Pediatric Autoimmune and Chronic Benign Neutropenia Differential Diagnoses

Updated: Sep 09, 2019
  • Author: Susumu Inoue, MD; Chief Editor: Lawrence C Wolfe, MD  more...
  • Print
DDx

Diagnostic Considerations

Acute transient leukopenia and neutropenia in small infants and young children are extremely common. Regardless of diagnosis, one needs to establish if the neutropenia is transient or chronic. Before suspecting chronic neutropenia, serial blood cell counts are needed. Most transient neutropenia associated with an infection in this age group resolves within 1-2 weeks. In a study of 143 neutropenic hospitalized patients in Greece, median duration of neutropenia was only 3.3 days (range 1-22 d).Two of these children were eventually diagnosed with autoimmune neutropenia. [24]  In a series reported by Lindqvist et al, the mean duration of an absolute neutrophil count of less than 500/μL was longer, 0.5 months with an infectious episode [25]

Differentiating AIN from ethnic neutropenia may be difficult. Inquiring about the ethnicity of the patient and parents is important. As previously mentioned, a high frequency of benign neutropenia is widely recognized in African Americans, Yemenite and Falasha Jews, Black Beduin, blacks of South African extraction, West Indians, Arab Jordanians, and various tribal groups inhabiting the United Arab Emirates. [16] Ethnic neutropenia does not cause frequent infections. The gene that is responsible for ethnic neutropenia is identified to be the DARC (Duffy antigen/chemokine receptor) gene. [18, 19] Thus, children with the above ethnic backgrounds, if their red blood cells are Duffy negative, are likely to have ethnic neutropenia.

AIN of infancy usually lasts at most 2-3 years before spontaneous resolution. If it persists beyond age 4-5 years with a benign course, and if the child is of one of the ethnicities listed above, one may suspect ethnic neutropenia. A family history of neutropenia may be helpful in this differentiation. However, neutrophil counts increase with age even in individuals with ethnic neutropenia. [26] Thus, the absence of a family member with neutropenia does not exclude the diagnosis of ethnic neutropenia.

In iso (allo)-immune neutropenia of infancy, evaluate maternal serum for neutrophil antibodies, usually anti–HNA-1 or anti–HNA-2. A positive result is consistent with iso (allo)-immune neutropenia. Suspect iso (allo)-immune neutropenia or severe congenital neutropenia if profound neutropenia is present at or shortly after birth.

Antineutrophil antibodies may not be detectable in children with AIN. In their analysis of 240 children with AIN, Bux et al detected granulocyte-specific antibodies during the first investigations in only 74% of patients. [27] In 26% of patients, "Repeated antibody testing with additional samples up to 3 times was necessary for detection of antibodies." Audrain et al found that only 60% of the patients were positive for the antibodies. Seventy-three percent of these cases were anti–HNA-1 antibodies. [28] They found that younger patients had a higher positivity rate than older children and children with HNA-1 antigen were overrepresented, suggesting this antigen may trigger antibody formation more frequently than other neutrophil antigens.

In a patient with an enlarged spleen, consider hypersplenism, glycogen storage disease, and lipid storage disease in the differential diagnosis.

The following should alert physicians to a diagnosis other than AIN:

  • Severe illness

  • Life-threatening infections

  • Significant hepatosplenomegaly

  • Neutrophil count fewer than 200 from day 1 of life

  • Purpura and/or thrombocytopenia

  • Hemorrhagic findings

  • Moderate to severe anemia

  • Lymphopenia

  • Monocytosis

  • Consanguinity

Aside from the diseases listed in the next subsection, disorders that can mimic the symptoms of autoimmune neutropenia include the following:

  • Iso (allo)-immune neutropenia in neonates

  • Cyclic neutropenia

  • Ethnic neutropenia/leukopenia

  • Hypersplenism

  • Neutropenia due to drugs

  • Neutropenia associated with systemic autoimmune disease

  • Severe congenital neutropenia, autosomal recessive and autosomal dominant

  • Transient leukopenia/neutropenia associated with viral infection

  • Neutropenia associated with congenital immunodeficiency

Go to Neutropenia for complete information on this topic.

Differential Diagnoses

  • **Severe congenital neutropenia, sporadic, autosomal recessive, and autosomal dominant:

  • *Barth syndrome

  • *Cartilage hair hypoplasia

  • *Glycogen storage disease type 1b

  • *Griscelli syndrome

  • *Hermansky-Pudlak syndrome

  • *Hyperimmunoglobulin M syndrome

  • *Kostmann syndrome

  • *Schwachman-Diamond syndrome

  • *WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome

  • Chediak-Higashi Syndrome

  • Cyclic neutropenia

  • Ethnic neutropenia/leukopenia

  • Glucose 6 phsophatase catalytic subunit 3 deficiency

  • Hypersplenism

  • Iso (allo)-immune neutropenia in neonates

  • May-Hegglin Anomaly

  • Myelokathexis

  • Neutropenia associated with congenital immunodeficiency

  • Neutropenia associated with systemic autoimmune disease

  • Neutropenia due to drugs

  • Pediatric HIV Infection

  • Transient leukopenia/neutropenia associated with viral infection