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    Severe Congenital Neutropenia

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    Submitted by: Nora Tang
    (This entry belongs to Entry Collection "MedlinePlus ")

    Definition

    Severe congenital neutropenia is a condition that causes affected individuals to be prone to recurrent infections.

    1. Introduction

    People with this condition have a shortage (deficiency) of neutrophils, a type of white blood cell that plays a role in inflammation and in fighting infection. The deficiency of neutrophils, called neutropenia, is apparent at birth or soon afterward. It leads to recurrent infections beginning in infancy, including infections of the sinuses, lungs, and liver. Affected individuals can also develop fevers and inflammation of the gums (gingivitis) and skin. Approximately 40 percent of affected people have decreased bone density (osteopenia) and may develop osteoporosis, a condition that makes bones progressively more brittle and prone to fracture. In people with severe congenital neutropenia, these bone disorders can begin at any time from infancy through adulthood.

    Approximately 20 percent of people with severe congenital neutropenia develop certain cancerous conditions of the blood, particularly myelodysplastic syndrome or leukemia during adolescence.

    Some people with severe congenital neutropenia have additional health problems such as seizures, developmental delay, or heart and genital abnormalities.

    2. Frequency

    The incidence of severe congenital neutropenia is estimated to be 1 in 200,000 individuals.

    3. Causes

    Severe congenital neutropenia can result from mutations in one of many different genes. These genes play a role in the maturation and function of neutrophils, which are cells produced by the bone marrow. Neutrophils secrete immune molecules and ingest and break down foreign invaders.

    Gene mutations that cause severe congenital neutropenia lead to the production of neutrophils that die off quickly or do not function properly. Some gene mutations result in unstable proteins that build up in neutrophils, leading to cell death. Other gene mutations result in proteins that impair the maturation or function of neutrophils, preventing these cells from responding appropriately to immune signals.

    About half of all cases of severe congenital neutropenia are caused by mutations in the ELANE gene. Another 10 percent are caused by mutations in the HAX1 gene. The other genes each account for only a small percentage of all cases of this condition. In about one-third of people with severe congenital neutropenia, the cause of the disorder is unknown.

    4. Inheritance

    Most cases of severe congenital neutropenia are classified as sporadic and occur in people with no apparent history of the disorder in their family. Some of these cases are associated with changes in specific genes; however in some cases the cause of the disorder is unknown.

    When severe congenital neutropenia is caused by mutations in the ELANE gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Mutations in a few other genes that cause this condition are also inherited in an autosomal dominant pattern.

    When severe congenital neutropenia is caused by mutations in the HAX1 gene, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Many cases of this condition are caused by genetic mutations that are inherited in an autosomal recessive pattern.

    In rare cases, severe congenital neutropenia is inherited in an X-linked recessive pattern. In these cases, the gene that causes the condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

    5. Other Names for This Condition

    • congenital agranulocytosis

    • congenital neutropenia

    • infantile genetic agranulocytosis

    • Kostmann disease

    • Kostmann's agranulocytosis

    • Kostmann's syndrome

    • severe infantile genetic neutropenia

    The entry is from https://medlineplus.gov/genetics/condition/severe-congenital-neutropenia

    References

    1. Berliner N. Lessons from congenital neutropenia: 50 years of progress inunderstanding myelopoiesis. Blood. 2008 Jun 15;111(12):5427-32. doi:10.1182/blood-2007-10-077396. Review.
    2. Dale DC, Makaryan V. ELANE-Related Neutropenia. 2002 Jun 17 [updated 2018 Aug 23]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K,Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University ofWashington, Seattle; 1993-2020. Available fromhttp://www.ncbi.nlm.nih.gov/books/NBK1533/
    3. Fioredda F, Iacobelli S, van Biezen A, Gaspar B, Ancliff P, Donadieu J, AljurfM, Peters C, Calvillo M, Matthes-Martin S, Morreale G, van 't Veer-Tazelaar N, deWreede L, Al Seraihy A, Yesilipek A, Fischer A, Bierings M, Ozturk G, Smith O,Veys P, Ljungman P, Peffault de Latour R, Sánchez de Toledo Codina J, Or R,Ganser A, Afanasyev B, Wynn R, Kalwak K, Marsh J, Dufour C; Severe AplasticAnemia the Inborn Error, and the Pediatric Disease Working Parties of theEuropean Society for Blood and Bone Marrow Transplantation (EBMT) and Stem CellTransplant for Immunodeficiencies in Europe (SCETIDE). Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Bloodand Marrow Transplantation. Blood. 2015 Oct 15;126(16):1885-92; quiz 1970. doi:10.1182/blood-2015-02-628859.
    4. Makaryan V, Zeidler C, Bolyard AA, Skokowa J, Rodger E, Kelley ML, Boxer LA,Bonilla MA, Newburger PE, Shimamura A, Zhu B, Rosenberg PS, Link DC, Welte K,Dale DC. The diversity of mutations and clinical outcomes for ELANE-associatedneutropenia. Curr Opin Hematol. 2015 Jan;22(1):3-11. doi:10.1097/MOH.0000000000000105. Review.
    5. Rosenberg PS, Alter BP, Link DC, Stein S, Rodger E, Bolyard AA, Aprikyan AA,Bonilla MA, Dror Y, Kannourakis G, Newburger PE, Boxer LA, Dale DC. Neutrophilelastase mutations and risk of leukaemia in severe congenital neutropenia. Br JHaematol. 2008 Jan;140(2):210-3.
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    7. Schäffer AA, Klein C. Genetic heterogeneity in severe congenital neutropenia: how many aberrant pathways can kill a neutrophil? Curr Opin Allergy Clin Immunol.2007 Dec;7(6):481-94. Review.
    8. Shu Z, Li XH, Bai XM, Zhang ZY, Jiang LP, Tang XM, Zhao XD. Clinicalcharacteristics of severe congenital neutropenia caused by novel ELANE genemutations. Pediatr Infect Dis J. 2015 Feb;34(2):203-7. doi:10.1097/INF.0000000000000522.
    9. Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K. Severe congenitalneutropenias. Nat Rev Dis Primers. 2017 Jun 8;3:17032. doi: 10.1038/nrdp.2017.32.Review.
    10. Xia J, Bolyard AA, Rodger E, Stein S, Aprikyan AA, Dale DC, Link DC.Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patientswith severe congenital neutropenia. Br J Haematol. 2009 Nov;147(4):535-42. doi:10.1111/j.1365-2141.2009.07888.x.
    11. Zeidler C, Germeshausen M, Klein C, Welte K. Clinical implications of ELA2-,HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. Br J Haematol. 2009 Feb;144(4):459-67. doi: 10.1111/j.1365-2141.2008.07425.x.
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