Severe Congenital Neutropenia

Severe congenital neutropenia (SCN) affects myelopoiesis and has many different subtypes. SCN manifests in infancy with life-threatening bacterial infections. The treatment proven to be effective is the administration of granulocyte colony-stimulating factor, which elevates the decreased neutrophil count. Kostmann disease (SCN3) has an autosomal recessive inheritance pattern, whereas the most common subtype, SCN1, has autosomal dominant inheritance.

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Etiology

General facts

In 50%–60% of cases, severe congenital neutropenia (SCN) is due to an autosomal dominant ELANE gene mutation. However, the initial mutation described by Kostmann was in HAX1, which is inherited in an autosomal recessive pattern. X-linked recessive inheritance is due to mutations in the Wiskott-Aldrich syndrome (WAS) gene protein (WASP).

Subtypes

The following table summarizes each subtype of SCN, the genes involved and their function, as well as their mode of inheritance.

Table: Subtypes of SCN
TypeGene mutatedProtein affectedMode of inheritance
SCN1ELANE (19p13.3)Neutrophil elastase (mutation leads to misfolded protein, which leads to increased apoptosis)AD
SCN2GFI1 (1p22.1)Repressor of transcriptional processes (mutation leads to loss of repression)AD
SCN3HAX1 (1q21.3)HCLS1-associated protein X-1 (functions in control of apoptosis)AR
SCN4G6PC3 (17q21.31)G6Pase—mutation leads to abolished enzyme activity, aberrant glycosylation, and enhanced apoptosis of myeloid cellsAR
SCN5VPS45 (1q21.2)Vesicle mediated protein (controls vesicular trafficking)AR
SCNXWAS (Xp11.23)—implicated in Wiskott-Aldrich syndromeWASP—regulator of actin cytoskeleton (mutation is a gain-of-function mutation leading to loss of autoinhibition)X-linked recessive
AD: autosomal dominant
AR: autosomal recessive
G6Pase: glucose-6-phosphatase

Classification

Origin of neutropenia

Neutropenia may arise from any of 3 pathogenic pathways:

  • Insufficient bone marrow production: destruction and infiltration of the bone marrow by infection, malignancy, or drug toxicity
  • Shifts in and increased destruction of neutrophils from the circulating pool of cells
  • Neutrophilic injury may arise from immunologic disorders:
    • Systemic lupus erythematosus
    • Drug toxicities 
    • Splenic sequestration

Types of neutropenia

Hereditary:

  • Congenital neutropenia
  • Inherited and very severe
  • Autosomal dominant inheritance pattern most common
  • More common in infants and young children
  • Chronic neutropenia (Kostmann syndrome):
    • Aggressive condition
    • Transmitted via autosomal recessive pattern
  • Cyclic neutropenia:
    • Presents in many members of a family
    • Occurs every 3 weeks and continues for 3–6 days per cycle
    • Symptoms: infections, fever, and ulcer
    • Most children improve after puberty.

Acquired: 

  • More common than hereditary types
  • Immune-mediated neutropenia
  • Drug-induced neutropenia:
    • Drug acts as a hapten inducing antibody formation.
    • Common culprits: 
      • Quinidine 
      • Aminopyrine
      • Penicillin 
      • Cephalosporins
      • Phenothiazines 
      • Sulfonamides
      • Hydralazine

Autoimmune:

  • Can be primary or secondary
  • Primary form: 
    • Antineutrophil antibodies that cause peripheral destruction 
    • Usually mild and self-limited
  • Secondary form:
    • Usually due to another autoimmune disease, infection, or malignancy
    • Very rare in infants and more likely in patients > 1 year of age

Infectious:

  • Viral: 
    • Measles
    • Influenza
    • EBV
    • CMV
    • Viral hepatitides
    • HIV
  • Bacterial/parasitic:
    • Typhoid
    • Toxoplasmosis
    • Brucellosis
    • Rickettsial infections
    • Malaria
    • Dengue fever

Mixed: chronic benign neutropenia

  • Rare form
  • Can lead to life-threatening infections
  • More common in children < 4 years of age

Clinical Presentation

Signs and symptoms

  • Recurrent mucosal infections, more so in the mouth, throat, and skin, due to low immunity
  • Septicemia
  • Fever and chills
  • Otitis media
  • Stomatitis and periodontitis
  • Splenomegaly
  • Petechial bleeds and easy bruisability due to depression of other cell lines in most conditions
  • Growth retardation
  • General body malaise
  • Poor appetite and weight loss

Complete history and physical examination

  • Family history is important.
  • Children often present with a history of:
    • Pneumonia
    • Ear infections
    • Tonsillitis
    • Gastroenteritis
    • Skin infections
    • Pharyngitis
  • On physical examination:
    • Fever (many times there is a fever without focal signs of disease)
    • Ulcers
    • Gingivitis
    • Abscesses
    • Pneumonia
    • Skin infections
    • Cervical lymphadenopathy
    • Growth retardation

Diagnosis

  • Absolute neutrophil count (ANC):
    • In neutropenia, the ANC is reduced.
    • In infants: ANC < 1000/µL
    • Children > 1 year of age: ANC < 1500/µL (the same definition as an adult)
    • ANC is used to classify neutropenia: 
      • Mild: ANC 1000–1500/µL
      • Moderate: ANC 500–1000/µL
      • Severe: ANC < 500/µL
  • First orders to place:
    • CBC/DIFF: 
      • Will show a low neutrophil count in the peripheral circulation 
      • Aids in calculation of ANC
    • Bone marrow aspiration (BMA) and biopsy:
      • Hypercellular marrow indicates peripheral destruction.
      • Hypocellular marrow indicates bone marrow infiltration and failure.
  • For clinical concern about infection, order:
    • Cultures (blood, urine, sputum, and wounds)
    • Urinalysis
    • Skin biopsy
    • Stool ova/parasites and cultures
  • Beneficial imaging studies:
    • Radiography of long bones (in cases of congenital neutropenia)
    • Chest X-ray and chest CT if patient has signs of pneumonia
    • Abdominal ultrasonography to evaluate splenomegaly
Calculation of ANC with example

How to calculate ANC with example

Image by Lecturio. License: CC BY-NC-SA 4.0

Management

General approach to treatment

  • Remove any offending drugs.
  • Practice good oral hygiene.
  • Use stool softeners (as needed).
  • Perform adequate skin care.
  • Correct folic acid deficiency (if present).
  • Dietary modifications (including ingestion of properly cooked meats, clean water, and avoidance of acidic foods)

Specific therapies

  • Antibiotics (to address any coexisting infections)
  • Granulocyte colony-stimulating factor administration 
    • Improves neutrophil counts and immune function 
    • Risks: Myelofibrosis and AML
  • Granulocyte transfusion (to replenish any granulocyte deficiencies)
  • IV immunoglobulin (to address any autoimmune component to the neutropenia)
  • Corticosteroids (to lead to overall immunosuppression in cases of autoimmune neutropenia)
Severe congenital neutropenia Granulocyte colony stimulating factor

Effects of granulocyte-colony stimulating factor (G-CSF)
Th2: type 2 T helper cell
TREF: T regulatory cells

Image by Lecturio. License: CC BY-NC-SA 4.0

Differential Diagnosis

  • Leukemias, particularly AML: produce neutropenia through bone marrow suppression of normal hematopoietic cell lineage due to overproduction of the malignant cell line. Leukemias will often present with markedly elevated WBCs, however, which can be particularly useful in differentiating from neutropenia. Additionally, neutropenia and leukemia are frequently seen in combination due to the side effects of many chemotherapeutic agents. 
  • Aplastic anemia: result of complete bone marrow failure to produce hematopoietic cells. Patients with aplastic anemia will demonstrate pancytopenia rather than isolated neutropenia, a helpful differentiation tool between the 2 entities. Aplastic anemia is frequently a secondary diagnosis , caused by autoimmune syndromes, radiation therapy, chemotherapy, or postviral syndromes. Treatment is complex but can include antithymocyte globulin, cyclosporine, or bone marrow transplantation, depending on severity, patient age, and previously attempted therapies. 
  • Lymphoma: produces neutropenia using a similar mechanism as the leukemias. If the bone marrow space is overproducing malignant lymphoid cells, there is not enough bone marrow space to appropriately create the other hematopoietic cell lines. Thus, neutropenia will be seen with a significantly elevated lymphocyte count, which will help differentiate the etiology of neutropenia from other causes. Lymphoma is treated with chemotherapy and commonly includes the R-CHOP—a combination of rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone.

References

  1. Coates, T.D. (2021). Overview of neutropenia in children and adolescents. In Newburger, P., et al. (Ed.), UpToDate. Retrieved May 22, 2021, from https://www.uptodate.com/contents/overview-of-neutropenia-in-children-and-adolescents
  2. Berliner, N. (2020). Approach to the adult with unexplained neutropenia. In Newburger, P., et al. (Ed.), UpToDate. Retrieved May 22, 2021, from https://www.uptodate.com/contents/approach-to-the-adult-with-unexplained-neutropenia
  3. Fischer, A. (2018). Primary immune deficiency diseases. Chapter 344 of Jameson J., et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.

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