Introduction

The name used to describe a disease may be descriptive, as in X-linked agammaglobulinaemia, or it may take the name(s) of the discoverer(s) as a short and convenient label. Both X-linked agammaglobulinaemia (XLA) and Wiskott-Aldrich Syndrome (WAS) are primary immune deficiencies which are inherited as sex-linked disorders. XLA is effectively described by its name, since it is a lack (a) of gamma globulins in the blood (aemia). "Wiskott-Aldrich" does not tell the reader anything about the disease; here follows an essay to define Wiskott-Aldrich Syndrome.

This disease is both rare (4 per million live male births) and complex. Research over recent years has made encouraging progress in understanding WAS and has made the diagnosis easier and more precise. I will begin with a description of the symptoms of WAS, move on to the current understanding of why the disease occurs, describe the current research and where it is leading, and finish by discussing treatment.

The Symptoms of Wiskott-Aldrich Syndrome

WAS was first described in 1937 by Wiskott. He noticed a large Munich family in which three brothers were severely ill from birth with an identical set of symptoms: i.e. eczema, a tendency to bleed and bruise without previous injury, and recurrent infections. However, their four sisters were quite well. Seventeen years later Aldrich reported the same combination of symptoms (known as a syndrome in medical terms) in members of a family in which 16 of 40 males were affected over four generations, but no females, suggesting sex-linked inheritance. It is from these two clinical reports that the name of this primary immune deficiency is derived.

When all of these features are present in severe forms, a diagnosis of WAS is usually made during the first year of life. The boy infant is severely ill, with the first symptoms usually appearing before he is six months old. Many cases are fortunately less severe, but then the diagnosis is less clear and the disease may not be diagnosed for several years. The need to carry out laboratory tests that can make a diagnosis in these cases comes from the suspicion raised by the patient's symptoms; so an awareness of the condition in the first place is an important factor.

Immune deficiency is a consistent feature in true WAS. This appears as a susceptibility to infections although the severity of the immune deficiency varies greatly between patients. Patients may suffer a variety of infections with viruses, fungi, and other organisms. At the same time antibody production is often deficient in both quantity and quality. Patients cannot make enough antibodies to those bacteria which cause ear, sinus or chest infections. This problem used to be detected by finding that the naturally occurring blood group antibodies (called isohaemagglutinins) were missing. Nowadays it is usually detected by immunisation with a variety of vaccines. These deficiencies in antibodies result in bacterial infection of the ears, sinuses, etc. - indeed, the sort of infections with which patients with Hypogammaglobulinaemia suffer.

Most patients with WAS also suffer from spontaneous bleeding and bruising because their blood does not clot properly. For blood to clot, it has to have a complete set of plasma proteins called clotting factors, as well as good numbers of normal clotting cells known as platelets. Platelets are cell fragments which have budded from a bone marrow cell, the megakaryocyte, and circulate in the blood. Platelets in WAS are abnormal; they are small and don't work well. They survive in the blood for less time than normal platelets because they are destroyed in the spleen. The result is a low platelet count, known as thrombocytopenia, and this results in bleeding and bruising. The extent of these problems also varies in patients with WAS.

Eczema, the third major problem of WAS sufferers, is like the eczema of small children and is, yet again, of variable severity. It is treated like atopic eczema in children. There is an allergic component to the severe forms which, if recognised, can give clues which might help in treatment. In WAS there is not only soreness, itching, etc., but also problems of bleeding into the rash and susceptibility to infection which can complicate the rash.

Other problems affect some, though not all, patients with WAS. Undoubtedly the most worrying is a slightly increased incidence of cancer, particularly lymph node cancer. The risk has been estimated at about one hundred times that of the general population and obviously it increases, as other cancer risks do, as patients grow older.

In short WAS is a very serious, if rare, primary immunodeficiency. The variation in severity of individual cases must be emphasised; for example, some families with the laboratory abnormalities of WAS just have thrombocytopenia with eczema, but no immune deficiency.

Why does WAS occur?

Tlie final answer to that question will come from genetic studies which are in progress. The fact that this primary immune deficiency is so clearly sex-linked must mean that the primary genetic fault is an abnormality of a gene somewhere on the X-chromosome. The responsible gene has not yet been fully identified (cloned), but so-called linkage studies have closely defined where to look for it. Once the gene has been cloned, it will be possible to define the protein made by that gene.

Scientists can already predict that this protein will play a part in putting together the surface membrane of those cells which are abnormal in WAS. It is known that the cell walls of these cells, lymphocytes, and platelets are abnormal, due to instability of particular molecules which make up the cell walls. This instability is due to a failure of a process called glycosolation; glycosolation makes many proteins more stable and enables them to function better. This abnormality has resulted in a relatively easy test (CD43 test) which is useful in the diagnosis of WAS in doubtful cases.

Just what part this abnormality plays in causing the immune deficiencies in WAS is unknown. It may play a part in the growth of T lymphocytes after they have been stimulated to respond to infection. It may also affect the function of B lymphocytes which are responsible for producing antibodies in response to infection. The problem is with stability of the molecules on the cell surface.

The prediction, then, is that the protein manufactured by the gene on the X-chromosome will prove to be an enzyme required to make proteins stable on the cell surface.

The clinical care of patients with WAS

We now need to discuss the diagnosis, treatment, prognosis, and family management in WAS. At present the diagnosis depends on awareness and recognising the possibility of WAS, given an infant's symptoms and family history. It must be remembered that a significant proportion of patients will not have a family history because they are in the first generation to express the genetic disorder. Next, in the laboratory, faults in platelet structure, size and function, as well immunological tests, must be made to confirm the diagnosis. As pointed out earlier, studies of CD43 on the lymphocyte surface can be most helpful.

The risk of bleeding is reduced by keeping the platelet count as high as possible and avoiding drugs, such as aspirin and certain anti-rheumatics, which interfere with platelet function. It may be necessary to give a platelet transfusion in a crisis. Surgery to remove the spleen (splenectomy) usually raises the platelet count dramatically and permanently, and this may be necessary if difficult problems persist. However, it must be remembered that splenectomy adds to the immune deficiency, and both the immunologist and the haematologist need to be involved.

The immune deficiency is routinely managed by careful and early attention to any infection, by antibiotics, and by appropriate physiotherapy. Immunologists are increasingly convinced that patients with WAS benefit from replacement therapy with intravenous immunoglobulin. This has also made splenectomy a much safer procedure.

Bone marrow transplantation provides a more fundamental approach for severely affected patients. When it is successful, it corrects both the thrombocytopenia and immune defect, as well as the eczema. Good results are reported if bone marrow is available from a brother or sister with the same "tissue type" as the patient. Thie process of transplanting matched marrow from unrelated donors is more complex, and any decision has to be made for the individual, especially since WAS itself varies greatly in severity.

The decision to attempt bone marrow transplantation is helped by a well-informed view of the prognosis of WAS. When it is severe, the prognosis is poor and bone marrow transplantation must be given early consideration. However, modern antibiotics, immunoglobulin, and better treatment for eczema are improving the outlook for most patients considerably. The immunology laboratory is diagnosing WAS in patients with much milder disease, so that past experience is no longer relevant to the prognosis or management of these patients. A cure by gene therapy is the goal for the 1990s.

Finally, families with sons with WAS need genetic advice. Particularly pertinent is the detection of female members of the family who are carrying the defective gene; they are not affected themselves because they have one good copy of the gene on one of their two X-chromosomes. The defective gene cannot yet be identified directly, but because the good gene is vital to normal function, the defective X-chromosome in carriers is switched off completely in order that the cells can function properly. This "switch-off " state can be detected in the laboratory and is used to detect "carrier status" so that informed genetic counselling can be given to the family.

Summing up

So what are we going to call this condition?. The "X-linked glycosolation defect" syndrome might be a suggestion, but I think you will agree sticking to the names of the discoverers is more attractive. I think that Wiskott and Aldrich would be amazed by how far we have come in understanding their disease, and how close we are to a much fuller explanation of the disease and, in the end, through gene therapy, its cure.

Dr TB Wallington
Regional Immunology Service
South Western Regional Transfusion Centre
Bristol