Congenital Neutropenia Patient With Hypomorphic Biallelic CSF3R Mutation Responding to GCSF

Abstract

Congenital neutropenia (CN) is a rare disorder, and the most common gene responsible for CN is ELANE. Furthermore, the mutations of HAX1, G6PC3, and JAGN1 genes may cause CN. These patients generally find great benefit from subcutaneous administration of Granulocyte Colony Stimulating Factor (GCSF). In recent years, Biallelic Colony Stimulating Factor 3 Receptor (CSF3R) mutations have been described as an underlying defect of CN in several children. In contrast to the previous group, the patients who have a CSF3R mutation do not respond to GCSF treatment. Here, we present a CN patient with hypomorphic biallelic CSF3R mutation responding to GCSF.

Homozygous c.130–131 ins A (pW44X) mutation in the HAX1 gene as the most common cause of congenital neutropenia in Turkey: Report from the Turkish Severe Congenital Neutropenia Registry

“…Although GM‐CSF treatment is not generally effective in patients with SCN, it has been reported to be beneficial in patients with biallelic CSF3R mutations, and, accordingly, one of our patients responded very well to GM‐CSF treatment . Another patient in our cohort with hypomorphic biallelic CSF3R mutation responded well to G‐CSF …”

“…One patient with a biallelic CSF3R mutation responded well to G‐CSF, which has not been previously reported in children with this mutation, and accordingly, the other patients with this biallelic CSF3R mutation did not respond to G‐CSF treatment . However, one of these children was treated with granulocyte macrophage colony‐stimulating factor (GM‐CSF), which increased her ANC to above 1000/mm 3 .…”

Loss‐of‐function mutations in CSF3R cause moderate neutropenia with fully mature neutrophils: two novel pedigrees

“…2 To date, 8 families with 11 (inherited) loss-of-function mutations in CSF3R in 10 patients have been reported (Table SI). [3][4][5][6][7][8][9][10] These patients suffer from congenital neutropenia and cannot be treated with G-CSF due to refractoriness. The consequence of G-CSF-R deficiency for cellular differentiation, effector functions and signal transduction in human primary neutrophils have not been studied in detail.…”

A congenital CSF3R mutation in chronic neutropenia reveals a vital role for a cytokine receptor extracellular hinge motif in the response to granulocyte colony‐stimulating factor

“…Not only does this report add to the accumulating number of documented CN patients with CSF3R mutations, 10–19 it also proves that an isolated homozygous‐CSF3R hinge motif mutation is detrimental for CSF3 responses, yet leaves baseline terminal granulopoiesis unscathed.…”

“…[6][7][8][9] Rare cases of CN with germline mutations in CSF3R have been described previously. [10][11][12][13][14][15][16][17][18][19] These mutations usually affect the extracellular domain of the receptor, unlike somatic CSF3R mutations arising in hematopoietic clones after prolonged CSF3 treatment, which usually affect the intracellular domain.…”