Neutropenia, Severe Congenital, 5, Autosomal Recessive

A number sign (#) is used with this entry because severe congenital neutropenia-5 (SCN5) is caused by homozygous mutation in the VPS45 gene (610035) on chromosome 1q.

Description

Severe congenital neutropenia-5 is an autosomal recessive primary immunodeficiency disorder characterized primarily by neutropenia and neutrophil dysfunction, a lack of response to G-CSF, life-threatening infections, bone marrow fibrosis, and renal extramedullary hematopoiesis (summary by Vilboux et al., 2013).

For a general phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (202700).

Clinical Features

Vilboux et al. (2013) reported 5 consanguineous families, 4 of Palestinian and 1 of Moroccan origin, in which 7 children had severe congenital neutropenia. All the children presented in infancy with poor weight gain, hepatomegaly, splenomegaly, and severe infections or deep-seated abscesses associated with neutropenia. Other features included poor response to G-CSF, hypergammaglobulinemia, nephromegaly due to extramedullary hematopoiesis, and nucleated red cells in the peripheral blood, suggesting bone marrow damage or stress. Two affected children underwent hematopoietic stem cell transplantation (HSCT) from matched related donors; both died of infection after failed engraftment. A third child died of infection before HSCT could be performed, and the other 2 children were awaiting the procedure. In the Moroccan family, the 2 affected children also had neurologic abnormalities manifest as delayed development, cortical blindness, hearing loss, and thin corpus callosum; both children died of infections before transplantation could be performed. Bone marrow biopsy showed distortion of hematopoietic tissue and prominent fibrosis. There were increased numbers of abnormally hypolobulated neutrophils and numerous apoptotic nuclei. Peripheral blood neutrophils showed few granules and abundant mitochondria, suggesting abnormal myeloid differentiation.

Stepensky et al. (2013) reported 3 patients from 2 unrelated consanguineous Palestinian families with severe congenital neutropenia and myelofibrosis. Two deceased sibs with a similar disorder were also described. The patients presented between 1 and 7 months of age with recurrent bacterial infections, predominantly pneumonia and soft tissue infections. Laboratory studies showed profound neutropenia, progressive anemia, and later development of thrombocytopenia. Peripheral blood smear showed anisocytosis and poikilocytosis, neutropenia, and thrombocytopenia with few giant platelets. Bone marrow biopsy showed myeloid hyperplasia and fibrosis. Other features included nephromegaly, splenomegaly, and osteosclerosis. Two patients died at age 3 months and 3 years, respectively. One patient underwent successful bone marrow transplant, but was later diagnosed with a pervasive developmental disorder; none of the other patients had neurologic disorders. Two other patients were listed for transplant.

Inheritance

The transmission pattern of SCN5 in the families reported by Vilboux et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected children from 4 consanguineous Palestinian families with severe congenital neutropenia-5, Vilboux et al. (2013) identified a homozygous mutation in the VPS45 gene (T224N; 610035.0001). The mutation, which was found by homozygosity mapping and whole-exome sequencing, segregated with the disorder in the families and was not found in several exome databases or in 250 ethnically matched controls. Affected Moroccan sibs with the disorder had a different homozygous mutation (E238K; 610035.0002). Study of 1 patient's cells showed normal mRNA levels, but decreased amounts of VPS45 protein with altered intracellular localization. Patient neutrophils showed impaired neutrophil chemotaxis, impaired superoxide production, impaired migration, decreased beta-1 integrin (ITGB1; 135630) expression, and decreased levels of the VPS45-interacting proteins rabenosyn-5 (ZFYVE20; 609511) and syntaxin-16 (STX16; 603666). Mutant fibroblasts and bone marrow cells also showed increased apoptosis compared to controls. Many of these defects were corrected by transfection of wildtype VPS45. A zebrafish model of Vps45 deficiency showed a marked paucity of neutrophils.

Stepensky et al. (2013) identified a homozygous T224N mutation in the VPS45 gene in 3 patients from 2 consanguineous Palestinian families with SCN5. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. It segregated with the disorder in the family and was not found in 120 Palestinian control individuals or in the Exome Variant Server. Analysis of the mutation in the yeast ortholog showed that it caused a decrease in cellular levels of the protein (about 50% compared to control), suggesting that it destabilizes the protein and abrogates its function in the endosomal pathway. Patient cells showed severely decreased levels of mutant VPS45 protein, decreased numbers of lysosomes, and decreased alpha-granules in platelets. Patient neutrophils and bone marrow myeloid cells showed accelerated apoptosis.