Kostmann Syndrome and Neutropenia Quiz

Neutropenia Overview

• Neutropenia is a common lab finding in adults and children
• Underlying causes are diverse and include benign conditions, autoimmune disorders, infections, and malignancies
• Clinical lab data from hematology, microbiology, molecular biology/cytogenetics, and clinical chemistry are crucial for diagnosis
• This review highlights the clinical, hematologic, and molecular genetic features of major neutropenia entities
• An algorithm-based approach is outlined to classify neutropenias

Defining Neutropenia

• Normal adult ANC ranges from 1.5 to 7.0 x 10⁹/L
• Lower limit of ANC varies based on patient age and ethnicity (e.g., up to 25% of African American children/adults have an ANC between 1.0 and 1.5 x 10⁹/L)
• Neonates and infants typically have a lower normal ANC (~2.5 x 10⁹/L)
• Most labs define neutropenia in infants with ANC < 2.5 x 10⁹/L and in adults with ANC < 1.5 x 10⁹/L

Classifying Neutropenia

• Neutropenia is categorized into mild, moderate, and severe based on ANC levels
• Stratification takes the clinical context into account (e.g., general good health, associated disease, etc.)
  • Mild: 1.0 to 1.5 x 10⁹/L, usually minimal risk of infection
  • Moderate: 0.5 to 1.0 x 10⁹/L, usually minimal risk of infection but some moderate cases
  • Severe: <0.5 x 10⁹/L, moderate to severe risk of infection

Age-Related Causes of Neutropenia

• Neonates: Primarily infections, maternal hypertension/drug treatment, maternal antibody production, and constitutional disorders (e.g., cyclic neutropenia, Kostmann syndrome, Chediak-Higashi syndrome)
• Infants/Children: Infections, autoimmune neutropenia, neoplasms replacing the bone marrow, idiosyncratic drug reactions, secondary autoimmune neutropenia in collagen-vascular disorders, immunodeficiencies, megaloblastic anemia, myeloablative therapies, constitutional neutropenia disorders, and copper deficiency
• Adults: Idiosyncratic drug reactions (most common in ambulatory patients), infections, neoplasms replacing the bone marrow, myeloablative therapies, secondary autoimmune neutropenia in collagen vascular disorders, and autoimmune disorders (including white blood cell aplasia)

Neutropenia Classification by Bone Marrow Reserve

• Neutropenia with decreased bone marrow reserve (BM reserve): categorized into primary and secondary, each involving defects in granulopoiesis or suppression of normal granulopoiesis
• Neutropenia with normal BM reserve: describes cases where the issue originates from factors not directly impacting granulopoiesis within the bone marrow

Examples of Disorders with Decreased BM Reserve

• Severe congenital neutropenia (Kostmann syndrome): Characterized by apoptosis of precursor cells, linked to mutations in ELA2

  • Frequent, severe infections starting in infancy
  • Slow progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)

• Shwachman-Diamond syndrome: Fas-mediated granulocyte apoptosis is triggered.

  • Usually develops as a result of a SBDS mutation
  • Increased risk of exocrine pancreatic deficiency, short stature, steatorrhea

Examples of Disorders with Normal BM Reserve

• Chronic benign neutropenia of infancy and childhood: Predominantly caused by antineutrophil antibodies, often evident before the 14th month of life, and typically characterized by low ANC (usually below 500/mm³).
• Non-immune chronic benign neutropenia: Associated with increased apoptosis, the severity varies, and is often detected as a finding in routine blood work, in routine checkups
• Ethnic or benign familial neutropenia: An uncharacterized pattern, but diagnoses are similar in family members

Diagnostic Approach to Neutropenia

• Thorough clinical history and physical exam are prerequisites for any lab testing.
• Radiographic findings can be crucial in select patients.
• Serial complete blood counts (CBCs), morphologic review of the peripheral blood smear, immune status testing, collagen vascular disease evaluation, viral infection testing, and bone marrow biopsy are essential.

Additional Causes of Neutropenia

• Nutritional deficiencies (e.g., protein-calorie malnutrition, folate/copper/B12 deficiency)
• Viral infections (e.g., EBV, CMV, HIV, Hepatitis, measles)
• Neonatal neutropenia associated with hypertensive mothers
• Drug-induced neutropenia
• Autoimmune neutropenia (associated with conditions like ITP, AIHA, etc)
• Alloimmune neutropenia
• Hypersplenism (sequestration or destruction)
• Infection-related neutropenia