The Severe Chronic Neutropenia
International Registry

Severe Congenital Neutropenia or Kostmann Syndrome

Congenital neutropenia, often also called Kostmann syndrome is a rare type of neutropenia that is present at birth. It is an inherited disease and therefore, more than one family member can be affected, but sporadic occurrence with only one patient in a family is also possible. However, there is no antenatal testing currently available. Congenital neutropenia is usually very severe, and neutrophils are often completely absent in the blood of these patients at the time of diagnosis. Patients who are diagnosed with congenital neutropenia or Kostmann syndrome usually show what is known as a maturation arrest in the early stages of neutrophil development in the bone marrow. This means that their neutrophils rarely fully mature into the cells that are capable of fighting infections.

These patients suffer from severe bacterial infections, such as omphalitis (infection of the navel), pneumonia, skin abscesses or otitis media (ear infections) during their first few months of life. Therefore, in most patients congenital neutropenia is diagnosed early during infancy. A blood test and a bone marrow sample are required in order to obtain a correct diagnosis.

When a bone marrow is taken for diagnostic reasons, firstly the cells are looked at under the microscope and secondly the cells are used for other investigations, such as cytogenetic evaluation, analysis of the G-CSF receptor and, if possible, a sample is sent to the SCNIR bone marrow cell bank to be used for research purposes.

With the cytogenetic evaluation the chromosomes of the bone marrow are studied. Most of the time, in the majority of patients with neutropenia, this test is completely normal. Changes in the chromosomes of cells can be harmless, but in some cases changes could indicate a possible progression towards leukaemia. This is the most important reason for routine annual bone marrow investigations.

The analysis of the G-CSF receptor gives us information on the structure of this receptor. The receptor is localised on all granulocytes. The purpose of this particular receptor is the binding of the cytokine G-CSF in order to give a signal to the cell to maturate, to divide itself or to enhance function. In some congenital neutropenia patients the G-CSF receptor develops changes that also could indicate progression towards leukaemia and therefore this analysis is another sensitive indicator that needs to be tested on a regular basis.

As soon as congenital neutropenia is diagnosed, patients should commence treatment with a haematopoietic growth factor called G-CSF (also known as filgrastim or lenograstim). Clinical trials of Normal Karyotype Monosomy 7 G-CSF treatment began at Amgen in 1987. This treatment was found to result in a dramatic increase in life expectancy and quality of life in these patients. As soon as the patientís neutrophil counts have improved and stabilised, a near normal life can be lead e.g. going to Kindergarten or school, participation in sports. Before G-CSF was available, most patients died from severe bacterial infections within their first few years of life because no other treatment was able to correct their neutropenia adequately. Even antibiotic therapy could only prolong the life of these patients for a short while, because both neutrophils and antibiotics are necessary to overcome bacterial infections. The only option for a complete cure of Kostmann syndrome is a bone marrow transplant (BMT).

G-CSF is a natural cytokine produced by the human body. A cytokine is a protein produced by cells, which are essential for the regulation of other cells. Patients with congenital neutropenia also produce G-CSF, but for reasons still largely unknown, the response of their neutrophils to the normal amounts of G-CSF in the blood is reduced. The lower the neutrophil count, the greater the risk of infection. Occurrence of severe bacterial infections is strongly correlated with low neutrophil counts. In most patients bacterial infections resolve and reoccur less frequently as soon as the neutrophil count stabilises after initiation of G-CSF treatment at around 1000/mm3 (1.0 x 109/l). Individual people vary, some will fight off infection with a lower neutrophil count, and others will need a higher count.

In congenital neutropenia patients, response to G-CSF treatment is also different. This is why there is a big variation in the dose (amount) of G-CSF that different people receive. For more information regarding G-CSF see chapter TREATMENT FOR SEVERE CHRONIC NEUTROPENIA. Only a very small subgroup of patients with congenital neutropenia does not respond to even very high doses of G-CSF. In patients, who do not respond to G-CSF doses of 100 mcg/kg or more within fourteen days, a search for a bone marrow donor should be started immediately and BMT should be performed as soon as a matching donor is identified. The BMT procedure is very complex: for more information contact your physician.

During the last 10 years, data has been collected on more than 700 patients with chronic neutropenia. These data indicate that patients who have severe congenital neutropenia have an increased risk (around 9%) of developing leukaemia compared to healthy individuals. Therefore, it is strongly recommended that all patients with congenital neutropenia have a bone marrow examination and cytogenetic analysis on a yearly basis. BMT may be considered if the cytogenetics in the bone marrow shows any specific abnormalities.

Besides neutropenia, patients with congenital neutropenia may have a reduced bone density, which can lead to osteopenia or osteoporosis, thinning of the bones (usually seen in elderly women). Osteoporosis may even be seen in children with severe chronic neutropenia, but the reasons for this are not clear. The changes in the mineral content of the bone (amount of calcium) possibly represent an additional symptom of the underlying genetic defect. However, according to all information currently available, only very few patients will actually experience clinical problems, such as pain and/or fractures due to their osteoporosis. The exact cause of osteoporosis is not fully known, nor are the long-term implications fully understood. Therefore it is important to monitor the patient's bone density on a regular basis to ensure the safety and well being of the patient.