Summary
This information explains the rare immune condition called X-linked lymphoproliferative type 1 (XLP1) disorder.
XLP1 is also known as Duncan’s disease, SAP deficiency and classic XLP.
Type 2 XLP is quite different from type 1 and is described separately here.
The content has been produced jointly between Immunodeficiency UK, Great Ormond Street Hospital (GOSH) and the Great North Children’s Hospital and in association with the XLP Research Trust. The information has been reviewed by our Patient Representative Panel and by families affected by XLP1.
X-linked lymphoproliferative type 1 (XLP1) disorder is a rare immune condition that affects around 1 in every 1 million males. In affected individuals, the body cannot properly regulate an important type of white blood cell (lymphocytes) in response to a viral infection, usually the Epstein-Barr virus that causes glandular fever. The resulting excessive number of lymphocytes is known as lymphoproliferation.
Causes of XLP1
XLP1 is caused by a mutation (change) in a gene named SH2D1A, which is important for producing a protein that regulates cells of the immune system, known as lymphocytes. This protein – called SAP (short for ‘SLAM associated protein’) – may be absent or abnormal so that it affects the development of specific lymphocytes called Natural Killer (NK) cells and the self-destruct pathway when cells are no longer needed.
Inheritance and XLP1
In many cases, XLP1 is an inherited condition, meaning it is passed on in families in the same way that physical characteristics, such as eye colour, are passed from parent to child. It is caused by a mutation (change) in a child’s genetic make-up. Specialists in genetics and genetic counselling are on hand to talk through the inheritance of XLP1 with you if needed, and we have a separate information leaflet devoted to the ‘Genetic aspects of primary immunodeficiency’.
X-linked disorders, such as XLP1, are the result of mutations in genes on the X chromosome and almost exclusively affect males. It is very rare for a female to develop symptoms of XLP1. A female who has a mistake on one of her two X chromosomes also has a normal X chromosome, which compensates for the abnormal one. This means that in almost all such situations, the female is healthy but is a ‘carrier’. A male who inherits an X chromosome carrying a mutation does not have a second X chromosome to compensate, so may be affected by an ‘X-linked recessive’ disorder.
Sometimes mutations can just happen by chance (sporadically) and are not inherited from parents.
The symptoms of XLP1 are very variable and can be divided into three groups as follows:
Haemophagocytic lymphohistiocytosis (HLH)
HLH occurs when the body reacts inappropriately to a ‘trigger’, usually an infection. Instead of fighting off the infection, some white blood cells (T-cells and macrophages) become over-activated, causing severe inflammation and damage to tissues, such as the liver, spleen and bone marrow. HLH affects around half of all children diagnosed with XLP1. Immunodeficiency UK has a piece of separate information devoted to HLH, available here.
Hypogammaglobulinaemia
This is the medical term for reduced levels of antibodies (immunoglobulin) in the blood, which leads to recurrent infections, such as coughs, colds and upset stomach.
Lymphoma
Children with XLP1 have a greatly increased risk of developing lymphoma (cancer of the immune system cells) compared with the general population. Lymphoma causes symptoms such as fever, fatigue, weight loss, loss of appetite and/or sudden enlargement of one or a few lymph nodes.
Other symptoms
A variety of other symptoms have been reported. These include bone marrow failure, causing anaemia and vasculitis.
Children often have an unremarkable childhood until primary-school age and exposure to the Epstein-Barr virus. This appears to trigger the development of symptoms, although the number and severity of symptoms is variable.
The most important step is recognising that there is a problem with the immune system and involving the right specialists to investigate and treat further.
Diagnosis depends on the recognition of suggestive clinical features, along with blood tests. There are many conditions that can cause similar symptoms and it is important that careful evaluation is performed to exclude any of these.
Blood tests are the main form of diagnosis and will be used to measure the levels of SAP present in the blood. If SAP is found to be absent or in low level, the presence of a gene mutation will also be checked through a blood sample.
A sample (biopsy) of bone marrow may also be taken, along with small samples of lymph node tissue. Bone marrow is the spongy tissue inside bones and contains cells that produce white blood cells, red blood cells and platelets. Bone marrow aspiration is a procedure that involves using a syringe to aspirate (‘suck out’) liquid bone marrow, usually from the hip bone. If there are neurological symptoms, such as headache, vomiting, irritability, visual disturbances or seizures, a sample of cerebrospinal fluid may be taken by lumbar puncture.
As XLP1 is such a rare disease, treatment is usually coordinated by a specialist centre experienced in treating rare immune disorders. There are two specialist centres in the UK that treat children with XLP1 – Great Ormond Street Hospital in London, and the Great North Children’s Hospital in Newcastle. The aim is to give enough treatment to control the overactive lymphocytes without losing protection against infection, while avoiding other side effects.
Some people affected by XLP1 are more likely to develop infections than normal and may benefit from regular (prophylactic) antibiotics and immunoglobulin replacement. ‘Live’ vaccines should be avoided. In many cases, an inactive form of a vaccine is available.
If lymphoproliferation is severe, giving immunosuppressant medications to dampen down (suppress) the immune system may be helpful. These medications reduce the overreaction and lessen the risk of tissue damage. Suppressing the immune system often involves courses of corticosteroids and chemotherapy medicines, usually given into a vein (intravenously) in hospital. This treatment usually puts the condition into ‘remission’ but does not offer a cure. The only definite ‘cure’ for XLP at present is a haematopoietic stem cell transplant (HSCT), where the bone marrow is replaced with donated stem cells that do not contain the overactive immune cells.
The outlook for children with XLP1 is improving all the time, owing to better recognition of the condition and improved diagnostic testing so that treatment can be started as quickly as possible. New types of medicine are also being developed to treat HLH more effectively and with fewer side effects. HSCT is currently the only cure for XLP1, but researchers are working hard to develop gene therapy as an alternative.
Genetic counselling for the family is important and will be initiated by the specialist centre. Prenatal diagnosis is available for future pregnancies, provided that the faulty gene can be identified. You can find out more information about genetic testing in our leaflet ‘Genetic aspects of primary immunodeficiency‘
You can download our information booklet here.
