Clinical Information

Inherited congenital neutropenia refers to a subset of primary immunodeficiencies impacting neutrophil maturation and function. The severity of the clinical manifestations in these disorders typically reflects the degree of neutropenia. Most cases of neutropenia are due to acquired (non-genetic) causes. Severe congenital neutropenia (SCN) is characterized by chronically low neutrophil count and recurrent, often life-threatening infections beginning in the first few months of life. Some individuals with SCN may also have an increased risk for myelodysplastic syndrome or acute myelogenous leukemia.(1-3) Cyclic neutropenia (CN) is characterized by periods of severe neutropenia and infections that last 3 to 5 days and recur at regular intervals.(1-5) Individuals with SCN or CN may also exhibit recurrent fevers, sinusitis, gingivitis, cellulitis, oral ulcers, colonic ulcers, and other manifestations of chronic infections.(1-5) Bone marrow biopsy on affected individuals may show arrest in myelopoiesis at the promyelocyte/myelocyte stage.(1-3)

The prevalence of inherited severe congenital neutropenia and cyclic neutropenia is estimated to range from 1:500,000 to 1:100,000 live births.(1-5) The genetic etiology of inherited congenital neutropenia is most commonly due to disease-causing variants in genes that play a role in neutrophil differentiation.(1) Inheritance can be autosomal recessive, autosomal dominant, or X-linked.

The most common causes of isolated congenital neutropenia are disease-causing variants in the ELANE and HAX1 genes, which encode neutrophil elastase and HCLS1(hematopoietic cell-specific Lyn substrate)-associated protein X-1, respectively. Autosomal dominant ELANE-related neutropenia is the most common cause of congenital neutropenia in children and may present with oral/colonic ulcers, recurrent upper and lower respiratory infections, and various infections of the soft tissue.(2,4,6) In addition, most cases of cyclic neutropenia are due to disease-causing variants in ELANE. Autosomal recessive Kostmann disease, caused by variants in the HAX1 gene, is the second most common cause of congenital neutropenia in children and presents similarly to ELANE-related neutropenia.(2,4,6) X-linked WAS-related disorders lead to a spectrum of congenital neutropenia phenotypes including Wiskott-Aldrich syndrome and X-linked congenital neutropenia.(5,6) Isolated severe congenital neutropenia may more rarely be due to disease-causing variants in several additional genes including CSF3R, CXCR2, GFI1 and WIPF1.(1,6)

Severe neutropenia may also be present as part of a multisystem disorder.(1) This panel assesses for many conditions in which neutropenia is seen in conjunction with extra-hematologic features, including but not limited to:

-Shwachman-Diamond syndrome, an autosomal dominant condition due to disease-causing variants in the SBDS gene, is also characterized by exocrine pancreatic dysfunction, bone abnormalities, and hematologic abnormalities.

-GATA2-deficieny (monocytopenia and mycobacterial infection [MonoMAC] syndrome), an autosomal dominant condition due to disease-causing variants in the GATA2 gene, demonstrates a wide spectrum of clinical presentations ranging from mild chronic neutropenia with monocytopenia to Emberger syndrome and predisposition to acute myeloid malignancy.

-Barth syndrome, an X-linked condition due to disease-causing variants in the TAZ gene, is also characterized cardiomyopathy, skeletal myopathy, growth delay, and distinctive facial features.

-Cohen syndrome, an autosomal recessive condition due to disease-causing variants in the VSP13B gene, is also characterized by hypotonia, developmental delays, microcephaly, failure to thrive in infancy, truncal obesity, ophthalmologic findings, joint hypermobility, a cheerful disposition, and characteristic facial features.

-WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, an autosomal dominant condition caused by variants in the CXCR4 gene, is also characterized by hypogammaglobulinemia and susceptibility to human papillomavirus.