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Genetics Home Reference: your guide to understanding genetic conditions
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Severe congenital neutropenia

Reviewed April 2010

What is severe congenital neutropenia?

Severe congenital neutropenia is a condition that causes affected individuals to be prone to recurrent infections. 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 cancer of the blood-forming tissue (leukemia) or a disease of the blood and bone marrow (myelodysplastic syndrome) during adolescence.

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

How common is severe congenital neutropenia?

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

What genes are related to severe congenital neutropenia?

Severe congenital neutropenia can result from mutations in at least five 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 15 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.

Related Gene(s)

Changes in these genes are associated with severe congenital neutropenia.

  • ELANE
  • G6PC3
  • GFI1
  • HAX1
  • WAS

How do people inherit severe congenital neutropenia?

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.

Many cases of severe congenital neutropenia are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Less often, this condition 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.

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.

Where can I find information about diagnosis or management of severe congenital neutropenia?

These resources address the diagnosis or management of severe congenital neutropenia and may include treatment providers.

  • Cincinnati Children's Hospital: The Severe Congenital Neutropenia International Registry (http://www.cincinnatichildrens.org/service/c/clinical-trials/search-studies/adult/chronic-neutropenia)
  • Gene Review: ELANE-Related Neutropenia (http://www.ncbi.nlm.nih.gov/books/NBK1533)
  • Genetic Testing Registry: Severe congenital neutropenia (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1853118)
  • Genetic Testing Registry: Severe congenital neutropenia 2, autosomal dominant (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2751288)
  • Genetic Testing Registry: Severe congenital neutropenia 4, autosomal recessive (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2675526)
  • Genetic Testing Registry: Severe congenital neutropenia autosomal dominant (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1859966)
  • Genetic Testing Registry: Severe congenital neutropenia X-linked (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1845987)
  • MedlinePlus Encyclopedia: Neutropenia--infants (http://www.nlm.nih.gov/medlineplus/ency/article/007230.htm)

You might also find information on the diagnosis or management of severe congenital neutropenia in Educational resources (http://www.ghr.nlm.nih.gov/condition/severe-congenital-neutropenia/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/severe-congenital-neutropenia/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about severe congenital neutropenia?

You may find the following resources about severe congenital neutropenia helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for severe congenital neutropenia?

  • congenital agranulocytosis
  • congenital neutropenia
  • infantile genetic agranulocytosis
  • Kostmann disease
  • Kostmann's agranulocytosis
  • Kostmann's syndrome
  • severe infantile genetic neutropenia

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about severe congenital neutropenia?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding severe congenital neutropenia?

autosomal ; autosomal dominant ; autosomal recessive ; bone density ; bone marrow ; cancer ; cell ; chromosome ; congenital ; deficiency ; developmental delay ; gene ; gums ; incidence ; infection ; inflammation ; inheritance ; inherited ; leukemia ; mutation ; myelodysplastic syndrome ; neutropenia ; neutrophils ; osteopenia ; osteoporosis ; protein ; recessive ; sex chromosomes ; sporadic ; syndrome ; tissue ; X-linked recessive

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Berliner N. Lessons from congenital neutropenia: 50 years of progress in understanding myelopoiesis. Blood. 2008 Jun 15;111(12):5427-32. doi: 10.1182/blood-2007-10-077396. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18544696?dopt=Abstract)
  • Borzutzky A, Reyes ML, Figueroa V, García C, Cavieres M. Osteoporosis in children with severe congenital neutropenia: bone mineral density and treatment with bisphosphonates. J Pediatr Hematol Oncol. 2006 Apr;28(4):205-9. (http://www.ncbi.nlm.nih.gov/pubmed/16679916?dopt=Abstract)
  • Boztug K, Klein C. Novel genetic etiologies of severe congenital neutropenia. Curr Opin Immunol. 2009 Oct;21(5):472-80. doi: 10.1016/j.coi.2009.09.003. Epub 2009 Sep 24. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19782549?dopt=Abstract)
  • Gene Review: ELANE-Related Neutropenia (http://www.ncbi.nlm.nih.gov/books/NBK1533)
  • Grenda DS, Murakami M, Ghatak J, Xia J, Boxer LA, Dale D, Dinauer MC, Link DC. Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood. 2007 Dec 15;110(13):4179-87. Epub 2007 Aug 30. (http://www.ncbi.nlm.nih.gov/pubmed/17761833?dopt=Abstract)
  • 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. Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia. Br J Haematol. 2008 Jan;140(2):210-3. Epub 2007 Nov 20. (http://www.ncbi.nlm.nih.gov/pubmed/18028488?dopt=Abstract)
  • 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. (http://www.ncbi.nlm.nih.gov/pubmed/17989524?dopt=Abstract)
  • Ward AC, Dale DC. Genetic and molecular diagnosis of severe congenital neutropenia. Curr Opin Hematol. 2009 Jan;16(1):9-13. doi: 10.1097/MOH.0b013e32831952de. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19057199?dopt=Abstract)
  • Welte K, Zeidler C. Severe congenital neutropenia. Hematol Oncol Clin North Am. 2009 Apr;23(2):307-20. doi: 10.1016/j.hoc.2009.01.013. (http://www.ncbi.nlm.nih.gov/pubmed/19327585?dopt=Abstract)
  • 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 patients with severe congenital neutropenia. Br J Haematol. 2009 Nov;147(4):535-42. doi: 10.1111/j.1365-2141.2009.07888.x. Epub 2009 Sep 22. (http://www.ncbi.nlm.nih.gov/pubmed/19775295?dopt=Abstract)
  • 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. Epub 2008 Dec 10. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19120359?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: April 2010
Published: December 16, 2014