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Neutropenia

Severe Chronic Neutropenia (SCN)

Intermittent neutropenia or Cyclical neutropenia 

Myelocyte arrest & Compensatory monocytosis

Bacterial infections & Septicaemia

Mouth Ulcers & Sore Gums

Perianal Dermatitis

Neutrophils are white blood cells which protect against bacterial and fungal infection. Babies should have a neutrophil count in excess of 1 x 10^9/l (1 billion per litre or 1000 cells per microlitre) and older children and adults in excess of 1.5 x 10^9/l (1.5 billion per litre or 1500 per microlitre). Doctors will often refer to these counts as "1" or "1.5" respectively. A neutrophil count of less than 0.5 x 10^9/l (500 per microlitre) is termed "severe neutropenia". Patients with counts in this range are at serious risk of bacterial infection. If such a low count is observed on multiple occasions, the patient is said to suffer from "Severe Chronic Neutropenia (SCN)". The risks are particularly severe if the neutrophil count is less than 0.2 x 10^9/l.

Although neutropenia is recognised as one of the major features of Barth Syndrome, it has never been detectedon any blood count in up to 10% of boys with the disease. However, in other boys with the disease, neutropenia may be the only initial feature of Barth Syndrome. The severity and nature of the neutropenia vary from boy to boy, and even during the childhood of any one boy.

There can be persistent severe chronic neutropenia or perfectly cyclical neutropenia (in the latter the neutrophil count cycles on a predictable time scale, usually of 3-5 weeks in Barth Syndrome). However, most boys will show a rather unpredictable pattern of neutropenia. An example is shown in this graph:

Unpredictable Neutropenia

Unpredictable neutropaenia, a common finding in Barth Syndrome 

The commonest symptoms due to the neutropenia are severe MOUTH ULCERS which may come and go as the neutrophil count waxes and wanes, sore/bleeding gums (especially on tooth brushing at times of the most severe neutropenia), skin spots or perianal rashes). Slow recovery or complicated chest or ear infections are also seen. These infections can potentially become very serious, leading to septicaemia and multiorgan failure.

There can be a wide range of counts between 0 and 10-15 x 10^9/l without any treatment to stimulate neutrophil production. This can easily cause diagnostic confusion since a boy may develop serious BACTERIAL INFECTION whilst his count is zero but subsequently mount a response to infection so that he has a normal neutrophil count by the time that he is seen in hospital. This is one reason why Barth Syndrome must be considered as a potential diagnosis in any boy with unexplained serious bacterial sepsis, particularly where there has been previous unexplained sepsis, cardiac or muscle problems, or multiple boys affected in one family who share the same female line of inheritance.

A bone marrow aspirate will usually show a lack of mature neutrophils but plenty of the other cells in the blood line that produces neutrophils. This is termed "myelocyte arrest" or "left shifted myelopoiesis". Many boys show a high monocyte count in their blood at the same time as their neutrophil count is very low. Doctors sometimes call this "compensatory monocytosis".

Boys who continue to have recurrent sore gums, mouth ulcers, perianal infections or other signs of persistent infection despite preventative antibiotics are often treated with granulocyte colony stimulating factor (G-CSF). This is a naturally occurring bone marrow hormone which stimulates the production of neutrophils and can now be synthesised in drug company laboratories. Use of G-CSF in boys with Barth Syndrome needs to be carefully managed since some boys respond so well that they may develop white blood counts as high as 60-80 x 10^9/l, while others may show little change in their counts but major reduction in infections.

Patients with Barth Syndrome can be infected by many different bacteria, but there seems to be an excess of infections caused by Streptococcal bacteria. These can spread around the body from a sore throat or from bacteria which normally live in the mouth. Another quite common problem is "Perianal Streptococcal Dermatitis". This perianal infection is easily misdiagnosed as thrush (fungal infection). It shows up as a bright red area around the anus, sometimes with spots spreading out onto the buttocks or thighs. There may be diarrhoea, blood streaking of stools or passage of mucus on stools due to infection within the rectum. Children may be lethargic and generally unwell with this infection and can have symptoms over many weeks or months. The infection is easily proven by an anal swab showing growth of Streptococci and will usually resolve within 1-2 days on treatment with penicillin. It is very important to recognise perianal Streptococcal dermatitis in neutropenic patients since this can be an important source of bacteria spreading throughout the body and bloodstream.