A number sign (#) is used with this entry because X-linked severe congenital neutropenia (SCNX) is caused by hemizygous mutation in the WAS gene (300392) on chromosome Xp11.

See also Wiskott-Aldrich syndrome (WAS; 301000), an allelic disorder.

For a discussion of genetic heterogeneity of severe congenital neutropenia, see 202700.

In a 3-generation family of European descent, Devriendt et al. (2001) described 5 males who presented with a novel X-linked immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia. Although X-linked inheritance and shifts in lymphocyte subsets were not known to be features of severe congenital neutropenia (202700), affected males in this pedigree had increased numbers of activated CD8+ T cells in the peripheral blood resulting in decreased CD4+/CD8+ ratios of 0.5 or less. Immunoglobulin levels and T-lymphocyte activation were normal. Platelets were not decreased, and there was no history of eczema in affected individuals. Bone marrow examination demonstrated a maturation arrest at the promyelocyte/myelocyte stage, without gross abnormalities in megakaryopoiesis or erythropoiesis.

In 2 patients with severe congenital neutropenia who were negative for mutation in the ELA2 gene (ELANE; 130130), Ancliff et al. (2006) identified mutations in the WAS gene (see MOLECULAR GENETICS). One patient presented in early infancy as a typical case of SCN, with severe neutropenia, maturation arrest at the promyelocyte stage in the bone marrow, and recurrent bacterial infections. His hemoglobin was low normal, and platelet numbers were usually within the normal range, although large-sized platelets were present. He had no bone marrow dysplasia. Immunologic analysis revealed low CD3(-)CD16/56(+) natural killer (NK) cell numbers and impaired lymphocyte proliferation responses to CD3 stimulation. The other patient was of Zairian parentage and presented at 4 years of age with fever of unknown origin, at which time he was found to have severe neutropenia with a normal hemoglobin level and platelet count, but with platelet anisocytosis including large platelets. Over 3 years, his lymphocyte numbers were intermittently reduced, but reversal of the normal CD4(+)/CD8(+) ratio, reduced CD3(-)CD16/56(+) NK cell numbers, and impaired lymphocyte proliferative responses to CD3 stimulation were invariably present. Subsequent bone marrow examination revealed trilineage dysplasia including bizarre megakaryocytic nuclear morphology with both abnormal giant megakaryocytes and micromegakaryocytes, hypogranular and markedly reduced granulopoiesis, and an excess of blasts, consistent with primary myelodysplasia. Ancliff et al. (2006) noted that later bone marrow examinations displayed a considerably less dysplastic morphology than that originally observed.

Beel et al. (2008) described a large 3-generation Irish kindred with X-linked severe congenital neutropenia, originally reported by Cryan et al. (1988), in which there were 10 affected males and 8 female carriers. Affected individuals showed considerable variation in infectious history, and the severity of neutropenia did not seem to correlate closely with susceptibility to infections. Five of the 10 affected males had monocytopenia. All had low or low-normal numbers of lymphocytes, with the most strikingly decreased subset being CD3(-)CD16/56(+) NK cells. Absolute B-lymphocyte counts were decreased in all 10 affected males. In contrast to previously studied SCNX patients, an inverted CD4/CD8 ratio was not a feature in this family. Platelet counts were low-normal or mildly reduced, with normal mean platelet volume. Female carriers showed intermediate findings, with low-normal neutrophil and platelet counts, and NK cell counts were higher than in affected males, but still below the normal range. The mean IgA level in affected adult males was significantly lower than in unaffected adult family members; Beel et al. (2008) stated that IgA levels were also decreased in 2 of the 3 patients studied by Devriendt et al. (2001), and suggested that low-normal IgA levels appear to be a feature of SCNX.

Devriendt et al. (2001) performed linkage studies with polymorphic markers spanning the entire X chromosome and markers spanning chromosome 19p13.3, the region containing the neutrophil elastase gene (ELANE; 130130), which is mutant in many cases of severe congenital neutropenia (202700). No evidence for linkage with 19p13.3 was found; evidence pointing to linkage to the proximal Xp region containing the Wiskott-Aldrich syndrome locus was found.

Mutation analysis of the WAS gene by Devriendt et al. (2001) revealed a missense mutation (L270P; 300392.0012) in all affected males and carrier females. Preferential inactivation of the X chromosome carrying the mutated WAS gene was found in some carriers, indicating that selection operates against the L270P allele in vivo. Noncarrier females had random X inactivation.

Ancliff et al. (2006) analyzed the WAS gene in 14 boys with severe congenital neutropenia who were negative for mutation in the ELA2 gene, 8 with classic SCN and 6 with evidence of myelodysplasia and/or immunologic abnormalities in addition to neutropenia, and identified 2 different mutations in 2 probands (S272P, 300392.0024; I294T, 300392.0025, respectively). Both patients had defects of immunologic function including a generalized reduction of lymphoid and NK cell numbers, reduced lymphocyte proliferation, and abrogated phagocyte activity. In vitro culture of bone marrow progenitors demonstrated a profound reduction in neutrophil production and increased levels of apoptosis, consistent with an intrinsic disturbance of normal myeloid differentiation as the cause of their neutropenia. Female carriers from both families showed nonrandom X inactivation.

Beel et al. (2008) analyzed the WAS gene in 60 members of a large Irish kindred segregating X-linked congenital neutropenia, originally reported by Cryan et al. (1988), and identified the I294T mutation in 10 affected males and 8 female carriers. Four of 6 female carriers showed random X-chromosome inactivation, and 2 female carriers showed no consistent pattern of asymmetric X-chromosome inactivation.

Devriendt et al. (2001) showed that the L270P mutation is located in the region of the WAS gene encoding the conserved GTPase binding domain. In vitro, the mutant protein was constitutively activated through disruption of an autoinhibitory domain in the wildtype protein, indicating that loss of WAS autoinhibition is a key event in X-linked severe congenital neutropenia.

Westerberg et al. (2010) created mice with mutations in the mouse Wasp gene corresponding to the human leu270-to-pro (L270P; 300392.0012) and ile294-to-thr (I294T; 300392.0025) mutations, which cause X-linked neutropenia. These mutations interfered with normal lymphocyte activation by inducing a marked increase in polymerized actin, decreased cell spreading, and increased apoptosis associated with increased genomic instability.