The biological basis for the substantial difference in risk of leukemic evolution for CyN (Cyclic neutropenia) versus SCN (Neutropenia, severe congenital, 1) is not known (PMID:25427142). The typical morphological finding is
a myeloid maturation arrest at the promyelocyte/myelocyte stage seen in conventional bone marrow smears. Heterozygous ELANE mutations are present in 80–100% of individuals with CyN and in 35–63% of SCN cases (PMID:21425445).
Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections ... Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections (Skokowa et al., 2007). About 60% of affected individuals of European and Middle Eastern ancestry have dominant ELANE mutations, resulting in a form of severe congenital neutropenia, which is designated here as SCN1. - Genetic Heterogeneity of Severe Congenital Neutropenia Severe congenital neutropenia is a genetically heterogeneous disorder showing autosomal dominant, autosomal recessive, and X-linked inheritance. Autosomal dominant SCN2 (613107) is caused by mutation in the protooncogene GFI1 (600871) on chromosome 1p22. Autosomal recessive SCN3 (610738) is caused by mutation in the HAX1 gene (605998) on 1q21.3; autosomal recessive SCN4 (612541) is caused by mutation in the G6PC3 gene (611045) on 17q21; and autosomal recessive SCN5 (615285) is caused by mutation in the VPS45 gene (610035) on chromosome 1q. X-linked SCN (SCNX; 300299) is caused by mutation in the WAS gene (300392) on Xp11. See also adult chronic idiopathic nonimmune neutropenia (607847) and chronic benign familial neutropenia (162700). - Susceptibility to Myelodysplastic Syndrome/Acute Myeloid Leukemia SCN patients with acquired mutations in the granulocyte colony-stimulating factor receptor (CSF3R; 138971) in hematopoietic cells define a group with high risk for progression to myelodysplastic syndrome and/or acute myeloid leukemia.
Gilman et al. (1970) described prolonged survival and death from acute monocytic leukemia at age 14 years and 10 months. About three-fourths of patients die before age 3 years. Fungal and viral infections had not been a problem. ... Gilman et al. (1970) described prolonged survival and death from acute monocytic leukemia at age 14 years and 10 months. About three-fourths of patients die before age 3 years. Fungal and viral infections had not been a problem. Freedman et al. (2000) stated that the Severe Chronic Neutropenia International Registry (SCNIR) in Seattle had data on 696 neutropenic patients, including 352 patients with congenital neutropenia, treated with GCSF from 1987 to 2000. The 352 congenital patients were observed for a mean of 6 years (range, 0.1 to 11 years) while being treated. Of these patients, 31 developed myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), for a crude rate of malignant transformation of nearly 9%. None of the 344 patients with idiopathic or cyclic neutropenia developed MDS/AML. Transformation was associated with acquired marrow cytogenetic clonal changes: 18 patients developed a partial or complete loss of chromosome 7, and 9 patients manifested abnormalities of chromosome 21 (usually trisomy 21; 190685). For each yearly treatment interval, the annual rate of MDS/AML development was less than 2%. Freedman et al. (2000) concluded that although the data did not support a cause-and-effect relationship between development of MDS/AML and GCSF therapy or other patient demographics, they could not exclude a direct contribution of GCSF in the pathogenesis of MDS/AML. Improved survival of congenital neutropenia patients receiving GCSF therapy may allow time for expression of the leukemic predisposition that characterizes the natural history of these disorders. In a review of immunodeficiencies caused by defects in phagocytes, Lekstrom-Himes and Gallin (2000) discussed severe congenital neutropenia.
After demonstrating mutations in the ELA2 gene (ELANE; 130130) in patients with cyclic neutropenia (162800), Dale et al. (2000) hypothesized that congenital neutropenia is also due to mutation in this gene. They performed mutation analysis by sequencing PCR-amplified ... After demonstrating mutations in the ELA2 gene (ELANE; 130130) in patients with cyclic neutropenia (162800), Dale et al. (2000) hypothesized that congenital neutropenia is also due to mutation in this gene. They performed mutation analysis by sequencing PCR-amplified genomic DNA for each of the 5 exons of the ELA2 gene and 20 bases of the flanking regions. In 22 of 25 patients with congenital neutropenia, 18 different heterozygous mutations were found. All 4 patients with cyclic neutropenia, but none of the 3 patients with Shwachman-Diamond syndrome (260400), had mutations of ELA2. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. In the congenital neutropenia patients, 5 different mutations were found in families with 2 or more affected members. Three instances of father-daughter pairs, 1 mother-son pair, and 1 mother with 2 affected sons by different fathers suggested autosomal dominant inheritance. Ishikawa et al. (2008) identified heterozygous mutations in the ELA2 gene in 11 (61%) of 18 Japanese patients with severe congenital neutropenia. Five (28%) patients had SCN3 (610738) due to mutation in the HAX1 gene. Among 109 probands with SCN, Smith et al. (2008) found that 33 (30%) had 24 different ELA2 mutations, 2 (2%) had WAS (300392) mutations, and 4 (4%) had HAX1 mutations. - Progression to Myelodysplastic Syndrome and Acute Myeloid Leukemia Dong et al. (1994) used RT-PCR to amplify cDNA for granulocyte colony-stimulating factor receptor (CSF3R; 138971) in patients with severe congenital neutropenia, referred to as Kostmann syndrome, and screened for mutations by single-strand conformation polymorphism (SSCP) analysis. In 1 patient, they identified a somatic point mutation that resulted in the cytoplasmic truncation of the GCSF receptor protein. The mutation was present predominantly in the granulocytic lineage. Further functional characterization demonstrated that the truncated receptor was unable to transduce a maturation signal. Dong et al. (1994) suggested that the mutant receptor chain may act in a dominant-negative manner to block granulocyte maturation. Dong et al. (1994) commented that congenital neutropenia may be a heterogeneous group of disorders with different basic etiologies. They also commented that cases of this disorder that terminated in acute leukemia had been reported (Gilman et al., 1970; Lui et al., 1978; Rosen and Kang, 1979) and that some patients with the disorder developed leukemia or myelodysplastic syndrome following treatment with GCSF. Dong et al. (1995) described mutations in the GCSFR gene in hematopoietic cells from 2 patients with acute myeloid leukemia and histories of severe congenital neutropenia. Like the mutation in the patient reported by Dong et al. (1994), the mutations truncated the C-terminal cytoplasmic region of the GCSF receptor. The mutation in one of the patients was already present in the neutropenic phase that preceded the development of acute myeloid leukemia. SCN patients are at increased risk of developing acute myelogenous leukemia (AML) or myelodysplasia (MDS). In the series of Welte and Dale (1996), 10% of the patients with SCN followed for 5 or more years developed AML or MDS. Patients with GCSFR mutations appeared to be at the greatest risk; Welte and Touw (1997) found that 8 of 16 patients with SCN and GCSFR mutations developed AML or MDS. Conversely, no patients with SCN and without a mutation of the CSF3R gene had been reported who developed AML or MDS. This striking association led to speculation that CSF3R mutations may contribute to leukemogenesis in these patients. Tidow et al. (1997) concluded that GCSFR mutations are acquired abnormalities detected in the process of evolution to acute myelocytic leukemia (AML). Dale et al. (2000) stated that prevalence data suggested that a minority of patients manifest this mutation, and it seemed much more likely that mutations of the ELA2 gene lead to compromised myeloid differentiation and create the risk for development of AML. Among 82 patients with SCN, Rosenberg et al. (2007) found no difference in the risk of MDS/AML in patients with mutant ELA2 (63%) compared to those with wildtype ELA2 (37%). The cumulative incidences at 15 years were 36% and 25%, respectively. Two of 4 patients with the G185R mutation (130130.0011) developed MDS/AML by 15 years follow-up, whereas none of 7 patients with the P110L (130130.0006) mutation or 5 patients with the S97L (130130.0008) mutation had developed MDS/AML.