Clinical implications of ELA2‐, HAX1‐, and G‐CSF‐receptor (CSF3R) mutations in severe congenital neutropenia

Abstract

Summary Congenital Neutropenia (CN) is a heterogeneous bone marrow failure syndrome characterized by a maturation arrest of myelopoiesis at the level of the promyelocyte/myelocyte stage with peripheral blood absolute neutrophil counts below 0·5 × 109/l. There are two major subtypes of CN as judged by inheritance: an autosomal dominant subtype, e.g. defined by neutrophil elastase mutations (approximately 60% of patients) and an autosomal recessive subtype (approximately 30% of patients), both presenting with the same clinical and morphological phenotype. Different mutations have been described (e.g. HAX1, p14 etc) in autosomal recessive CN, with HAX1 mutations in the majority of these patients. CN in common is considered as a preleukemic syndrome, since the cumulative incidence for leukemia is more than 25% after 20 years of observation. Leukemias occur in both, the autosomal dominant and recessive subtypes of CN. The individual risk for each genetic subtype needs to be further evaluated. Numbers of patients tested for the underlying genetic defect are still limited. Acquired G‐CSFR (CSF3R) mutations are detected in approximately 80% of CN patients who developed acute myeloid leukemia independent of the ELA2 or HAX1 genetic subtype, suggesting that these mutations are involved in leukemogenesis. As the majority of patients benefit from G‐CSF administration, HSCT should be restricted to non‐responders and patients with leukaemic transformation.

Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells

“…These results indicate that SCN-iPS cells provide a useful disease model for SCN, and the activation of the Wnt3a/β-catenin pathway may offer a novel therapy for SCN with ELANE mutation. apoptosis | unfolded protein response | SCN disease model S evere congenital neutropenia (SCN) is a heterogeneous bone marrow (BM) failure syndrome characterized by severe neutropenia at birth, leading to recurrent infections by bacteria or fungi (1). SCN patients reveal an arrest in neutrophil differentiation in the BM at the promyelocyte or myelocyte stage (1), as well as a propensity to develop myelodysplastic syndrome and acute myeloid leukemia (2).…”

“…apoptosis | unfolded protein response | SCN disease model S evere congenital neutropenia (SCN) is a heterogeneous bone marrow (BM) failure syndrome characterized by severe neutropenia at birth, leading to recurrent infections by bacteria or fungi (1). SCN patients reveal an arrest in neutrophil differentiation in the BM at the promyelocyte or myelocyte stage (1), as well as a propensity to develop myelodysplastic syndrome and acute myeloid leukemia (2). Current treatment by high-dose granulocyte-colony stimulating factor (G-CSF) administration induces an increase in the number of mature neutrophils in the peripheral blood of most SCN patients (3).…”

Gingivitis in Children and Adolescents

“…Caries, calculus and poor oral hygiene, place the patient at risk for oral pain, bleeding, super infection and tissue necrosis, exacerbating gingival signs and symptoms (Cooper et al, 2000). Severe persistent gingival inflammation and stomatitis are some of the features of severe congenital neutropenia heightened by susceptibility to bacterial infections due to impaired bone marrow myelopoiesis and an absolute neutrophil count (ANC) in the peripheral blood of < 0.2 x 10 9 /L (Okada et al, 2001;Zeidler et al, 2009). Periodontal manifestations may range from marginal gingivitis to rapidly progressive periodontal disease with advancing bone loss, which may affect both primary and permanent dentitions, but primarily the permanent dentition (Zeidler et al, 2000).…”

Genistein Protects Hematopoietic Stem Cells against G-CSF–Induced DNA Damage

“…Several lines of evidence lend support to this hypothesis. First, acquisition of hyperproliferative mutations of the G-CSFR increases the risk of leukemic transformation (14). Second, it has been demonstrated that HSCs preferentially use error-prone DNA repair pathways when entering cell cycle, and chromosomal deletions are often seen not only in patients with SCN and AML, but also in patients with aplastic anemia treated with G-CSF (7,9,14,15).…”