Kostmann syndrome is a cogenital and severe neutropenia characterized by the absence of neutrophil granulocytes. Without these components of the immune system, patients with the syndrome are far more susceptible to infection than average. Long-term administration of G-CSF may be considered as a therapeutic measure.
What is Kostmann syndrome?
A subset of white blood cells is known as neutrophil granulocytes. These leukocytes are part of the nonspecific and innate immune system and are involved in both phagocytosis and exocytosis of granules. Accordingly, neutrophil granulocytes ingest and remove larger extracellular particles. They also excrete foreign substances and pollutants and thus perform important tasks in the immunological defense against pathogens. Kostmann syndrome is a symptom complex caused by absent neutrophil granulocytes. The disease exists from birth and has a genetic cause. The syndrome was first described in the 20th century by the Swedish physician Kostmann. The case of the first description corresponded to a family within which six children were affected by the disease. Kostmann called the syndrome infantile genetic agranulocytosis at that time. The name Kostmann syndrome was later adopted in honor of the first describer. Kostmann syndrome belongs to the group of neutropenias. As such, reductions of neutrophil granulocytes are summarized. Within the neutropenias, Kostmann syndrome is considered a severe and congenital form associated with decreased resistance to infection.
Causes
As a cogenital neutropenia, Kostmann syndrome has a genetically inherited basis. There is less than one case for every 300,000 newborns. The symptom complex is therefore described as extremely rare. However, Kostmann himself was able to summarize factors in the examined cases that speak for a hereditary basis. The most decisive factor in this context is the fact that the family studied by Kostmann had no less than six children with the symptom complex. Subsequent cases of the syndrome have also shown that heritability of the disease often results in multiple cases in the same family. Only a few cases were isolated sporadic cases. The German pediatrician Klein identified the causative gene for Kostmann syndrome well after Kostmann’s initial description. This gene is HAX 1, which is affected by a mutation in patients with the syndrome, disrupting the established process within cells. The identified gene regulates apoptosis and thus programmed cell death. For this reason, mutation of the gene results in a severe restriction related to myelopoiesis and thus the maturation of white blood cells.
Symptoms, complaints, and signs
Kostmann syndrome patients suffer from infections far more frequently than average because of the lack of neutrophil granulocytes. Because of this immune deficiency, Kostmann syndrome becomes apparent in most cases shortly after birth. A few days after birth, rapidly spreading and particularly severe infections with bacterial pathogens often occur. In most cases, abscesses also form. After the second year of life, accompanying symptoms such as erosive gingivitis or aggressive periodontitis often develop in the oral cavity of the patient. Fever is a common accompanying symptom of these processes. Some of those affected also suffer from osteoporosis. The extent to which there is a connection between the two diseases has not yet been conclusively clarified. The patients’ weak defenses may also manifest as general weakness and lassitude, which is merely topped off by the aforementioned susceptibility to infections.
Diagnosis and course of the disease
Diagnosis for Kostmann syndrome is made by laboratory testing. On laboratory diagnosis, Kostmann syndrome manifests as severe neutropenia. In order to confirm the suspicion of the syndrome, a molecular genetic examination can take place, which provides evidence of the mutation of gene HAX 1 and thus confirms the suspected diagnosis. Patients with Kostmann syndrome are now considered to have a favorable diagnosis. However, this correlation has only been true since the discovery of antibiotic therapy. Before this breakthrough, the syndrome was associated with an unfavorable prognosis and mostly lethal course.
Complications
Due to Kostmann syndrome, affected individuals usually suffer from a severely weakened immune system. Infections and inflammations occur more frequently, so that the quality of life of those affected is considerably reduced as a result. The healing of wounds is also restricted and delayed by Kostmann’s syndrome. It is not uncommon for the syndrome to lead to the formation of abscesses. Those affected very often suffer from fever and are thus also restricted in their everyday life. Especially in children, Kostmann syndrome can lead to restrictions in development and delay it significantly. In most cases, there is also a general weakness and a significantly reduced ability to cope with stress. Those affected often appear tired and weary and no longer take an active part in everyday life. Treatment of Kostmann’s syndrome takes place with the help of antibiotics and other medications. No particular complications or complaints occur. However, affected individuals also rely on bone marrow transplantation to complete the treatment. The patient’s life expectancy remains unchanged if the treatment is successful. However, it is not uncommon for the parents of those affected to suffer from psychological symptoms or depression and also require psychological support.
When should one go to the doctor?
Kostmann syndrome cannot yet be treated causally. Nevertheless, the condition must be clarified and treated at an early stage to avoid any late complications. Parents who notice abscesses, recurrent fever, and other signs of Kostmann syndrome in their child are best to consult their pediatrician immediately. If other symptoms develop, such as gingivitis or periodontitis, medical advice is also needed. If there are signs of osteoporosis, a specialist must be consulted. Since the disease is an enormous burden for the children, physiotherapeutic treatment is always necessary as well. The family doctor can refer the parents to a specialist and, if necessary, also involve a psychologist. This is particularly necessary in the case of serious illnesses, as these also demand a great deal of strength from the relatives. If the child loses consciousness or suffers a serious infection, the emergency doctor must be called. The same applies in the case of falls due to an attack of weakness. In any case, Kostmann syndrome requires immediate clarification and treatment by the doctor. Any depression and personality changes must be treated by a therapist.
Treatment and therapy
Causal treatment is not yet available for Kostmann syndrome. However, causal therapeutic pathways for genetic mutations are now a subject of medical research. Thus, gene therapy treatment pathways may exist in the future. Up to now, the syndrome has been treated mainly symptomatically. In the case of acute infections, antibiotic treatment is given to put the pathogens out of action. As a long-term therapy, patients with Kostmann syndrome can be treated with G-CSF. This is a granulocyte colony stimulating factor. This peptide hormone is a cytokine and is produced by various tissues of the human body. G-CSF mainly shows a stimulating effect on the formation of granulocytes, which takes place in the bone marrow. In the long term, bone marrow transplantation may be considered as a therapeutic option for those affected by Kostmann syndrome. This transplantation takes place either through stem cell collection from bone marrow donation, peripheral blood stem cell donation, or umbilical cord blood donation. However, bone marrow transplantation in immunocompromised patients carries a high risk of infection, such as infection with cytomegalovirus, pneumococci, or gastrointestinal infections. In addition, rejection reactions may occur. For these reasons, the physician must carefully weigh the risks and benefits of transplantation in each individual case. For example, if the patient’s situation is stable because of long-term therapy with G-CSF, the risks of transplantation exceed the benefits that the individual would derive.
Outlook and prognosis
Kostmann syndrome is a genetic disorder.Since doctors and physicians are not allowed to change the genetics of human beings due to legal requirements, they face a limited scope of action in providing health care to the affected person. Patients must seek medical treatment throughout their lives if they wish to achieve a change in their health condition. If given medicines are discontinued or their dosage is changed in the course of life and without the consultation of the physician, an immediate deterioration of the general condition and an increase of the complaints are to be expected. In cooperation with the attending physician, the weakened immune system can be stabilized. Although a cure does not occur, various complaints can be minimized. Consequential symptoms are additionally treated symptomatically over a lifetime. These can lead to complications. In addition, the administration of medication is associated with side effects and risks. If the physician and patient decide to transplant the bone marrow based on the overall situation, the prospects for later health development improve. Nevertheless, the procedure is difficult and associated with numerous complications. In addition to rejection reactions of the organism and a longer waiting period for a suitable donor, there may be further significant impairments of the quality of life as well as well-being.
Prevention
Because Kostmann syndrome is a cogenital disorder and the actual cause of the causative mutation of HAX 1 has not yet been determined, the symptom complex cannot be prevented.
Follow-up
As a rule, the options for follow-up care in Kostmann syndrome prove to be relatively difficult, since it is a genetic disease that cannot be completely cured in the process. However, a doctor should be consulted at a very early stage so that no further complications or complaints can occur, since this disease usually cannot be cured on its own. In case of a desire to have children, the affected person should have a genetic examination and counseling performed so that the syndrome itself cannot occur again in the descendants. In many cases, those affected by Kostmann syndrome are dependent on taking antibiotics. The doctor’s instructions should always be followed, and attention should be paid to the correct dosage and regular use. Furthermore, regular checks and examinations by a doctor are important in order to detect further damage to the internal organs at an early stage. Those affected by Kostmann syndrome should take special care to protect themselves against infections and other ailments. In some cases, despite treatment, the life expectancy of the affected person with this disease is reduced.
What you can do yourself
In most cases, sufferers of Kostmann syndrome are dependent on lifelong therapy, so self-help is usually not an option. The complaints of the weakened immune system can be relatively well limited by the drugs in this case, so that illnesses and infections occur less often. However, these complaints can also be well avoided by simple hygiene measures. Wearing warm clothing in winter can also prevent frequent illnesses. Since those affected often suffer from fatigue or general weakness, children in particular need a lot of bed rest and must take care of their bodies. This can prevent illness and complications, especially in childhood. Furthermore, talking to other people affected by the syndrome can also help against psychological complaints or depression. In adolescents or children, the disease can lead to bullying or teasing, so that therapy can also be carried out in this case. As a rule, however, the symptoms can be very well limited with the help of medication, so that there is also no reduced life expectancy in the patient. Unfortunately, Kostmann syndrome cannot be prevented.