Primary Immunodeficiency Association

Dr Alison Jones, Clinical Immunologist at Great Ormond Street Hospital, provides an overview of Hyper IgM.

What is Hyper-IgM syndrome?
Hyper-IgM syndrome, or ‘Hypogammaglobulinemia with Hyper-IgM’ is one of the rarer inherited immunodeficiencies. It is difficult to estimate the actual number of affected individuals as there are almost certainly a number of undiagnosed cases. However, an European database dedicated to the most well understood form of the Hyper-IgM syndrome now exists and contains data from 130 families.

There are two types of Hyper-IgM syndrome, X-linked and Autosomal Recessive.

X-linked Hyper-IgM syndrome (XHIM) is the more common type and affects only males. ‘Carrier’ females have one copy of the abnormal gene on one of their two X chromosomes, but are themselves not affected. Sons of carriers have a 50% risk of inheriting the abnormal gene from their mothers. As males have only one X chromosome, if they inherit the abnormal gene they will be affected by the disease. Daughters of carriers have a 50% risk of being carriers. Approximately 30% of cases of XHIM arise as ‘new mutations’ and in these cases there is no previous history of the disorder in the family.
Autosomal Recessive Hyper-IgM syndrome (ARHIM) is much rarer and affects both sexes. People with this type have two copies of an abnormal gene, one inherited from each parent. Recently, a gene has been identified which is responsible for some cases of ARHIM, but in others the genetic defect remains unknown.

What are the main symptoms of Hyper-IgM syndrome?
In both types of Hyper-IgM syndrome children usually become ill between the ages of six months and two years, once the antibodies they received from their mothers during pregnancy have disappeared.

The commonest problems are recurrent infections - usually ear, throat, and chest infections - which may be severe and/or very frequent. If the underlying immunodeficiency is not spotted and treated appropriately, there is a risk of permanent damage to lungs or ears.
In some patients the first hint of an immunological problem is a serious form of pneumonia known as PCP (Pneumocystis carinii pneumonia), which occurs commonly in immunodeficiencies affecting T cells. Indeed, the fact that patients with Hyper-IgM syndrome are so prone to catch PCP provided a valuable clue in the search for the defect causing the X-linked form of this disorder.

In addition to frequent respiratory infections, various other problems can occur in Hyper-IgM syndrome:

Diarrhoea is common. One particular infection which causes diarrhoea and is commonly associated with Hyper-IgM syndrome is Cryptosporidium.
Other sites of infection may include bones and joints, causing osteomyelitis (infection of the bone) or arthritis.
Mouth ulcers can occur frequently, and are often associated with low numbers of certain white blood cells called neutrophils.
Some patients become anaemic, and may develop bruising as a result of a low platelet count (thrombocytopenia).
Liver problems may occur – see below.

How is Hyper-IgM syndrome diagnosed?
Although the name of this disorder might lead people to expect high levels of IgM (one of the three major classes of antibodies) - and this is often the case, this is not found in all patients. The most usual findings are low levels of IgG and IgA (the other two major classes of antibody), with either normal or high levels of IgM.

For XHIM a specific test is now available which confirms the diagnosis reliably, and in most cases the precise gene mistake can also be identified. It is then possible to analyse DNA from female family members to find out whether they are carriers of XHIM and to offer a prenatal diagnostic test very early in pregnancy, should the family wish it.

In some cases of ARHIM the precise gene abnormality can also be pinpointed, allowing prenatal testing for any future pregnancies.

Complications of Hyper-IgM syndrome
In recent years it has become clear that there is a particularly high rate of liver abnormalities in XHIM. The most common form of liver disease is known as sclerosing cholangitis, and involves abnormalities of the bile ducts which can eventually progress to severe liver damage and liver failure. The cause is uncertain - it is likely that infection with cryptosporidium plays a role, but autoimmunity and infection with viruses may also be involved.

Other types of liver disease which occur more frequently than usual in XHIM include hepatitis C and hepatitis B. Chronic liver disease caused by any of the above can progress to liver cancer, and there is also an increased incidence of malignancy in the gastro-intestinal tract (the gut).

How is Hyper-IgM syndrome treated?
The main treatment for Hyper-IgM syndrome until recently has been lifelong immunoglobulin replacement therapy, and this remains the case for all patients with the autosomal recessive form of the disorder (ARHIM). However, because of the high rate of liver disease and malignancy in XHIM, bone marrow transplantation (BMT) is considered in all affected boys. For those who are suitable for BMT, successful transplantation can cure them of their immunodeficiency.

Immunoglobulin doses are based on the individual’s weight, but also depend on the frequency of infections, general well-being and ‘trough’ IgG levels. (IgG is measured before each infusion and the dose adjusted to maintain the trough level within the normal range). Immunoglobulin infusions can be given intravenously (through the vein) or subcutaneously (under the skin). Intravenous infusions are usually required every three weeks, and subcutaneous infusions once or twice weekly. Although many people receive their immunoglobulin in hospital, more and more are moving on to home therapy which makes their overall quality of life much better.
It is important to guard against other infections which may not be prevented by immunoglobulin.
- For PCP this requires a daily dose of antibiotics, most usually Cotrimoxazole (Septrin).
- Protection against infection with cryptosporidium is provided by boiling all drinking water, or installation of a professionally fitted high performance (<1 micron) filter on domestic water supplies.
Any breakthrough infections should be treated promptly with antibiotics. Some patients continue to suffer from repeated infections in spite of adequate immunoglobulin treatment. They may need continuous antibiotics to prevent damage to organs such as lungs or ears. It is also important to look out for signs of long term damage to organs. This may mean regular assessments by ear, nose and throat specialists and respiratory specialists, as well as specialised scans to detect early signs of lung damage. Careful attention to teeth is also important, since tooth decay can be a source of infection and ill-health.
In some people neutropenia can be severe and persistent, contributing to frequent infections and mouth ulcers. This may improve with higher doses of immunoglobulin, but treatment with GCSF (Granulocyte Colony Stimulating Factor) which stimulates the bone marrow to boost neutrophil production may be needed. Anaemia and thrombocytopenia may also improve with higher doses of immunoglobulin.
It is important to monitor very carefully for signs of liver problems with regular liver function tests including a special one called g-GT (gamma glutamyl transferase), special X-rays and sometimes a liver biopsy. In some boys with XHIM, BMT may be recommended before there is any sign of liver disease, but for all others regular liver assessments are essential. (See below for further discussion of BMT in XHIM.)

Many people with Hyper-IgM syndrome lead normal, healthy lives, provided that they receive adequate replacement immunoglobulin and appropriate treatment for infections.

Bone Marrow Transplantation (BMT) for XHIM
BMT has been the standard treatment for very severe immunodeficiency for over twenty years, but was initially only performed in children for whom life expectancy was limited to a few years. During the past five years, there have been major advances in a number of areas relating to BMT:

The overall result of all these changes is that BMT can be offered to many more individuals than previously and outcomes have improved considerably.

XHIM was originally considered to be a disorder primarily of antibody deficiency, which would most appropriately be treated with immunoglobulin replacement. Increasing experience with XHIM has led to recognition of the high frequency of complications by the age of 25 years.

In the UK many discussions have been held in the past few years concerning the best management of boys affected by XHIM. Most prophylactic measures are clear cut. However, the current policy on BMT is not so clear. In patients without organ damage, BMT is now recommended if there is a matched sibling donor and should be carefully considered if there is a 9/10 or 10/10 matched unrelated donor. If no perfectly matched donor is available, or if the family prefer to follow a less radical treatment, it is considered reasonable to continue prophylactic therapy with very careful monitoring for evidence of liver disease. If signs of liver disease or other complications develop in spite of the best possible treatment BMT should be reconsidered.

At present there are a number of people affected by XHIM who already have liver disease. BMT can usually still be offered in this situation, but it is likely to be more complicated because of the effects of chemotherapy on the damaged liver.

For more information on BMT, please refer to the PiA’s booklet ‘Bone Marrow Transplants for Primary Immunodeficiencies’.

Will other treatments become available?
Now that the genetic defect underlying XHIM has been discovered, there is a real possibility of the development of gene therapy. This is a complex challenge, but early successes are being reported in another form of immune deficiency (X-linked severe combined immunodeficiency) and the range of disorders for which gene therapy may be available is likely to increase over the next few years.

On being asked to contribute to this booklet PiA member Andi Thomas said: "I would like to show other people with primary immunodeficiencies that it is possible to sustain recurring infections and still live a normal life."

Background
I don't really see my condition as a problem, rather as something to outwit. At 38 I am allegedly the oldest known surviving Hyper-IgM patient and I intend to keep it that way. I was incredibly ill for the first twelve years or so of my life with recurring chest and bowel problems, junior rheumatoid arthritis, problems keeping food down, problems absorbing nutrients from what food I did keep down, perforated ear drums... I became a bit of a guinea pig in that any new drugs on the market were given to me in an effort to see if they helped. However, as you will read, the cocktail of drugs must have done me some good.

Childhood
As a child I was in and out of hospital for minor operations on my ears culminating in an operation to patch up a hole in one of my eardrums with a piece of vein from my right arm. At the age of four I was unable to move due to rheumatoid arthritis. Then there were numerous blood samples, tablets, injections, and weekly intramuscular injections of gammaglobulin.

When I was well I tried to do what other children did. I made the most of the bits in between illnesses when I was well enough to go out and play. I was very lucky in that I had a very supportive family who looked after me and encouraged me. I was diagnosed very early - at 18 months - and so had treatment from that age. This I believe is very important to my current wellbeing. I also had a very positive attitude to being well and a very, very negative attitude to being ill!

Gradually I began to feel better. From about the age of twelve or so, my limbs did not swell and I was eating properly and putting on weight. Life became more exciting as I began to play sport and felt wonderful at the age of sixteen to be picked for the school Rugby 2nd XV, playing on the wing. I still had my problems - particularly chest infections and abscesses - but if I was ill I tried as hard as I could to be positive and aid my recovery.

Current situation
So far I have been successful in my chosen career, recently becoming a Registered Safety Practitioner and Fellow of The Institution of Occupational Safety and Health. It hasn't been easy, and after a succession of employers being none too sympathetic about the amount of time I had away from work, I decided to become self-employed. It is not easy working for yourself at the best of times, but working for yourself and having a primary immunodeficiency… well, I can now work around my hospital appointments! When I am unwell I can usually do something at home on my PC. In addition, most clients are sympathetic and allow me to re-schedule any work for a later date - although this is something I try to avoid.

General outlook
I suffer, as many of us do, with recurring infections, battles with my GP to allow me to infuse at home (which I now do), and long discussions with my consultant immunologist about whether to go ahead with a bone marrow transplant. The decision rests upon whether I continue in good health. I still suffer from some problems but I play sports, go to concerts, travel and ski when I can afford to. I am also lucky to have a very supportive partner.

Anyone who has a primary immunodeficiency is going to face problems. However, I feel it is very important to be positive about your health. Having a positive attitude to life has contributed to my overall wellbeing.

This article is dedicated to the memory of Daisy Ellen Cole and Peter Harbourne, both of whom may be gone but are not forgotten.

Bone Marrow Transplantation Transfer of bone marrow, obtained by aspiration
usually from the hip bones, from a donor to a recipient. In this case the donor bone marrow replaces the recipient bone marrow and provides a new immune system, curing the immunodeficiency.

Chromosome A structure, present in the nucleus of all body cells (apart from red blood cells), which stores genetic information. Normally humans have 23 pairs.

Cryptosporidium An unusual infection which causes diarrhoea and may become chronic. It affects mainly the gastrointestinal tract (gut) and bile ducts. It may be linked with the development of liver disease.

DNA DNA is the chemical part of the chromosomes, which provides the genetic code (information).

Gene Section of DNA on a chromosome, which 'codes' for a particular protein.

Gene therapy Replacement of a defective gene with a normal copy in order to cure a genetic disorder.

Neutropenia Reduced numbers of neutrophils (infection-fighting white blood cells) in the blood stream.

Platelets Tiny cell fragments which circulate in the bloodstream, and are important in preventing bleeding.

T cells White blood cells produced in the bone marrow and processed in the thymus (a gland in your chest). They play a very important part in co-ordinating and regulating the activities of the different cells in your immune system.

Medical information published by the PiA is approved by our Medical Advisory Panel. However, it is intended for general guidance only, and should not be used in place of the personal consultation needed with your physician.