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Autoimmune lymphoproliferative syndrome

This is part of Rare diseases.

Diagnosis: Autoimmune lymphoproliferative syndrome

Synonyms: ALPS, Canale-Smith syndrome

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Publication date: 2013-12-27
Version: 2.0

The disease

Autoimmune lymphoproliferative syndrome (otherwise known as ALPS) is a disease where the body cannot rid itself of white blood cells through the process of programmed cell death (PCD). Instead, these cells accumulate in the lymph glands, spleen and liver and cause recurrent or chronic swelling of these organs, as well as causing autoimmune disease. There is also an increased risk of cancer of the lymphatic cells (lymphoma). There are several types of the syndrome, ALPS-FAS being the most common.

The disease was described in 1967 by American haematologists Virginia Canale and Carl H Smith, but it was named for the first time in 1995.

Occurrence

It is estimated that in Sweden between five and ten people have the disorder.

Cause

The syndrome is caused by mutations in one of several genes which control the formation of (code for) certain important proteins which play a significant role in the process of programmed cell death (apoptosis) in the immune system. This is a well-regulated process which, among other things, determines the size and form of various organs. Apoptosis is especially important in the immune system as it eliminates cells which the body no longer needs, after an infection for example.

One of the proteins governing apoptosis is FAS, which acts a receptor on the cell surface. Among other things, FAS controls the life span of white blood cells (lymphocytes). Defective FAS is the cause of approximately 70 per cent of cases of autoimmune lymphoproliferative syndrome. The FAS protein is activated when another protein, FAS ligand, binds to it. Other genes code for caspases, intracellular proteins which control apoptosis. Certain of these proteins activate the cell death mechanism which leads to apoptosis, while others activate a survival response. Mutations in the genes for caspase 8, caspase 10, NRAS and KRAS can, in rare cases, cause autoimmune lymphoproliferative syndrome. In approximately 20 per cent of cases, the cause is unknown.

Description Gene Protein Chromosome
ALPS-FAS TNFRSF6 FAS 10q23.31
ALPS-sFAS TNFRSF6 (somatic mutation) FAS 10q23.31
ALPS-FASLG TNFSF6 FAS-ligand 1q24.3
ALPS-CASP10 CASP10 CASP10 2q33.1
ALPS-U unknown unknown unknown
ALPS-related conditions
ALPS associated with caspase 8 CASP8 caspase-8 2q33.1
RALD (ALPS associated with RAS) Somatic mutation in NRAS or KRAS NRAS or KRAS respectively 1p13.3

Table: Mutations in the above genes cause ALPS

The immune system consists of an elaborate set of mechanisms which interact to protect us against bacteria, viruses and other pathogens. There is a distinction between innate immunity and adaptive immunity. There are also a number of natural mechanisms in, for example, the skin, mucous membranes and the acids of the stomach, which protect us against infection.

The innate immune system consists of many different proteins, certain white blood cells such as phagocytes (cells that ingest other cells), and natural killer (NK) cells. On their surfaces phagocytes have different receptors which recognize certain patterns typical of different pathogens, enabling them to destroy many of these invading micro-organisms. Other cells contain similar receptors which can recognize dangerous substances, irrespective of whether these substances have been produced by the body or originate from an external source.

The adaptive immune system collaborates with the innate immune system. It recognizes specific pathogens, and can tailor individual responses to attack and kill them. The adaptive immune system memorizes its response and successively becomes more effective.

Two types of white blood cells, B cells and T cells, play a key role in the adaptive immune system. These cells are also called T lymphocytes and B lymphocytes and are formed by the blood stem cells in bone marrow. The role of B cells is to create antibodies which attach themselves to the pathogen and then activate the phagocytes which destroy it. T cells have several different functions. They can activate B cells so that they produce antibodies, attack cells infected by viruses, and release chemical messengers (cytokines) which attract phagocytes to cells infected by viruses. T cells also have the vital role of regulating our immune systems, deciding when we need to defend ourselves, and against what. They also determine when an immune reaction is suspended. Certain T cells assist both B cells and other T cells.

Of the potential T cells which originate in the thymus, only 5 per cent learn to recognize pathogens and other threats. Ninety per cent of T cells do not develop this function, while a small proportion of cells learns, wrongly, to attack its host, thus causing autoimmune diseases. Together, these inactive and sometimes dangerous cells make up more than 95 per cent of the total, and a careful control system exists to ensure that they are eliminated in the apoptosis process. In autoimmune lymphoproliferative syndrome the control system works, but not the apoptosis process. The result is that a large number of harmful cells are released into the blood and accumulate in the tonsils, the lymph glands and the spleen. These T cells do not carry the markers indicating normal T cells, and are usually referred to as double negative T cells (Tαβ+CD3+CD4-CD8-).

Heredity

The inheritance pattern is complicated. The inheritance pattern of autoimmune lymphoproliferative syndrome is autosomal dominant, although in cases where a normal DNA analysis does not show a mutation, it has been established that many people with the disease have an acquired (somatic) mutation only, in the TNFRSF6 gene. NB This genetic mutation is found only in double negative T cells. The somatic mutation is not inherited, and the risk of passing it on is minimal.

An autosomal dominant pattern of inheritance means that one of the parents has the disease, and so has one normal and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it on.

Figure: Autosomal dominant inheritance

Symptoms

The degree of severity of symptoms may vary greatly. Usually symptoms present during the early years of life, but with increasing knowledge of the disease, adults with less obvious symptoms may also be diagnosed with the condition. The most common symptoms are enlarged lymph glands (lymphadenopathy), enlarged spleen (splenomegaly) and enlarged liver (hepatomegaly).

Changes in the lymph glands can range from minor enlargements to massive swellings located in the chest cavity and abdomen. Swellings may be clearly evident and cause discomfort to the patient. Once they have developed they do not change, although they may temporarily shrink in size during periods of bacterial and viral infections. Enlargements of the lymph glands are usually not associated with a raised temperature or night sweats, and swellings are not hard, as they are in cases of lymphoma. The degree of spleen enlargement may vary greatly from time to time in a single individual, and differ greatly from person to person. The spleen may become so enlarged that it exerts pressure on the groin. Apart from the discomfort, there is a risk of injury to the spleen in connection with shocks or blows to the body.

Apart from the immunological function, to create antibodies, the function of the spleen is also to remove old and damaged blood cells. However, a severely enlarged spleen can lead to an excessive destruction of cells, which may result in a reduction in the number of red blood cells, and also possibly of thrombocytes. This condition is known as hypersplenism. Generally, hypersplenism is treated with blood transfusions. Spleen enlargement is usually most pronounced during pre-school years, often becoming smaller (though not normal) spontaneously when the young person is of school age, or adolescent. If the spleen shrinks, the symptoms of hypersplenism become less pronounced and the need for blood transfusions less acute.

Liver enlargement is often minor and does not affect normal organ function. The thymus gland may also be enlarged. In serious cases the lungs can be affected by the enlargement of the lymph glands.

Approximately 50 per cent of individuals with autoimmune lymphoproliferative syndrome suffer from other autoimmune diseases (conditions where the body builds defences against itself). Examples include haemolytic cytopenia (reduced numbers of blood cells in the blood), haemolytic anaemia (anaemia caused by the abnormal breakdown of red blood cells), immune-mediated thrombocytopenia (reduced numbers of blood platelets) and autoimmune neutropaenia (reduced numbers of a particular type of white blood cell called neutrophil granulocytes). Cytopenia is often serious, difficult to treat and may be life-threatening.

More unusual symptoms include inflammation of the small blood vessels of the kidney (glomerular nephritis), inflammation of the optic nerve (neuritis), Guillain-Barré syndrome (inflammation of the peripheral nerve system), two liver diseases (primary biliary cirrhosis and autoimmune hepatitis), inflammation of the joints (arthritis) and inflammation of the blood vessels (vasculitis).

Skin rashes or weals (urticaria) are common, and are thought to be an autoimmune response. Individuals may also develop a rash (petechiae) consisting of pin-sized spots on the body, the result of minor, subcutaneous bleeding. This is caused by low levels of blood platelets in the blood.

The risk of developing autoimmunity remains constant throughout the individual’s life, and symptoms often become more severe with age. However, the risk of developing enlarged lymph glands and spleen diminishes from adolescence onwards. Established autoimmune disorders tend to follow a set pattern of regularly recurring symptoms.

The syndrome carries with it an increased risk of developing cancers of the lymph glands, including Hodgkins and non-Hodgkins lymphomas.

Diagnosis

For a diagnosis of autoimmune lymphoproliferative syndrome, a number of criteria need to be met.

Core criteria:

  • Chronic (>6 months), non-malignant, non-infectious lymphadenopathy and/or splenomegaly
  • Elevated levels of CD3+TCRαβ+CD4+CD8+ double negative T cells (>1.5 per cent of the total number of lymphocytes or >2.5 per cent of CD3+ lymphocytes) if lymphocyte levels are normal or elevated.

Additional criteria:

Primary

  • Defective lymphocyte apoptosis in two examinations.
  • Mutation (innate or acquired) in TNFRSF6 (codes for FAS), TNFSF10, (codes for FAS ligand) or CASP10.  

Secondary  

  • In plasma, elevated levels of sFASL (>200 pg/ml), IL-10 levels (>20 pg/ml), vitamin B12 levels (>1500 ng/l) and/or IL-18 levels >500 pg/ml
  • Typical immunohistological characteristics
  • Autoimmune cytopenias, (haemolytic anaemia, thrombocytopenia and/or neutropaenia) with elevated levels of IgG (polyclonal hypergammaglobulinaemia)
  • Family history of non-malignant/non-infectious lymphoproliferation with or without autoimmunity.

Definite diagnosis requires: both core criteria, plus at least one primary criterion.

Probable diagnosis requires: both core criteria, plus at least one secondary criterion.

Autoimmune lymphoproliferative syndrome may be suspected in cases where individuals experience recurrent or chronically swollen lymph glands and an enlarged spleen and liver, and show symptoms of autoimmune disease.

The diagnosis can be confirmed by a DNA analysis. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnostics, as well as pre-implantation genetic diagnostics (PGD) in association with IVF (in vitro fertilization), are available to families where the mutation is known.

Treatment/interventions

Treatment is determined by the nature and severity of symptoms. Many people with the syndrome manage without treatment. The only treatment which can completely cure autoimmune lymphoproliferative syndrome is a haematopoietic stem cell transplantation, but the disease is rarely so serious that it warrants such an intervention.

Cortisone treatment and immunosuppressants

Cortisone is currently the only medication where the results of treatment have been confirmed as positive. It is often given for short periods, although longer courses of treatment may sometimes be necessary. Treatment outcomes, as well as adverse effects, are dosage-related. Side effects of cortisone treatment include restricted growth (in children), an increased risk of infection, high blood pressure, brittle bones (osteoporosis) and weight gain, as well as psychological side effects such as mood swings, depression and sleep problems. Individuals undergoing cortisone therapy should always be carefully monitored to evaluate treatment results and adverse effects. There are current guidelines for diagnosing and treating individuals with an elevated risk of osteoporosis as a result of long-term cortisone treatment.

As high dosages of cortisone may lead to serious side effects, it is usually supplemented with other immunosuppressive medicaton, which both reduces the need for cortisone and makes it more effective. The most commonly used immunosuppressants are mycophenolic acid, rituximab and sirolimus. Of the three, sirolimus is most effective at shrinking enlarged spleens and reducing the size of lymph glands in the majority of cases. In this way, hypersplenism is reduced, along with the need for blood transfusions.

Immunosuppressants also usually help skin rashes.

Removal of the spleen

If pharmaceuticals do not succeed in reducing the size of the spleen it may be removed (splenectomy). This improves the blood cell count and reduces the risks and discomfort that are associated with an enlarged spleen. If possible this operation should be postponed until the child is at least five or six years of age, when the risk of infection is less. It is also important that, as a complement to the most common vaccines, the individual receives vaccines against bacteria such as pneumococcus and meningococcus, which are encapsulated by polysaccharides. For people without a spleen, it is primarily these bacteria which carry increased risks of bacterial infection and blood poisoning (sepsis). If individuals develop a high temperature or their general condition deteriorates, they should immediately seek medical attention so they can receive antibiotics.

Blood transfusions

In severe cases of anaemia, blood transfusions help replace missing red blood cells. However, blood transfusions also provide the individual with excessive quantities of iron, which are stored in the body and may cause injury to organs including the liver, heart and lungs. If frequent blood transfusions are required, it is important that ferritin levels are monitored as they indicate the amount of iron stored in the body. Where ferritin levels are high, medication should be administered to increase the excretion of iron (iron chelation therapy). As this medication can give side effects, regular medical check-ups are essential.

Haematopoietic stem cell transplantation (HSCT)

Haematopoiesis refers to the formation of blood cells. In some cases, haematopoietic stem cell transplantation (otherwise known as a bone marrow transplant) has successfully been carried out on individuals with autoimmune lymphoproliferative syndrome.

Blood stem cells are immature cells which can develop into all blood cell types. They are found primarily in bone marrow, but are also plentiful in blood from the umbilical cord. A stem cell transplant provides the opportunity to replace the sick stem cells with those from a healthy person. In such cases the donor must have the same tissue type as the recipient.

To optimize the chances of successful transplantation, the recipient of the marrow should be as free from infection as possible and in good physical condition. The intervention itself is fairly simple, but the preparations, aftercare and major risks make it a highly demanding procedure. The stem cells are given as a drip directly into a blood vessel and find their way into the recipient’s bone cavities where they grow, supplying the patient with a new immune system with healthy blood cells. It may take up to a year before the new bone marrow is fully functional.

Other points

As far as possible, infection should be avoided. As well as the common childhood vaccinations, individuals with the syndrome should be vaccinated against influenza every year and against the pneumococcus pathogen approximately every five years.

It is extremely important that both the individual with autoimmune lymphoproliferative syndrome, and his/her family, are offered psychological and social support. It is also important that personnel at the child’s day care centre or school are informed about the syndrome. The school should have a plan for how, in the event of increased absences, the child will be helped to achieve his or her goals. Risks associated with an enlarged spleen should also be noted. If the child has an enlarged spleen it is especially important that the physical education teacher is informed. The spleen must be protected against blows and shocks so it does not rupture.

Contact sports like ice hockey, football, handball, martial arts and riding are not recommended.

Practical advice

In the US, spleen guards made of rigid plastic to protect enlarged spleens during sports or games can be tailor-made for individuals. It is possible to buy similar guards in Sweden, where they are used for example in motor cross competitions.

People who do not have a spleen should carry a special ID card. Contact the Primary Immunodeficiency Organization (PIO). See under “Organizations for the disabled/patient associations etc.”

National and regional resources in Sweden

Paediatric Immunology, Department of Medicine, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Resource personnel

Professor Anders Fasth, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, fax: +46 31 84 30 10, email: anders.fasth@gu.se.

Courses, exchanges of experience, recreation

PIO, the Primary Immunodeficiency Organization in Sweden, offers training, support, information and the opportunity to meet others in the same situation. PIO publishes information and organizes regular lectures and information meetings for people with primary immunodeficiency disorders, their relatives and other interested parties. Weekend courses are held annually for children and young people with primary immunodeficiency disorders and their families. Regular joint meetings over several days are held with members of the Nordic immunodeficiency organizations. For further information contact PIO. Find address under “Organizations for the disabled/patient associations” below.

IPOPI, the International Patient Organisation for Patients with Primary Immunodeficiencies, of which PIO is an affiliate, arranges a conference in conjunction with a biennial international medical conference for doctors and nurses interested in immunodeficiency. IPOPI conferences are conducted in English. For further information, contact PIO, under “Organizations for the disabled/patient associations.“

Organizations for the disabled/patient associations etc.

PIO, The Primary Immunodeficiency Organization in Sweden, Mellringevägen 120 B, SE-703 53 Örebro, Sweden. Tel: +46 19 673 21 24, email: info@pio.nu, www.pio.nu.

Courses, exchanges of experience for personnel

SLIPI, Swedish Physicians’ Association for Primary Immunodeficiencies organizes meetings and conferences, www.slipi.nu.

SISSI, Swedish Nurses’ Association for Primary Immunodeficiencies.The association publishes a newsletter and has regular conferences for members. In alternate years this is organized in collaboration with ESID, IPOPI and INGID, www.sissi.nu.

ESID, European Society for Immunodeficiencies.
The Society has regular international conferences and summer schools for doctors and researchers, www.esid.org.

INGID, International Nursing Group for Immunodeficiencies. The Group arranges international meetings in collaboration with ESID and the international patient organization IPOPI, www.ingid.org.

Research and development

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Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under “Mer hos oss“ in the column on the right-hand side. Postage will be charged for bulk orders.

The material below can be ordered from PIO (the Primary Immunodeficiency Organization). See contact information under “Organizations for the disabled/patient associations etc.” Unless otherwise mentioned, in Swedish only.

  • Primär immunbrist hos barn och vuxna. Primary immunodeficiency in children and adults. Ninth edition, 2010.
  • Så mår immunförsvaret bättre. Living with primary immunodeficiency. Some practical advice. 1999.
  • The story of primary immunodeficiency. (In English.) 1999
  • En skola för alla. Practical advice on creating a better school environment for those with primary immunodeficiency. One binder for the institution and one for the student. Third edition, 2012.
  • Studera med primär immunbrist. Practical advice for university or college students with primary immunodeficiency. One brochure for the institution and one for the student. First edition, 2008.
  • Lathund för ansökan av vårdbidrag. Updated, 2012.

Literature

Canale VC, Smith CH. Chronic lymphadenopathy simulating malignant lymphoma. J Pediat 1967; 70: 891-899.

Dowdell KC, Niemela JE, Price S, Davis J, Hornung RL, Oliveira JB et al. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood 2010; 115: 5164-5169.

Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995 16; 81: 935-946.

Holzelova E, Vonarbourg C, Stolzenberg MC, Arkwright PD, Selz F, Prieur AM et al. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med 2004; 351: 1409-1418.

Kuehn HS, Caminha I, Niemela JE, Rao VK, Davis J, Fleisher TA et al. FAS haploinsufficiency is a common disease mechanism in the human autoimmune lymphoproliferative syndrome. J Immunol 2011; 186: 6035-6043.

Magerus-Chatinet A, Stolzenberg MC, Loffredo MS, Neven B, Schaffner C, Ducrot N et al. FAS-L, IL-10, and double-negative CD4- CD8- TCR alpha/beta+T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function. Blood 2009; 113: 3027-3030.

Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De Somer L et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood 2011; 118: 4798-4807.

Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood 2010; 116: e35-40.

Oliveira JB, Gupta S. Disorders of apoptosis: mechanisms for autoimmunity in primary immunodeficiency diseases. J Clin Immunol 2008; 28: 20-28.

Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood 2011; 118: 5741-5751.

Rao VK, Price S, Perkins K, Aldridge P, Tretler J, Davis J et al. Use of ritumixab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS). Pediatr Blood Cancer 2009; 52: 847-852.

Rao VK, Dugan F, Dale JK, Davis J, Tretler J, Hurley JK et al. Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome. Br J Haematol 2005; 129: 534-538.

Takagi M, Shinoda K, Piao J, Mitsuiki N, Takagi M, Matsuda K et al. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. Blood 2011; 117: 2887-2890.

Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol 2009; 145: 101-106.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: autoimmune lymphoproliferative syndrome, ALPS

GeneReviews (University of Washington)
www.genetests.org (select “GeneReviews “, then “Titles “)
Search: autoimmune lymphoproliferative syndrome, ALPS, Canale-Smith syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor Anders Fasth, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.

The relevant organizations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication

Date of publication: 2013-12-27
Version: 2.0
Publication date of the Swedish version: 2012-12-06

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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