Nuclear factor-kappa B essential modulator (NEMO) deficiency syndrome is a rare type of primary immunodeficiency disease and is very variable in the symptoms it causes and how it progresses over time. It mostly affects the skin and immune system but has the potential to affect all parts of the body, including the lungs, urinary tract and gastrointestinal tract.
What causes NEMO deficiency syndrome?
A condition that affected the skin and immune system was first described in 1986. The faulty gene causing the condition – the nuclear factor-kappa B Essential Modulator gene – was identified in 1999. The NEMO gene can also be referred to as the Inhibitor of Kappa B Kinase gamma (IKK gamma). This gene plays an important part in the development of the skin and immune system in the womb. The degree to which the gene is affected is very variable – in the most severe forms, a pregnancy will not be viable and the fetus will be miscarried.
Typically NEMO deficiency syndrome is X-linked so only affects boys. There is a mutation (change) affecting the NEMO gene on the X chromosome. Females have two X chromosomes so the unaffected one usually compensates for the changed one. Males have one X chromosome and one Y chromosome so the condition usually only occurs in boys, although girls can be carriers and could pass on NEMO deficiency syndrome to any sons.
Other forms of the syndrome involving NEMO-related pathways can be passed on from parent to child in an autosomal dominant manner – this means that a child only has to inherit the faulty gene from one parent to develop the condition. This autosomal dominant type of NEMO deficiency syndrome can affect both boys and girls.
What are the signs and symptoms of NEMO deficiency syndrome?
NEMO deficiency syndrome affects the skin and the immune system primarily although the symptoms brought about by these effects can be very variable.
Children with NEMO syndrome have a skin condition called ectodermal dysplasia (ED) – dysplasia is the word used to describe when something has not developed as it should – which means that the outermost layers of the skin have not formed properly. Affected children have thickened skin with few or no sweat glands, thin hair and abnormally formed teeth.
Many parts of the immune system are affected in NEMO deficiency syndrome including the B lymphocytes, T lymphocytes, neutrophils and macrophage cells. This makes the body much more susceptible to infections, particularly those caused by Pneumococcus and Staphylococcus Aureus and mycobacteria similar to tuberculosis. The infection may affect all areas of the body – for instance, meningitis is quite common in infancy – and may be the first indicator of a primary immunodeficiency disease.
As well as being unable to fight infections as well as usual, the immune system may develop an ‘autoimmune response’ – that is, it starts to attack the body cells instead of foreign invaders such as bacteria and viruses. This can cause gut problems such as severe diarrhoea and abdominal pain.
How is NEMO deficiency syndrome diagnosed?
As NEMO deficiency syndrome is so rare and the symptoms so variable even within the same family, diagnosis may take a long time to reach so is best dealt with at a specialist centre with experience of rare primary immunodeficiency diseases. Doctors may initially suspect some type of an immune system disorder but a specialist centre will be able to carry out the tests needed to narrow it down to NEMO deficiency syndrome.
Initially, the doctor will take a clinical history of which symptoms have appeared and when. Blood tests will be needed to look at the levels of the various cells affected in NEMO deficiency syndrome. They may also show signs of infection or autoimmune response. Genetic tests – also using a blood sample – will be needed to identify the mutation on the NEMO gene.
How is NEMO deficiency syndrome treated?
The aim of treatment is to prevent infections so children will usually be started on immunoglobulin treatment as soon as a diagnosis is reached. Immunoglobulin is also known as IgG or antibody. It is a blood product and is given as replacement for people who are unable to make their own antibodies. It is the mainstay of treatment for patients affected by primary antibody deficiency. Immunoglobulin can be given by infusion through a cannula into a vein (intravenously or IV), or by rapid subcutaneous infusions (SC) under the skin using a portable infusion pump or by hand.
In addition to immunoglobulin treatment, children may need to take antibiotics or antifungal medicines to prevent infections or treat them promptly when they occur. Regular monitoring and check-ups will help to catch infections early. If an autoimmune response occurs, this can be treated with steroid and/or biologic medicines to damp down the immune system so relieving the symptoms.
In some severely affected patients, NEMO deficiency syndrome is treated using a bone marrow or blood stem cell transplant. The aim is to replace the faulty immune system with an immune system from a healthy donor. Healthy bone marrow is rich in stem cells, from which all the cells of the immune system develop, and it is possible to take bone marrow from a healthy individual whose tissue type matches the patient and give it by transfusion into the patient.
This requires treatment with chemotherapy first to remove the existing immune system, and is a fairly new treatment for NEMO deficiency syndrome so long term data needs to be collected to see how the condition is changed. It is important to remember that a bone marrow transplant will only change the immune cells and that the tissues of organs, including the gut, lungs and skin will still carry the NEMO mutation.
What happens next?
The outlook for children with NEMO deficiency syndrome is variable and depends on the severity of the gene mutation and therefore the symptoms present. With regular monitoring and prompt treatment of infections, many children can grow up to lead a near-normal life. Other children may be more severely affected, suffering repeated and serious infections, which can shorten the lifespan.