New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing

Abstract

Neutrophils are the most common type of leukocyte in human circulating blood and constitute one of the chief mediators for innate immunity. Defined as a reduction from a normal distribution of values, neutropenia results from a number of congenital and acquired conditions. Neutropenia may be insignificant, temporary, or associated with a chronic condition with or without a vulnerability to life-threatening infections. As an inherited bone marrow failure syndrome, neutropenia may be associated with transformation to myeloid malignancy. Recognition of an inherited bone marrow failure syndrome may be delayed into adulthood. The list of monogenic neutropenia disorders is growing, heterogeneous, and bewildering. Furthermore, greater knowledge of immune-mediated and drug-related causes makes the diagnosis and management of neutropenia challenging. Recognition of syndromic presentations and especially the introduction of next-generation sequencing are improving the accuracy and expediency of diagnosis as well as their clinical management. Furthermore, identification of monogenic neutropenia disorders is shedding light on the molecular mechanisms of granulopoiesis and myeloid malignancies.

Functional compensation between hematopoietic stem cell clones in vivo

“…Many hematopoietic diseases arise from either an abnormal abundance (e.g., myeloproliferative disorder, thrombocytosis, leukocytosis, and erythrocytosis) or an abnormal deficiency (e.g., myelodysplastic syndrome, neutropenia, agranulocytosis, and thrombocytopenia) of certain blood cell types [3][4][5]. Many hematopoietic diseases arise from either an abnormal abundance (e.g., myeloproliferative disorder, thrombocytosis, leukocytosis, and erythrocytosis) or an abnormal deficiency (e.g., myelodysplastic syndrome, neutropenia, agranulocytosis, and thrombocytopenia) of certain blood cell types [3][4][5].…”

“…It is critically important to understand how the functional deficiencies of a subset of HSCs impact the overall HSC network. Many hematopoietic diseases arise from either an abnormal abundance (e.g., myeloproliferative disorder, thrombocytosis, leukocytosis, and erythrocytosis) or an abnormal deficiency (e.g., myelodysplastic syndrome, neutropenia, agranulocytosis, and thrombocytopenia) of certain blood cell types [3][4][5]. The initial stages of these diseases may involve a latent period during which a patient's healthy HSCs can sufficiently compensate for the deficiencies of diseased cells to ameliorate disease symptoms.…”

Neutropenia congénita de tipo IV: reporte de un caso

“…4,6 En la Tabla 2 se detalla la clasificación de las neutropenias congénitas monogénicas y sus características clínicas. 6,7 En el 2009, Dursum y cols., describieron por primera vez, en dos hermanos de Turquía, la asociación de neutropenia grave intermitente con un síndrome caracterizado por hipertensión pulmonar, comunicación auricular de tipo ostium secundum y cambios displásicos con un patrón de herencia autosómico recesivo. 8 Por su parte, Boztug, Banka y cols., describieron un subgrupo de pacientes con NCG con mutaciones bialélicas en el gen de G6PC3, que codifica la subunidad catalítica 3 de la glucosa 6 fosfatasa.…”

Neutropenia in the age of genetic testing: Advances and challenges

“…This review focuses on practical considerations for germline genetic testing of neutropenia, including which patients to test, which tests to send, and interpretation of results. The reader is referred to other excellent recent publications for a comprehensive review of genetic neutropenia disorders or a review of the clinical evaluation and management of neutropenia disorders …”