What are the causes of pancytopenia in children?

Causes of Pancytopenia in Children

Inherited Bone Marrow Failure Syndromes

Systematic exclusion of inherited bone marrow failure syndromes is mandatory before diagnosing acquired aplastic anemia in any child with pancytopenia. 1

Fanconi Anemia

• Presents typically at school age (5–10 years) with progressive marrow failure, short stature, thumb or radial ray anomalies, café-au-lait spots, and renal malformations 2, 1
• Carries high risk of evolution to AML/MDS 2, 1
• Diagnosis confirmed by chromosome breakage test (DEB or MMC) in children with unexplained pancytopenia and physical anomalies 1

Dyskeratosis Congenita

• Classic triad: nail dystrophy, reticular skin hyperpigmentation, and oral leukoplakia 2, 1
• Progresses to bone marrow failure, pulmonary fibrosis, hepatic fibrosis, and risk of AML/MDS 2, 1
• Diagnosis via telomere length measurement by flow-FISH 1

Diamond-Blackfan Anemia

• Presents in infancy with macrocytic anemia, short stature, craniofacial anomalies (cleft palate, hypertelorism), thumb defects, and congenital heart disease 2, 1
• Later risk of MDS/AML 2, 1

Shwachman-Diamond Syndrome

• Features exocrine pancreatic insufficiency with steatorrhea, growth failure, skeletal anomalies, and neutropenia evolving to pancytopenia 2, 1
• 10–20% develop MDS/AML 2, 1

Severe Congenital Neutropenia

• Absolute neutrophil count <0.5 × 10⁹/L with recurrent severe infections 2, 1
• 11% cumulative risk of MDS/AML by median age 16.2 years 2, 1

SAMD9/SAMD9L-Associated Syndromes

• Account for 8–18% of childhood MDS 2, 1
• Present with cytopenias, immunodeficiency, growth restriction, adrenal hypoplasia (MIRAGE syndrome), and developmental delay 2, 1

Clinical clues for inherited disorders include thrombocytopenia from early life, positive family history, or characteristic physical anomalies such as short stature, thumb abnormalities, skin pigmentation changes, or nail dystrophy. 1

Acquired Bone Marrow Disorders

Aplastic Anemia

• Most common cause of pancytopenia in children, accounting for 20–52.3% of cases 3, 4
• Bone marrow shows hypocellularity 5
• HLA-DR15 typing identifies patients likely to respond to immunosuppressive therapy 1

Myelodysplastic Syndrome (MDS)

• Accounts for approximately 10.7–21.3% of pediatric pancytopenia cases 1, 4
• Defined by ≥10% dysplastic cells in ≥1 lineage 1
• Requires bone marrow aspirate, core biopsy, flow cytometry, and cytogenetics (≥15 metaphases) for diagnosis 1

Acute Leukemias (ALL/AML)

• Together with MDS, account for approximately 21% of presentations 1, 3
• Detection of blasts on peripheral smear mandates immediate same-day bone marrow evaluation 1
• Acute lymphoblastic leukemia is the most common malignant cause in children 6, 7

Nutritional Deficiencies

Megaloblastic Anemia

• Single most common etiological factor, accounting for 21.8–28.4% of pediatric pancytopenia cases 3, 6, 7
• Caused by vitamin B12 or folate deficiency producing macrocytic anemia with hypersegmented neutrophils 1
• Severe thrombocytopenia (platelets ≤20 × 10⁹/L) occurs in 25.2% of these patients 3
• Skin and mucosal bleeding occurs in 45.1% despite being nutritional in origin 3
• Testing required before initiating therapy 1

Infectious Causes

Enteric Fever

• Accounts for 30% of infection-related pancytopenia 3
• Infections overall account for 21–23% of pediatric pancytopenia cases 3, 6

Miliary Tuberculosis

• Notable infectious etiology in developing countries 6

Hemophagocytic Lymphohistiocytosis (HLH)

• Manifests with pancytopenia, fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and ferritin often >10,000 ng/mL 1
• Accounts for 3.4% of cases 4

Parvovirus B19

• Should be investigated when bone marrow shows hypoplastic pattern 1

HIV and Hepatitis C

• HIV causes pancytopenia via direct marrow suppression, opportunistic infections, and drug toxicity 1
• Universal screening for both HIV and hepatitis C is advised in children with unexplained pancytopenia 1

Other Infections

• Brucellosis presents with mild transaminitis and pancytopenia; bone marrow culture provides highest diagnostic yield 1
• Ehrlichiosis causes pancytopenia with highest case-fatality rate in children <10 years 1
• CMV post-transfusion mononucleosis syndrome produces high fever, pancytopenia, and atypical lymphocytosis 1

Autoimmune and Immunodeficiency Disorders

Systemic Lupus Erythematosus (SLE)

• Causes immune-mediated cytopenias 2, 1
• ANA and anti-dsDNA typically positive 2, 1

Autoimmune Lymphoproliferative Syndrome (ALPS)

• Presents with chronic lymphadenopathy, splenomegaly, and multilineage cytopenias 2, 1
• Confirmation requires FAS-gene mutation testing 2, 1

Common Variable Immunodeficiency (CVID)

• Associated with recurrent infections, abnormal serum immunoglobulins, and cytopenias 1

Hematologic Malignancies with Infiltration

Non-Hodgkin Lymphoma

• Requires excisional lymph node biopsy with immunophenotyping and cytogenetics 1
• Fine-needle aspiration alone is insufficient 1

Neuroblastoma

• Rare cause of pancytopenia in children 4

Peripheral Destruction and Sequestration

Hypersplenism

• Can be more common cause of hematologic abnormalities than marrow disease in conditions like sarcoidosis 1
• Splenomegaly in true ITP occurs in <3% of cases; its presence should trigger evaluation for secondary etiologies 2, 1

Drug-Induced and Toxic Causes

Methotrexate

• May rarely induce pancytopenia even at low weekly doses, especially with renal impairment or concurrent sulfonamides 1
• Typically occurs 4–6 weeks after dose escalation 1

Conventional Chemotherapy

• Causes pancytopenia through direct marrow suppression and mucosal barrier injury 1

Immune Checkpoint Inhibitors

• Anti-CTLA-4 and anti-PD-L1 produce immune-related hematologic toxicity in <5% of patients with notable mortality risk 1

Diagnostic Evaluation Algorithm

Initial Mandatory Tests

• CBC with differential, reticulocyte count, and peripheral smear reviewed by hematopathologist to exclude pseudothrombocytopenia, identify blasts, dysplasia, or schistocytes 1
• Repeat CBC in heparin or citrate tube to rule out EDTA-dependent pseudothrombocytopenia (≈0.1% prevalence) 1
• LDH, haptoglobin, indirect bilirubin, and direct antiglobulin test to assess hemolysis 1
• HIV and hepatitis C serology in all children 1
• Vitamin B12, folate, and iron studies before bone marrow examination 1
• ANA and anti-dsDNA when systemic autoimmune features present 2, 1
• Serum immunoglobulin panel (IgG, IgA, IgM) to detect immunodeficiency 2, 1

Absolute Indications for Bone Marrow Examination

• Abnormalities beyond isolated thrombocytopenia on CBC or smear 2, 1
• Systemic "B-symptoms" (bone pain, fever, night sweats, weight loss) 1
• Hepatosplenomegaly or unexplained lymphadenopathy 2, 1
• Peripheral blasts (necessitates same-day marrow assessment) 1
• Failure to improve after 3–6 months of observation or minimal response to first-line therapy 2, 1
• Unclear diagnosis after initial laboratory work-up 1

Specialized Testing for Inherited Syndromes

• Chromosome breakage test (DEB or MMC) for Fanconi anemia in children with unexplained pancytopenia and physical anomalies 1
• Telomere length measurement (flow-FISH) for dyskeratosis congenita 1
• PNH screening by flow cytometry in suspected aplastic anemia 1

Critical Pitfalls to Avoid

Do not attribute pancytopenia with splenomegaly to ITP; splenomegaly occurs in <3% of true ITP and mandates evaluation for secondary causes. 2, 1

• Do not delay peripheral smear review; 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 work-up 1
• Do not miss inherited bone marrow failure syndromes; obtain detailed family history and examine for subtle physical findings (short stature, thumb abnormalities, skin pigmentation, nail changes) 2, 1
• Do not omit testing for HIV, hepatitis C, or H. pylori, as these are treatable contributors 1