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Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes w...

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. Other autosomal dominant forms are SCN2 (613107), caused by mutation in the protooncogene GFI1 (600871) on 1p22; and SCN8 (618752), caused by mutation in the SRP54 gene (604857) on 14q13.

Autosomal recessive forms include SCN3 (610738), caused by mutation in the HAX1 gene (605998) on 1q21; SCN4 (612541), caused by mutation in the G6PC3 gene (611045) on 17q21; SCN5 (615285), caused by mutation in the VPS45 gene (610035) on 1q21; SCN6 (616022), caused by mutation in the JAGN1 gene (616012) on 3p25; and SCN7 (617014), caused by mutation in the CSF3R gene (138971) on 1p34.

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. Approximately 80% of SCN patients who develop AML are heterozygous for somatic CSF3R mutations (summary by Klimiankou et al., 2016).

▼ Clinical Features
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.

▼ Clinical Management
Bonilla et al. (1989) administered recombinant human granulocyte colony-stimulating factor (GCSF; 138970) to 5 patients. All 5 patients showed a response and had sustained neutrophil counts of 1,000 cells per microliter or more for 9 to 13 months while receiving subcutaneous maintenance therapy. Preexisting chronic infections resolved and the number of new infectious episodes decreased. Bonilla et al. (1989) raised the possibility that the receptors are defective and do not respond to GCSF unless it is administered in pharmacologic doses. This possibility appeared to be confirmed by the findings of Dong et al. (1994) of somatic mutation in the GCSFR gene (138971).

In SCN, absolute neutrophil counts are usually less than 200 cells per cubic millimeter, with a remainder of the blood counts relatively normal (Dale et al., 2000). Treatment with GCSF leads to an increase in neutrophil counts to more than 1,000 cells per cubic millimeter in 90% of patients and results in significant improvements in survival and quality of life (Dale et al., 1993; Bonilla et al., 1994).

Yakisan et al. (1997) noted that although r-metHuGCSF treatment of children with severe congenital neutropenia has substantially improved the patients' quality of life and life expectancy, bone pain and unusual fractures have been reported in treated patients. The authors reviewed roentgenograms in 29 of 30 patients to evaluate bone loss before and during treatment and assessed bone mineral status in 17 of the 30 patients. Their data indicated a high incidence of bone mineral loss in children with severe congenital neutropenia. The investigators concluded that it is more likely that the bone loss was caused by the pathophysiologic features of the underlying disease; however, they could not rule out the possibility that r-metHuGCSF accelerates bone mineral loss.

▼ Biochemical Features
Myeloid precursor cells from patients with severe congenital neutropenia (SCN) require pharmacologic dosages of recombinant human granulocyte colony-stimulating factor (GCSF) to differentiate normal neutrophils. Because JAK2 (147796), a nonreceptor tyrosine kinase, is involved in the signaling pathway of GCSF, Rauprich et al. (1995) studied the expression and activity of JAK2 in neutrophils from SCN patients during therapy. The immunoprecipitated JAK2 protein showed increased tyrosine phosphorylation in neutrophils from SCN patients as compared with that in neutrophils from healthy controls. Rauprich et al. (1995) pointed out that only a few patients, who subsequently develop acute myeloid leukemia, have a point mutation in the cytoplasmic region of the GCSF receptor, resulting in a truncation from the C terminus of the receptor and an inability of the receptor to transduce the signal on GCSF stimulation. Thus they suspected that various defects are responsible for SCN. That pharmacologic doses of GCSF are required to overcome the neutropenia suggested a defect of other specific molecules in the GCSF signal transduction pathway. The primary defect does not appear to be in JAK2; it may be that the phosphotyrosines on the receptor create binding sites for STAT proteins (signal transducers and activators of transcription; see 600555).

Skokowa et al. (2006) found significantly decreased or absent LEF1 (153245) expression in arrested promyelocytes from patients with congenital neutropenia. LEF1 decrease resulted in defective expression of downstream target genes, including CCND1 (168461), MYC (190080), and BIRC5 (603352). Promyelocytes from healthy individuals showed highest LEF1 expression. Reconstitution of LEF1 in early hematopoietic progenitors from 2 individuals with congenital neutropenia resulted in the differentiation of these progenitors into mature granulocytes. LEF1 directly bound to and regulated the transcription factor CEBPA (116897). The findings indicated that LEF1 plays a role in granulopoiesis.

▼ Molecular Genetics
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.

Associations Pending Confirmation

For discussion of a possible association between autosomal dominant severe congenital neutropenia and variation in the TCIRG1 gene, see 604592.0008.

▼ Animal Model
To test the hypothesis that CSF3R mutations may contribute to leukemogenesis in SCN patients, McLemore et al. (1998) generated mice carrying a targeted, 'knock-in' mutation of their Csf3r gene that reproduced the mutation found in a patient with SCN and AML. A point mutation (C to T at nucleotide 2403) was introduced into exon 17 of the Csf3r gene, using homologous recombination in embryonic stem cells. The mutation generated a premature stop codon that led to truncation of the C-terminal 96 amino acids and reproduced the mutation found in a patient with SCN by Dong et al. (1995). The mutant allele was expressed in a myeloid-specific fashion at levels comparable to the wildtype allele. Mice heterozygous or homozygous for this mutation had normal levels of circulating neutrophils and no evidence for a block in myeloid maturation, indicating that resting granulopoiesis was normal. However, in response to GCSF treatment, these mice demonstrated a significantly greater increase in the level of circulating neutrophils. This effect appeared to be due to increased neutrophil production as the absolute number of GCSF-responsive progenitors in the bone marrow and their proliferation in response to GCSF was increased. Furthermore, the in vitro survival and GCSF-dependent suppression of apoptosis of mutant neutrophils were normal. Despite this evidence for a hyperproliferative response to GCSF, no cases of AML were detected. These data demonstrated that the GCSFR mutation found in patients with SCN is not sufficient to induce either an SCN phenotype or AML in mice. McLemore et al. (1998) suggested that the results represent strong evidence that these mutations are not responsible for the impaired granulopoiesis present in patients with SCN. In fact, the results of the study suggested that expression of the mutant GCSFR on myeloid progenitors may render them hyperresponsive to GCSF. Whether this altered GCSF-responsiveness contributes to the development of AML and/or MDS in patients with SCN will require further study.

At about the same time as the report by McLemore et al. (1998), Hermans et al. (1998) reported that mice either heterozygous or homozygous for a mutation in the Csf3r gene had no normal resting granulopoiesis and had reduced numbers of neutrophils in their blood, indicating a block in maturation due to the truncation of the GCSF receptor. Hermans (1998) suggested that the increased expression of truncated GCSF receptor in the model of McLemore et al. (1998) may have compensated for the mutation and explained the absence of neutropenia.

▼ History
Hedenberg (1959) found that addition of sulfur-containing amino acids to tissue cultures led to maturation of white cells. L'Esperance et al. (1973) showed that the disease could be reproduced in tissue culture. Barak et al. (1971) also cultured marrow cells from a patient with this disease.

L'Esperance et al. (1975) proposed heterogeneity of this disorder because in soft agar cultures of bone marrow one patient showed 'loose' colonies developing only to promyelocytes, whereas a second produced normal neutrophil colonies. Maturation arrest occurs at the promyelocyte stage.

Hansen et al. (1977) found association with HLA-B12 (see 142830) and postulated linkage disequilibrium. A gene controlling neutrophil differentiation was presumably closely linked to the HLA complex. Hansen et al. (1977) suggested that the relationship may reflect a basic function of the histocompatibility system, namely, coding for cell-surface determinants fundamental to cell-cell recognition and to control of cellular differentiation.

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