Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history

Abstract

This review focuses on the classification, diagnosis and natural history of congenital neutropenia (CN). CN encompasses a number of genetic disorders with chronic neutropenia and, for some, affecting other organ systems, such as the pancreas, central nervous system, heart, bone and skin. To date, 24 distinct genes have been associated with CN. The number of genes involved makes gene screening difficult. This can be solved by next-generation sequencing (NGS) of targeted gene panels. One of the major complications of CN is spontaneous leukaemia, which is preceded by clonal somatic evolution, and can be screened by a targeted NGS panel focused on somatic events.

HSCT may lower leukemia risk in ELANE neutropenia: a before–after study from the French Severe Congenital Neutropenia Registry

“…The patients included in this study were all entered in the French Severe Chronic Neutropenia Registry (FSCNR). First created in 1993, with prospective enrollment of all CN types [1], the FSCNR was certified as a national registry by health authorities in 2008, and its case completeness was ascertained by verification through multiple sources. The database was approved by the French computer watchdog commission (CNIL certificate no.…”

“…Congenital neutropenia (CN) is a group of rare and inherited hematological disorders characterized by chronic profound neutropenia caused by impaired differentiation of neutrophilic granulocytes. Often diagnosed early in life, CN is defined as recurrent, life-threatening bacterial infections (e.g., skin infections, otitis, gingivitis, abscesses and sepsis) [1]. The elastase, neutrophilexpressed (ELANE) gene encodes neutrophil elastase, and is responsible for ELANE neutropenia, which is probably the most frequent and one of the most severe CN forms, based on its infection rate [2].…”

A rare form of congenital neutropenia: VPS45 deficiency

“…Furthermore, SCN may complicate as myelodysplastic syndrome (MDS) and acute myeloblastic leukaemia (AML). [1][2][3][4] Most common gene defects associated with congenital neutropenia are the neutrophil elastase (ELANE), growth factor independent 1 transcription repressor (GFI1), haematopoietic cell-specific LYN substrate 1 (HCLS1)-associated protein X-1 (HAX1) and glucose 6 phosphatase catalytic subunit 3 (G6PC3) deficiency. 5 In Chediak-Higashi syndrome, Hermansky-Pudlak syndrome type 2, Griscelli syndrome type 2 and LAMTOR2 deficiency, neutropenia together with hypopigmentation may be seen in the course of the disease, especially during haemophagocytosis.…”

“…Sometimes neutropenia accompanies with combined immunodeficiency disorders, such as CD40LG deficiency, serine/threonine kinase 4 (STK) 4 deficiency and adenosine deaminase deficiency. [1][2][3][4] Vacuolar sorting protein (VPS) 45 gene deficiency, which was described in 2013, is an autosomal recessive SCN leading to progressive fibrosis in bone marrow. 6,7 Vps45 is a peripheral membrane protein which controls membrane signal trafficking through the endosomal system.…”

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 …”