Hematology

Severe congenital neutropenia

Severe congenital neutropenia

What every physician needs to know:

Severe congenital neutropenia (SCN) is a rare heterogenous disorder characterized by chronic severe neutropenia (absolute neutrophil count [ANC] less than 500/uL) and arrest of neutrophil maturation at the promyelocyte/myelocyte stage, due to a constitutional genetic defect.

Patients with SCN are usually diagnosed in the first year of life and present with frequent and/or life-threatening infections. Autosomal recessive, autosomal dominant and sporadic forms exist. The autosomal recessive form of SCN, known specifically as Kostmann syndrome, was described in 1956 and is now known to be due to HCLS1-associated protein X-1 (HAX1) mutations. Fifty percent of the autosomal dominant forms of SCN are attributed to ELANE (formerly ELA2) mutations.

The mainstay of care is supportive treatment with granulocyte colony-stimulating factor (G-CSF) titrated to maintain an ANC (absolute neutrophil count) of 1,000 to 2,000/uL. Bone marrow transplantation is the only curative option. Annual bone marrows are required due to the risk of transformation to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) in non-syndromic SCN.

Are you sure your patient has severe congenital neutropenia? What should you expect to find?

Patients with severe congenital neutropenia usually present in the first year of life with:

  • Severe persistent neutropenia, ANC less than 500/uL

  • Frequent, life-threatening infections. Recurrent fevers, mouth ulcers, gingivitis, otitis media, pneumonia, liver abscesses, and skin infections are common

  • Maturation arrest of neutrophil precursors in the bone marrow at the promyelocyte/myelocyte stage

Beware of other conditions that can mimic severe congenital neutropenia:

Cyclic neutropenia

Characterized by regular oscillations in neutrophil number with a mean of 21 day cycles and a nadir period of 3 to 6 days, associated with reciprocal monocytosis due to mutations in the ELANE gene. Patients present with recurrent fever and mouth ulcers as well as other infections. Clinical course is generally more benign than SCN patients, although G-CSF is often employed. Diagnosis is confirmed by assessment of complete blood counts with differentials (CBCPD) done twice weekly for 6 weeks.

Autoimmune neutropenia of childhood

Immune destruction of neutrophils due to acquired neutrophil-specific autoantibodies. Often identified incidentally as patients generally have a benign clinical course with no significant increased risk for infections. Neither prophylatic antibiotics, nor recombinant human G-CSF are usually needed. Expected to resolve spontaneously within months to a few years.

Neonatal alloimmune neutropenia

Immune destruction of neutrophils, due to a maternal immune response to fetal alloantigens from fetal neutrophils bearing antigens that are different from the mother's neutrophils, similar to Rh disease of the newborn. Neutropenia can be severe and last up to 3 months.

Neonatal isoimmune neutropenia

Immune destruction of neutrophils due to the passive transfer of maternal immunoglobulin G (IgG) autoantibodies to neutrophil-specific antigens, in infants of mothers with autoimmune neutropenia. Often seen with mothers who have systemic lupus erythematosus. Neutropenia can be severe but generally lasts less than 6 weeks.

  • Promyelocytic leukemia (AML-M3)

  • Drug-induced neutropenia

Which individuals are most at risk for developing severe congenital neutropenia:

Patients with a known family history of SCN are most at risk for the disease. Both genders are affected equally. African Americans are less frequently affected.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

  • Complete blood count with platelets and differential

  • Anti-neutrophil antibodies

  • Bone marrow aspirate with flow cytometry and cytogenetics to exclude leukemia

  • Quantitative immunoglobulins to exclude dysgammaglobulinemia

  • ELANE gene testing and in consanguineous families, HAX-1 gene testing

What imaging studies (if any) will be helpful in making or excluding the diagnosis of severe congenital neutropenia?

Imaging studies do not play a significant role in diagnosing SCN, although directed imaging studies may serve to confirm/characterize infections.

If you decide the patient has severe congenital neutropenia, what therapies should you initiate immediately?

G-CSF at an initial dose of 5mcg/kg/dose subcutaneously daily should be started promptly once the diagnosis is recognized. If the ANC does not improve within 14 days, increase the dose of G-CSF to 5 mcg/kg/dose subcutaneously, twice daily. The dose of G-CSF may be doubled every 14 days if the patient's ANC is not increasing to 1,000/uL, until a dose of 80mcg/kg is reached.

If the patient remains unresponsive, then bone marrow transplantation is the only recourse. For patients who do respond to G-CSF, the dose should then be titrated to achieve an ANC 1,000 to 2,000/uL. Additionally, appropriate antibiotics directed at any active infections should be started.

More definitive therapies?

Once the diagnosis of SCN is recognized and G-CSF started, the patient should be evaluated for a stem cell transplant (SCT), as SCT is the only definitive cure. For patients with a sibling match, allogeneic bone marrow transplant (BMT) should be considered as first-line therapy.

A matched unrelated donor allogeneic SCT should also be considered for patients who do not respond to 80mcg/kg of G-CSF, since these patients are at increased risk for infectious complications and transformation to MDS/AML.

What other therapies are helpful for reducing complications?

Prophylactic antibiotics are not routinely required for patients who are able to maintain an ANC 1,000 to 2,000/uL while on G-CSF.

What should you tell the patient and the family about prognosis?

Prior to the advent of G-CSF in the late 1980's, patients with SCN were managed with observation and repeated courses of antibiotics since no effective primary treatments existed. Patients generally succumbed to infection in the first or second decade of life. However, now that G-CSF is routinely used in the management of SCN with 90% of patients responding, outcomes are significantly improved with respect to infectious complications. However, the cumulative risk of myelodysplasia or acute leukemia at 10 years of observation on G-CSF treatment is 21%.

Current goals of therapy include prompt initiation of G-CSF treatment to minimize infectious complications, consideration of SCT for patients with a matched sibling donor or for those patients who are treatment refractory, and to monitor patients annually for transformation to MDS/AML with a bone marrow aspirate with cytogenetics.

What if scenarios.

What if the patient has a fever?

For temperatures greater than 38.3°C, patients with an ANC less than 1,000/uL should be urgently evaluated by a physician. Blood cultures and urine cultures should be obtained, broad-spectrum antibiotics administered and the patient should be admitted for observation for at least 48 hours to confirm negative cultures. Additional workup should be dictated by the patient's presenting symptoms.

Pathophysiology

SCN is a heterogeneous disease that results from a variety of gene mutations, each culminating in an arrest of neutrophil development at the promyelocyte/myelocyte stage and a paucity of circulating neutrophils, leading to increased infection risk.

The most common lesion is a mutation in the ELAINE gene, which encodes for neutrophil elastase and accounts for 50% of the autosomal dominant cases of SCN. Neutrophil elastase is a serine protease synthesized in the early stages of primary granule formation in promyelocytes. Interestingly, the ELANE mutations result in neutropenia not necessarily through loss of protease function secondary to the mutation, but instead, through triggering the unfolded protein response in the cell resulting in early cell apoptosis.

In the original kindred described by Kostmann with autosomal recessive SCN, the causative mutation is in the HAX1 gene. HAX1 is suggested to be involved in stabilizing mitochondrial membrane potential in neutrophils. Disruption of HAX1 is believed to result in failure to maintain normal mitochondrial function and to accelerate apoptosis.

What other clinical manifestations may help me to diagnose severe congenital neutropenia?

Patients with SCN frequently have oral ulcers, bleeding gums, or gingivitis on exam of their oropharynx, as well as frequent skin infections.

As most of SCN is heritable, it is important to ask about any other affected members of the family. Inquiring about early loss of teeth, frequent infections, and/or sudden death from overwhelming infection can be helpful. Additionally, confirming whether the patient has any full-siblings for potential human leukocyte antigen (HLA) typing is useful in thinking about SCT as a treatment option.

What other additional laboratory studies may be ordered?

Repeat complete blood counts with differential should be routinely obtained every 3 months, to titrate G-CSF dose. Additionally, annual bone marrow aspirates with cytogenetics should be obtained to monitor for transformation to MDS/AML.

If the bone marrow reveals a neutrophil arrest at the promyelocytic/myelocyte stage and the ELANE gene testing is negative, save deoxyribonucleic acid (DNA) from the patient for future genetic analysis, to facilitate new disorders to be discovered.

If the ELANE gene testing is negative consider further genetic testing for other rarer syndromes associated with neutropenia such as: Shwachman-Diamond syndrome, glucose-6-phosphate catalytic subunit 3 and dyskeratosis congenita, Chediak-Higashi syndrome, zinc finger protein Gfi-1 (GFI-1), Wiskott-Aldrich syndrome, Hermansky Pudlak type II, glycogen storage disease type IB, WHIM syndrome. These syndromes can now be evaluated by genetic testing and have clinical features outside of their hematologic findings.

What’s the evidence?

Kostmann, R. "Infantile genetic agranulocytosis. A new recessive lethal disease in man". Acta Paediatr. vol. 105. 1956. pp. 1-78.

[Severe congenital neutropenia was first described as an autosomal recessive disorder associated with severe neutropenia that was identified in a population of an isolated northern parish in Sweden. It was characterized by a deficiency of a mature neutrophil in the bone marrow and peripheral blood.]

Klein, C, Grudzien, M, Appaswamy, G. "HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease)". Nat Genetics. vol. 30. 2007. pp. 86-92.

[Using a genome linkage study in candidate gene sequencing in consanguineous pedigrees with severe congenital neutropenia, mutations in HAX1 were identified.]

Dale, DC, Person, RE, Bolyard, AA. "Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia". Blood. vol. 96. 2000. pp. 2317-2322.

[This study documented that constitutive mutations in the ELANE gene (encoding neutrophil elastase) were found in the majority of patients with both severe congenital and cyclic neutropenia.]

Dale, DC, Bolyard, AA, Schwinzer, BG. "The Severe Chronic Neutropenia International Registry: 10- Year Follow-Up Report". Supp Cancer Ther. vol. 3. 2006. pp. 223-234.

[Data from this severe chronic neutropenia international registry documented that treatment with pharmacological doses of G-CSF had proven to be effective in restoring the neutrophil count in the majority of severe chronic neutropenia patients with the concomitant reduction in infection related events. However, some chronic neutropenia patients remain unresponsive to the G-CSF.]

Rosenberg, PS, Zeilder, C, Bolyard, AA. "Stable long-term risk of leukemia in patients with severe congenital neutropenia maintained on G-CSF". Brit J Haem. vol. 150. 2010. pp. 196-199.

[Patients with severe congenital neutropenia have a 10 to 30% risk of evolving to acute myelogenous leukemia in their lifetime. Patients with or without ELANE mutations are at approximately equal risk.]

Choi, SW, Boxer, LA, Pulsipher, MA. "Stem cell transplantation in patients with severe congenital neutropenia with evidence of leukemic transformation". Bone Mar Trans. vol. 35. 2005. pp. 473-477.

[This report documents the outcome for six patients with severe congenital neutropenia who underwent hematopoietic stem cell transplantation for myelodysplasia or acute myelogenous leukemia. Two patients survived who did not receive induction chemotherapy prior to transplantation, whereas four patients pre-treated with induction chemotherapy died.]

Bouma, G, Ancliff, PJ, Thrasher, AJ, Burns, SO. "Recent advances in the understanding of genetic defects of neutrophil number and function". Brit J Haem. vol. 151. 2010. pp. 312-32.

[This review describes the pathophysiology of various forms of severe congenital neutropenia and neutrophil dysfunction based on an understanding of the genetic defects affecting neutrophil number and function.]
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