Severe congenital neutropenias

Abstract

Severe congenital neutropenias are a heterogeneous group of rare haematological diseases that are characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life. The most frequent pathogenetic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte-colony stimulating factor (G-CSF) signalling pathway. The pathophysiological mechanisms of these conditions are the object of extensive research and are not fully understood. Furthermore, severe congenital neutropenias may predispose to myelodysplastic syndromes or acute myeloid leukaemia. Molecular events in the malignant progression include acquired mutations in CSF3R (encoding G-CSF receptor) and subsequently in other leukaemia-associated genes (such as RUNX1) in a majority of patients. Diagnosis is based on clinical manifestations, blood neutrophil count, bone marrow examination, and genetic and immunological analyses. Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophils count, reduction of infections and drastic improvement of quality of life. Haematopoietic stem cell transplantation is the alternative treatment. Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (e.g. trisomy 21, monosomy 7) as well as somatic pre-leukaemic mutations are recommended.

CSF3R Mutations are frequently associated with abnormalities of RUNX1, CBFB, CEBPA, and NPM1 genes in acute myeloid leukemia

“…CSF3R mutations in membrane-proximal and cytoplasmic regions can result in sustained activation of the Janus kinase (JAK) and SRC-family tyrosine kinase nonreceptor 2 (TNK2) kinase pathways, respectively, and can be blocked by kinase inhibitors. 2 CSF3R mutations also are identified in approximately 30% of patients who have severe congenital neutropenia (SCN) 3,4 and other hematologic malignancies, including atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia, acute myeloid leukemia (AML), and early T-cell precursor lymphoblastic leukemia, 2 but are rarely observed in patients with B-cell acute lymphoblastic leukemia (B-ALL), myelodysplastic syndrome (MDS), juvenile myelomonocytic leukemia, essential thrombocythemia, and other diseases. 5,6 CSF3R mutations are uncommon in AML and have been reported in 3% of patients who have an intermediate-risk AML karyotype, in 1.9% to 3.6% of patients with pediatric AML, and in 1% of adults with AML.…”

Ethnic benign neutropenia: A phenomenon finds an explanation

“…Familial, inherited neutropenias (NPs) represent a spectrum of disorders, spanning from severe congenital NPs (SCNP; e.g., due to ELANE, HAX and other mutations with recessive or dominant heredity), representing the most austere NP form with a high risk for life‐threatening bacterial infections and progression to myelodysplastic syndrome (MDS) and acute leukemia . In the other end of the spectrum is ENP, also called benign familial NP (OMIM 611862), considered not to confer an increased propensity for bacterial or fungal infections despite ANCs around 1 G/L, which, in other NPs, may represent a risk for such infections.…”

How we approach: Severe congenital neutropenia and myelofibrosis due to mutations in VPS45

“…4, 12 As such, VPS45 is sometimes referred to as severe congenital neutropenia Type 5 (SCN5). 6 Whilst neutrophil granules can be formed, they cannot be released from the cell because of impaired trafficking of endosomes, and the neutrophils themselves demonstrate an impaired ability to migrate to areas of infection and inflammation.…”

“…due to mutations in ELANE, G6PC3 ), the neutrophils of VPS45 also demonstrate increased apoptosis. 4, 5, 12, 13 …”