Publication date: 2011-10-18
Version: 1.0
D70
Severe congenital neutropenia, SCN, describes a group of rare congenital immunodeficiencies. SCN is characterised by low levels, or a total absence, of neutophil granulocytes (peni = a lack, neutropeni = lack of neutrophil granulocytes).
Neutrophil granulocytes are white blood cells which are a normal part of the immune system and are usually found in very large quantities in the blood. They are a type of phagocyte (phagein= eat, cyt = cell). These cells quickly and efficiently travel from the blood to sources of infection and there ingest foreign particles, including bacteria. Neutrophil granulocytes are formed in the bone marrow and have a high turnover. Individuals with severe congenital neutropenia can very easily develop serious bacterial infections.
The disease was described for the first time in 1950 by the Swedish paediatrician, Rolf Kostmann. Kostmann disease was previously synonymous with severe congenital neutropenia, but now the name refers to a particular form of the disease.
Life-long, chronic neutropenia is also a component of other congenital diseases such as cyclical neutropenia, Shwachman Diamond syndrome, Cohen syndrome, Barth syndrome and glycogen storage disease type 1b. Chronic neutropenia can also occur in other primary immunodeficiency diseases including hyper-IgM syndrome, agammaglobulinemia and severe combined immunodeficiency. Separate information on these diseases is available in the Rare Disease Database of the Swedish National Board of Health and Welfare.
Severe congenital neutropenia is found in one or two individuals per million inhabitants. In Germany it is estimated that one child in every 240,000 is born with severe congenital neutropenia. Applying these rates to Sweden means that one child is born with the disease every two or three years. It is estimated that there are between 15 and 20 children with the disease in Sweden.
Some years ago a genetic mutation was identified as being a cause of severe congenital neutropenia. The gene was first named ELA-2, but later re-named ELANE. It controls the formation of (codes for) the neutrophil elastase protein. The protein has antibacterial properties and is often present where there is inflammation. Mutations in ELANE have been established in approximately 60 per cent of those with sporadic or autosomalt dominant patterns of inheritance of severe congenital neutropenia. It has not yet been established how the mutation in ELANE causes neutropenia. One theory is that it changes the properties of the protein, causing cells to die prematurely - a process known as apoptosis.
People with Kostmann disease have mutations in the HAX1 gene. The gene codes for protein HAX-1, which is found in the mitochondria (small components of the cell functioning as its power source) and is necessary to protect the cell from uncontrolled cell death. Individuals with specific mutations in the HAX1 gene also have neurological symptoms including mild cognitive disability and epilepsy, indicating that protein HAX1 is important for the working of brain cells.
In some isolated cases of severe congenital neutropenia, mutations in genes WAS, GF1, G6PC3 and CSF3R have been established. One third of individuals with severe congenital neutropenia, however, do not carry any known mutations but the clinical presentation is similar.
In severe congenital neutropenia there is also a deficiency in the antibacterial substance LL-37, which is present in neutrophils. LL-37 is an important element in defences against bacteria found on the skin and in mucous membranes.
In some individuals severe congenital neutropenia with a neutrophil elastase deficiency is caused by a new mutation in the ELANE gene. This means that a genetic change occurs for the first time in the individual, and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children.
An autosomal dominant pattern of inheritance means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.
In Kostmann disease, which is caused by a mutation in the HAX1 gene, the pattern of inheritance is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.
A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.
Neutrophil granulocyte deficiency results in serious bacterial infections. The first symptoms of the disease often present at birth or during the first weeks of life. Most infections are caused by bacteria on the skin or in the mucous membranes. Children often develop boils, umbilical cord infections and severe oral infections. Recurring inflammation of the middle ear is common, as are serious infections including pneumonia and septicaemia. If these conditions are not treated with antibiotics, they may lead to life-threatening infections.
In newborns where neutrophil granulocyte levels are low or the cells fail to function normally, it may take an unusually long time for the umbilical stump to fall off. For this reason, tests should be carried out on all children whose umbilical stumps have not fallen off after six weeks in order to establish the numbers of neutrophil granulocytes and their functionality.
Before the first teeth erupt, children often develop painful ulcers in the oral cavity. When the teeth have erupted, inflammation of the gums (gingivitis) is often chronic and can lead to tooth loss, sometimes while the child is of pre-school age. Chronic inflammation causes gums to bleed easily when teeth are being brushed.
Recurring infections affect children’s overall health and they do not grow normally. One reason children with severe congenital neutropenia are sometimes shorter than their peers may be because of recurring infections. However, the disease itself may be the cause as growth remains restricted even after children receive treatment.
As well as neutropenia, the disease can also cause reduced bone density resulting in brittle bones (osteoporosis). The cause of this is unknown. Some people with the disease also have an enlarged spleen.
Severe congenital neutropenia is one of a group of diseases called congenital bone marrow failure syndrome. Many of these diseases carry an increased risk of developing myelodysplastic syndrome (MDS) and leukemia (acute myeloid leukemia, AML). Myelodysplastic syndrome is associated with serious abnormalities in bone marrow function and the production of blood. It leads to a deficiency of different sorts of blood cells and usually develops into acute myeloid leukemia. Individuals with acquired chronic neutropenia do not have an increased risk of developing MDS and AML.
Chronic neutropenia may occur at any stage of life (acquired neutropenia). The disease may develop independently or as a symptom of another, underlying disese. Degrees of severity vary. The most common form of childhood chronic neutropenia is autoimmune neutropenia. This disease occurs in both adults and children but in children it is usually a temporary condition. Degrees of sensitivity to infection vary, but such infections are seldom severe. Another form is idiopathic (no known cause) neutropenia, which can also occur in both children and adults. Short term (acute) neutropenia may sometimes be caused by infections and medication. Neutropenia may also occur as an early symptom of a malignant disease of the blood such as leukemia, but then it is usually in combination with low levels of haemoglobin and reduced numbers of blood platelets.
Blood tests for bacterial infections include a complete blood count (CBC) with differentials, and the analysis of different types of blood cells. Severe congenital neutropenia may be suspected if the number of neutrophil granulocytes is very low (lower than 0.5x109/L). The disease is associated with rather low blood haemoglobin levels, elevated levels of blood platelets (thrombocytes) and increased numbers of monocytes (another type of white blood cell). Levels of IgG (gammablobulin G) are often raised. Most of these changes are a result of the chronic inflammation which many people with the disease experience.
If sthe disease is suspected, bone marrow should be tested. In severe congential neutropenia, the precursor cells that should develop into mature neutrophils do not fully mature. This is termed a maturation block.
In severe congenital neutropenia, normal neutrophil granulocytes are not produced and those cells which are produced do not achieve maturity. In short, neutrophil production stops or neutrophil maturity is inhibited.
The diagnosis can be confirmed by a DNA analysis establishing mutations in ELANE, HAX1 or some other known genes.
A chromosome analysis of bone marrow cells should be carried out when the diagnosis of SCN is made, and again at regular medical check-ups. Chromosome abnormalities may be a precursor of leukemia. The G-CSF-receptor gene in bone marrow cells should be examined every year as acquired mutations in this gene may be a sign that leukaemia is developing.
Levels of LL-37 can be established in a blood test in cases where the disease is at an early stage, or the diagnosis is unclear. Regardless of the type of mutation which causes it, currently it is only in severe congenital neutropenia where low levels of this particular protein have been established.
Treatment starts with injections of growth factor G-CSF. This treatment is vital as antibiotics alone are not sufficient in cases of severe congenital neutropenia. The only cure for the disease is haematopoietic stem cell transplantation (HSCT or bone marrow transplant) but because of the risks involved, this is considered only when G-CSF treatment is not sufficiently effective.
Granulocyte stimulating factors (G-CSF)
Severe congenital neutropenia is currently treated with growth factor G-CSF. This is a protein which is produced in the body and ensures that neutrophil granulocytes divide, mature, function properly and have a normal life span. Synthetically generated G-CSF (recombinant) is usually administered in the form of an injection under the skin (subcutaneous) once per day. Individuals with severe congenital neutropenia do not have a G-CSF deficiency (or a receptor deficiency, G-CSFR) but have normal or high levels of growth factor. G-CSF supplements cause the numbers of neutrophil granulocytes to increase and reach near-normal or normal levels. G-CSF dosages are adjusted for each individual. The goal of treatment is to raise the number of neutrophils to more than1.0 x 109/L, and to control bacterial infections. High levels of neutrophils should be avoided.
In more than 90 per cent of cases, treatment is successful. The number of severe infections decreases and quality of life improves. However, this treatment does not cure the disease. Many patients still have problems with bacterial infections, particularly in the gums. The reason infections persist despite G-CSF treatment is thought to be an LL-37 deficiency.
Approximately 20 per cent of individuals with severe congenital neutropenia develop leukemia at some time in their lives, often preceded by chromosomal changes in bone marrow cells. It is not known if the development of leukaemia is connected to the G-CSF treatment or if it is a consequence of the disease itself. It is currently (2010) believed that G-CSF does not cause leukemia but can stimulate it if it is latent. The reason is that people with severe congenital neutropenia who do not receive G-SCF treatment may also develop leukaemia. The suspicion that G-SCF may cause leukaemia has caused parents and patients to decline medication, and may also have influenced physicians to be restrictive in its use. This has led to increased numbers of patients dying from severe bacterial infections.
If it is thought that the patient is developing leukaemia, haematopoietic stem cell transplantation may be carried out as a preventive measure. If the transplantation is carried out after leukemia has developed, the chance of treatment being successful is reduced. This is the reason why individuals with severe congenital neutropenia should submit blood samples every third month and undergo annual blood marrow tests.
Antibiotics
If the G-CSF treatment is successful, the need for antibiotics decreases. As the risk of infection in severe congenital neutropenia is elevated, people with the disease require treatment with antibiotics more frequently than others. As a rule they also need higher doses and a longer period of treatment. It is important that infections are detected at an early stage in order to start treatment promptly. For this reason it is very important that patients with the disease remain in close contact with health care services and the attending physician.
Haematopoietic stem cell transplantation (HSCT)
Blood stem cells are immature cells which can develop into all blood cell types. They are found primarily in bone marrow, but are also plentiful in blood from the umbilical cord. A stem cell transplantation provides the opportunity to replace defective stem cells with those from a healthy person. In such cases the donor must have the same tissue type as the recipient.
To optimise the chances of successful transplantation, the recipient of the bone marrow should be as free from infection as possible and in good physical condition. The intervention itself is fairly simple, but the preparations, aftercare and major risks make it a highly demanding procedure. The stem cells are given as a drip directly into a blood vessel and find their way into the recipient’s bone cavities where they grow, supplying the patient with a new immune system with new blood cells. It may take up to a year before the new bone marrow is fully functional.
Haematopoietic stem cell transplantation should be considered immediately if there are signs that leukemia is developing, or if G-CSF treatment is not proving effective. Transplantation may also be considered even if leukemia has not developed, especially if, in spite of treatment, the patient requires very high doses of G-CSF or has many bacterial infections.
Regular check ups
Individuals with severe congenital neutropenia need to have regular blood checks. Bone marrow tests should be carried out annually. At the same time, chromosomal abnormalities associated with myelodysplastic syndrome and acute myeloid leukaemia should be investigated (a cytogenetic examination), and it should be established whether there is a mutation in the G-CSF receptor.
It is recommended that a bone density test is carried out every three to five years.
Dental care and oral hygiene
Good levels of oral hygiene are very important, and in addition to brushing teeth with a soft toothbrush, the use of dental floss and a mouthwash, such as chlorhexidine and benzydamine, may be of value.
Regular visits to a dentist and dental hygienist can help prevent gum disease (peridontal disease) and tooth loss. Antibiotics should be given before dental procedures where bleeding may occur, including tooth extraction or the removal of plaque.
Living with severe congenital neutropenia
With G-CSF treatment, the prognosis for the majority of individuals with the disease is very good. Knowledge about the disease and the reasons for treatment are important, both for adults and children. Simple measures such as frequent hand washing and being careful about keeping wounds clean can help prevent bacterial infections.
It is important that children are vaccinated according to the programme offered by early years’ and school healthcare services.
As the disease has no visible signs it is important that staff at preschool and school, including play leaders, are informed that the child has severe congenital neutropenia. During certain periods children with the disease may have higher levels of absence than their peers, and during certain periods when infections are prevalent the child may need to stay home to avoid being infected. For this reason the school should have a plan for how the child can achieve his or her educational goals despite possible prolonged periods of absence.
- Be particular about hygiene, especially hand washing and keeping wounds clean.
- Get in touch with healthcare services immediately in cases of fever and/or infection.
- Avoid large crowds, especially during periods when infections are common.
- Humidifiers spread bacteria and fungal spores. If a humidifier is necessary, it should be regularly cleaned with bleach.
- The preschool or school should be adapted to meet the needs of the child. Measures may include routines for hand washing, keeping the home informed about injuries and wounds, careful cleaning routines and special times for the child to be present in communal areas at school.
- Regular nasal douches with saline solution can reduce infection.
Be especially careful with regard to food and hygiene during trips abroad as they often increase contact with new types of viruses and bacteria. Before such trips, the attending physician should be consulted as to necessary precautions and medication etc. It should be decided which telephone numbers, including those of emergency services and contact persons, are necessary. A list of experts on neutropenia in different European countries is available on the web page of The Severe Chronic Neutropenia International Registry (SCNIR). (See under, “Research and Development.”) It may also be useful to carry information material about the disease and contact details of the attending physician. Additional information may be necessary for customs authorities.
Children with severe congenital neutropenia are treated and monitored at clinics for children and young people, while adults have contact primarily with the haematology departments of hospitals’ medical centres or infection clinics. Health care is often provided in collaboration with Sweden’s county or regional hospitals.
DNA analyses of ELANE, HAX1 and CSF3R genes are carried out at the Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.
Expertise on oral problems associated with severe congenital neutropenia is provided by Children’s Dental Care, Institute of Odontology, Karolinska Institute, SE-141 04 Huddinge, Sweden provides. Tel: +46 8 524 800 00.
Expertise in orofacial problems can be found at Mun-H-Center, Institute of Odontology Gothenburg, Medicinaregatan 12A, SE-413 90 Gothenburg, Sweden. Tel: +46 31 750 92 00, fax: +46 31 750 92 01, email: mun-h-center@vregion.se, www.mun-h-center.
Children and young people
Dr Göran Carlsson, Paediatric Oncology, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 747 54, email: goran.carlsson@ki.se.
Professor Anders Fasth, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, fax: +46 31 84 30 10, email: anders.fasth@gu.se.
Adults
Professor Jan Palmblad, Medical Institute, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 93, email: jan.palmblad@ki.se.
Dr Daniel Tesfa, Haematology Center, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.
At its annual meeting PIO, the Primary Immunodeficiency Organisation, holds a lecture on immunodeficiency for patients and parents. Weekend courses are held annually by PIO for children and young people with primary immunodeficiency disorders and their families. These courses offer opportunities for sharing experiences, lectures and games. At regular intervals, PIO and the Nordic immunodeficiency associations organise joint meetings over a few days. They offer opportunities for learning, and exchanging information. For further information contact PIO. (See address under, “Organizations for the disabled/patient associations” below.)
IPOPI, the International Patient Organisation for Patients with Primary Immunodeficiencies, of which PIO is an affiliate, arranges a conference in conjunction with a biennial international medical conference for doctors and nurses interested in immunodeficiencies. Meetings are held in English and are excellent occasions for learning, and exchanging information. For further information, contact PIO. (See under “Organizations for the disabled/patient associations.”)
PIO, The Primary Immunodeficiency Organisation in Sweden, Mellringevägen 120 B, SE-703 53 Örebro, Sweden. Tel: +46 19 673 21 24, email: pio@telia.com, www.pio.nu.
ESID, European Society for Immunodeficiencies.The Society has regular international conferences and summer schools for doctors and researchers. www.esid.org.
INGID, International Nursing Group for Immunodeficiencies. The Group arranges international meetings in collaboration with ESID and the international patient organization IPOPI, www.ingid.org.
SISSI, Swedish Nurses’ Association for Primary Immunodeficiencies.The association publishes a worksheet and has regular conferences for members. In alternate years this is organized in collaboration with ESID, IPOPI and INGID, www.sissi.nu.
SLIPI, Swedish Physicians’ Association for Primary Immunodeficiencies organises meetings and conferences, www.slipi.nu.
SCNIR (the Severe Chronic Neutropenia International Registry) was founded in 1994 to follow the development of the disease, and its treatment and results in people with severe congenital neutropenia. The register is the most extensive collection in the world of long-term data on individuals with severe chronic neutropenia. On SCNIR’s website, http://depts.washington.edu/registry/, there is information on the disease. There is also a patient handbook in a number of languages including Swedish. (See under, “Information material.”)
In Sweden , a great deal of research is underway into severe congenial neutropenia and Kostmann disease.
Clinical research
Professor Jan-Inge Henter and Dr Göran Carlsson, Child Cancer Research Unit, Department of Women’s and Children’s Health, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden.
Professor Jan Palmblad, Department of Medicine, Karolinska University Hospital, SE-141 86 Huddinge, Sweden.
Professor Thomas Modéer, Children’s Dental Care, Institute of Odontology, Karolinska Institute, SE-141 04 Huddinge, Sweden.
Preclinical research
Associate professor Bengt Fadeel, Biochemical Toxology Unit, Institute for Environmental Medicine, Karolinska Institute, SE-171 77 Stockholm, Sweden.
Dr Katrin Pütsep, Department of Microbiology, Tumour and Cell Biology (MTC), Karolinska Institute, SE-171 77 Stockholm, Sweden.
Professor Niklas Dahl, Clinical Genetics, Department of Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden.
Professor Magnus Nordenskjöld, Genetics Section, Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden.
An information leaflet on severe congenital neutropenia summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2010-9-16). Address: SE-120 88 Stockholm, Sweden. Fax: +46 8 779 96 67, email: socialstyrelses@strd.se or tel: +46 8 779 96 66. Postage will be charged for bulk orders.
Living with severe chronic neutropenia. A handbook for patients and families, translated into Swedish and other languages, written for SCNIR (Severe Chronic Neutropenia International Registry). The handbok can be found at www.scner.de/handbook.sv.pdf.
The material below can be ordered from the +PIO (Primary Immunodeficiency Organization). (See contact information under, “Organizations for the disabled/patient associations etc.”) Unless otherwise mentioned, in Swedish only.
- Barn eller vuxna med primär immunbrist. Eighth edition, 2005.
- Så mår immunförsvaret bättre. Praktisk livsföring vid primär immunbrist - några råd. 1999.
- The story of primary immunodeficiency. 1999 (English)
- En skola för alla. Praktiska råd för en bättre skolmiljö vid primär immunbrist. En pärm till skolan och en till vårdnadshavarna. Third edition, 2010.
- Studera med primär immunbrist. Praktiska tips för universitets/högskolestudier vid primär immunbrist. En broschyr till skolan och en till studenten. First edition, 2008.
- Lathund för ansökan av vårdbidrag/fonder. Updated, 2008.
Information on MDS and AML (in Swedish only) can be ordered from the Swedish Leukemia Association, Box 1386, SE-172 27 Sundbyberg, Sweden.Tel: +46 8 546 40 540, email: info@blodcancerforbundet.se, www.blodcancerforbundet.se.
Carlsson G, Garwicz D, Nordenskjöld M, Fadeel B, Palmblad J, Henter J-I. Kostmanns syndrom till stor del klarlagt - genom svensk forskning. 50 år sedan Rolf Kostmanns banbrytande arbete om svår medfödd neutropeni. Läkartidningen 2006; 50: 4022-4027.
Carlsson G, Fasth A. Infantile genetic agranulocytosis, morbus Kostmann: presentation of six cases from the original “Kostmann family” and a review. Acta Paediatr 2001; 90: 757-764.
Carlsson G, Aprikyan AAG, Tehranchi R, Dale DC, Porwit A, Hellström-Lindberg E et al. Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome ñ, and excessive apoptosis of myeloid progenitor cells. Blood 2004; 103: 3355-3361.
Carlsson G, Wahlin, YB, Johansson A, Olsson A, Eriksson T, Claesson R et al. Periodontal disease in patients with severe congenital neutropenia of the original Kostmann family. J Periodontol 2006; 77: 744-751.
Carlsson G, Andersson M, Putsep K, Garwicz D, Nordenskjold M, Henter J-I, Palmblad J et al. Kostmann syndrome or infantile genetic agranulocytosis, part one: celebrating 50 years of clinical and basic research on severe congenital neutropenia. Acta Paediatr 2006; 95: 1526-1532.
Carlsson G, Melin M, Dahl N, Ramme KG, Nordenskjöld M, Palmblad J et al. Kostmann syndrome or infantile genetic agranulocytosis, part two: Understanding the underlying defects in severe congenital neutropenia. Acta Paediatr 2007; 96: 813-819.
Carlsson G, Van´t Hooft I, Melin M, Entesarian M, Laurencikas E, Nennesmo I et al. Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations. J Intern Med 2008; 264: 388-340.
Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA et al. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol 2003; 72: 82-93.
Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 2000; 96: 2317-2322.
Karlsson J, Carlsson G, Ramme KG, Hägglund H, Fadeel B, Nordenskjöld M et al. Low plasma levels of the protein pro-LL-37 as an early indication of severe disease in patients with chronic neutropenia. Br J Haematol 2007; 137: 166-169.
Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schaffer AA et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet 2007; 39: 86-92.
Klein C. Molecular basis of congenital neutropenia. Hematol 2009; 94: 1333-1336.
Kostman R. Hereditär reticulos: en ny systemsjukdom? Läkartidningen 1950; 47: 2861-2868.
Pütsep K, Carlsson G, Boman HG, Andersson M. Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study. Lancet 2002; 360: 1144-1149.
Rosenberg PS, Alter BP, Bolyard AA, Bonilla MA, Boxer LA, Cham B et al. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 2006; 107: 4628-4635.
Schäffer AA, Klein C. Genetic heterogeneity in severe congenital neutropenia: how many aberrant pathways can kill a neutrophil? Curr Opin Allergy Clin Immunol 2007; 7: 481-494.
Welte K, Zeidler C, Dale DC. Severe congenital neutropenia. Semin Hematol 2006; 43: 189-195.
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; 144: 459-467.
Xia J, Bolyard AA, Rodger E, Stein S, Aprikyan AA, Dale DC et al. Prevalence of mutations in ELANE, GF11, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. Br J Hameatol 2009; 147: 535-542.
OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim
Search: neutropenia, severe congenital
The Swedish Information Centre for Rare Diseases produced and edited this information material.
The medical expert who wrote the draft of this information material is Dr Göran Carlsson, Astrid Lindgren Children’s Hospital, Sweden.
The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.
An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.
Publication date: 2011-10-18
Version: 1.0
Publication date of the Swedish version: 2010-11-23
For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.