail changes) 7, 5, 6
• Do not perform bone marrow examination in typical isolated monocytosis following viral infection with otherwise normal parameters, but do not delay when red flags are present 1
• Do not omit HIV, hepatitis C, or H. pylori testing, as these are frequent treatable contributors to secondary cytopenias 1

Management Principles

Treatment of the underlying cause is the primary focus, with supportive care including transfusions for symptomatic anemia or severe thrombocytopenia to maintain quality of life and prevent complications. 1

• Immunosuppressive therapy (antithymocyte globulin plus cyclosporine) is recommended for non-severe aplastic anemia 1
• Hematopoietic stem cell transplantation is considered for severe aplastic anemia in appropriate candidates and remains the only curative option for primary myelofibrosis 1
• Hypomethylating agents (azacitidine) are recommended for higher-risk MDS patients not eligible for stem cell transplantation 1
• Antimicrobial therapy directed at specific pathogens, with H. pylori eradication, antiviral therapy for HIV/HCV, and appropriate antibiotics for bacterial infections 1, 3
• Nutritional replacement with vitamin B12, folate, or iron for deficiency states produces rapid improvement 3
• Immediate hematology consultation is mandatory for blasts on smear, unexplained cytopenias with organomegaly, or suspicion of malignancy 1