Great Ormond Street Hospital for Children NHS Foundation Trust: Information for Families Severe combined immunodeficiency (SCID)

This information sheet from Great Ormond Street Hospital explains the causes, symptoms and treatment of severe combined immunodeficiency and where to get help. SCID is the name given to a group of rare Blood cells and inherited disorders which cause severe Just under half of the volume of blood abnormalities of the . consists of blood cells which are tiny and This happens when white blood cells, can only be seen through a microscope. responsible for fighting , are The rest of the blood volume is plasma, missing or working poorly. Their absence a watery liquid which contains dissolved or poor function results in serious and proteins, sugars, fats, salts and minerals. often life threatening . There are three main types of cells in the Three types of can be blood: red blood cells, white blood cells affected: T and B and natural and platelets. killer (NK) cells. Not all cases of SCID are It is the white blood cells that play an identical but all children with SCID have important role in defending the body poorly working immune systems and will against infection. All blood cells are need protection from infection. derived from immature cells known The first case of SCID was reported in as stem cells, sometimes referred to as 1950 and, following a number of isolated “mother cells”. Some stem cells can be reports of affected children, the term SCID found in the blood, but the richest supply was introduced to describe the syndrome. is found in the bone marrow. Before the advent of modern medication The diagram on page 2 shows which and treatment, most affected babies did blood cells are affected in SCID. not survive beyond their first year. Today doctors understand much more about SCID. Treatment is now available that can reduce the risk of serious infection, and in many cases, cure the disorder.

Sheet 1 of 10 Ref: 2012F0479 © GOSH NHS Foundation Trust April 2012 Blood and Immune cells blood stream and are then referred to as tissue . Stem cells are cells that are capable of giving rise to all blood cells. Lymphocytes: these play a central role in the immune system. Red blood cells are also known as erythrocytes or red blood corpuscles. They There are several different types of contain haemoglobin which transports lymphocytes and these are the blood cells oxygen to all parts of the body. specifically affected in SCID: Platelets or thrombocytes play a vital „„B Cells sometimes referred to as B role in blood clotting or coagulation. Low lymphocytes, recognise and attack levels of platelets may cause bleeding that germs or foreign attackers. They is difficult to control. produce specific that fight a specific invader. These antibodies White blood cells or leukocytes are sometimes referred to as protect the body against infection gammaglobulins or Immunoglobulins. and fight it when it occurs. There are These work by recognising and binding three main types of white blood cell: to infecting organisms, ‘marking’ them , and lymphocytes. for destruction by other cells in the Granulocytes: the most common immune system. There are five main granulocytes are called . types of antibodies: IgA, IgD, IgE, IgG They are responsible for isolating and and IgM, of which IgA, IgG and IgM are destroying invading bacteria, literally the most common. ‘swallowing’ bacteria. For this reason „„T Cells also known as T lymphocytes, they are known as . Other also recognise and attack specific granulocytes are and germs or foreign attackers. They play and play a part in allergic reactions. an important role in co-ordinating the Monocytes: these play a role in immune defences and kill organisms protecting against certain infections such by secreting toxic chemicals called as fungal infection and (TB) lymphokines. T cells are especially and in cleaning up debris from sites of important for killing . infection or injury. They can leave the „„NK Cells or Natural Killer cells are able to kill cells directly. They kill a variety of target cells (such as tumour cells, infected cells, transplanted cells).

Sheet 2 of 10 Ref: 2012F0479 © GOSH NHS Foundation Trust April 2012 What causes SCID? deaminase (ADA) deficiency, MHC class II deficiency or recombinase activating gene SCID is caused by a defect or mutation in (RAG) deficiency. a child’s genetic make-up. It is an inherited condition – passed on in families in the same way as physical How is SCID inherited? characteristics are passed from parent to There are two main ways in which SCID child. can be inherited. These are autosomal In the centre of every cell in the body recessive type inheritance and X-Linked there are 46 string-like structures known inheritance. as chromosomes. The chromosomes are arranged into 23 matching pairs. For ease of identification the chromosome pairs are Autosomal Recessive numbered according to size from one to 23. Type Inheritance The last pair – number 23 – are the sex chromosomes which determine whether a

child is male or female. Carrier father Carrier mother

X/Y - normal copy of gene Each pair of chromosomes is like a double X/Y - affected copy of gene string of thousands of beads. Each bead X Y X X is a gene. Each gene is responsible for a certain characteristic (hair colour for XX X Y X XYX instance). Scientists know that each gene is responsible for producing a particular Carrier girl Affected boy Unaffected girl Unffected boy protein many of which are necessary for the Everyone is a carrier of around three to development of a normal immune system. five different genetic disorders. In most A defect in one of these genes results in cases a person never knows about them absence of the protein that is necessary because the fault lies in one gene of one for a functioning immune system. There chromosome and the other healthy half are a number of different genes that of the pair switches on to compensate for can be affected, each causing a different the faulty one. type of SCID. A problem only arises if a person’s partner These important findings now enable carries the same faulty gene as they doctors to make a much more specific do, and their child inherits both faulty diagnosis. The names given to the chromosomes. different types of SCID are based on the If coincidentally both parents carry the particular protein or gene that is deficient same faulty gene, there is a 25 per cent – for example gamma chain deficiency, chance of the child inheriting the two JAK 3 kinase deficiency, purine nucleoside affected copies (and therefore developing phosphorylase (PNP) deficiency, adenosine SCID), a 25 per cent chance of inheriting

Sheet 3 of 10 Ref: 2012F0479 © GOSH NHS Foundation Trust April 2012 the two unaffected copies (in which case If the affected gene is inherited and there are no problems) and a 50 per cent the child is a girl, the father’s healthy chance of inheriting one faulty gene from X chromosome will compensate for the either one of the parents - making the affected one passed on by her mother and child a carrier. the girl will be a carrier. Because undetected gene mistakes may If the child is a boy, the father will have be found in several family members, passed on his Y chromosome which is not autosomal recessive inheritance is most able to compensate for the affected X common in children whose parents are chromosome and the child will have SCID. related to each other. This means only boys will inherit X-Linked SCID, girls can only be carriers. Approximately 60 per cent of all cases of SCID are inherited in this way. If a mother carries the affected gene for X-Linked SCID, there is a 25 per cent chance of having either: an unaffected X-Linked Inheritance boy; an affected boy; an unaffected girl or a carrier girl (see diagram below). Approximately 40 per cent of all cases of Normal father Carrier mother SCID are thought to be caused in this way.

X/Y - normal copy of gene X/Y - affected copy of gene X Y X X What are the signs and symptoms of SCID? X XXY XX Y X Sometimes, babies seem well at birth and for the following weeks. This is probably Unaffected girl Unaffected boy Carrier girl Affected boy because they are partly protected by antibodies passed from mother to baby In X-Linked SCID (otherwise known as across the placenta during the last few gamma chain deficiency) the faulty gene months of pregnancy. is carried on the X chromosome (one of The first signs of SCID generally occur the sex chromosomes). within the first three to six months. Females have two X chromosomes, men As the baby’s immune system is not have one X and one Y. A mother will working properly, they will become highly pass on one of her X chromosomes to the susceptible to infection. baby while a father will pass on either an X or Y chromosome determining the sex The baby may suffer infections more of the child. frequently than other children – run of the mill problems such as coughs and If the mother has an affected gene on one colds will seem more severe and last of her X chromosomes there is a 50 per longer than would usually be expected, cent chance that her child will inherit the requiring repeated and prolonged courses affected one, and a 50 per cent chance of of treatment. inheriting the unaffected one.

Sheet 4 of 10 Ref: 2012F0479 © GOSH NHS Foundation Trust April 2012 The more common childhood infections Sometimes the first indication that such as thrush (), chicken pox something is wrong can be a serious life (varicella), virus (rubella) and cold threatening infection which causes a rapid sore virus (herpes simplex) can also be deterioration in the baby’s condition. dangerous for a baby with SCID and may It may be necessary for the baby to be even be life threatening. admitted to an intensive care unit for Germs in the environment which children emergency treatment. During the course are often exposed to, but do not cause of routine investigations, SCID may be if the immune system is healthy, suspected. can be devastating for a child with SCID. Depending on the type of SCID, it may be In particular pneumocystis carinii possible to diagnose or at least suspect (PCP), aspergillus, cytomegalovirus the disorder by performing a simple and are examples blood test known as a full blood count. of infections that can cause severe However, it will be necessary to perform , liver disease and severe more specialised immune blood tests to diarrhoea in children with SCID. confirm this. As a result of repeated infections, the Once SCID is suspected, the child will be baby may not feed well and may not gain referred to a specialist centre. weight as fast as expected. Many infants with SCID suffer from chronic diarrhoea even when an infection How is SCID initially cannot be identified, and this also treated? contributes to poor weight gain. There are two specialist centres in the Skin rashes are common, and may be country that treat children with SCID caused by candida infection (thrush), - Great Ormond Street Hospital and at or sometimes by a reaction in the skin Newcastle General Hospital. caused by maternal blood cells which Treatment will begin when the child will have crossed the placenta at birth. be referred to one of these centres. The immediate priorities will be to How SCID normally provide an environment which protects from infection, the appropriate tests and diagnosed? assessments made and initial treatment Before parents know their baby has given. SCID they many seek help from their GP The child will normally be admitted to because of repeated infections, poor a room or an area with ‘filtered air’ (to weight gain or feeding problems. remove germs). The child will usually be If parents or the GP are worried about restricted to this room and will not be a possible problem, the doctor usually able to mix with other children or go to makes a referral to a local paediatrician. the playroom.

Sheet 5 of 10 Ref: 2012F0479 © GOSH NHS Foundation Trust April 2012 This can be one of the most difficult Medication aspects of SCID. No baby likes to be The child will need , anti-viral separated from those closest to them. and (in some cases) anti-fungal medicines Parents will be able to stay with the baby to protect against serious infection. Most and will be encouraged to continue to medicines can be given in the form of feed, care for and play with them as much syrups. If the baby has an infection it may as they want. be necessary to give the medicines into a Parents will be told about the ways that vein, through a drip. they can avoid passing on infection, such Immunoglobulin () as washing hands thoroughly. It may be therapy necessary to keep visitors to a minimum. The child will not be able to produce Soon after admission it will be necessary enough natural antibody to fight to perform further blood tests to confirm infection. It is possible to replace some of the diagnosis of SCID. the missing antibody by giving treatment It is possible to examine all the different with immunoglobulin. blood cells and determine which cells Immunoglobulin is a solution of are missing or working poorly. More purified human antibodies which have specialised tests will be carried out to been removed from normal blood determine the precise genetic abnormality. donations. It provides temporary A range of investigations will be necessary protection against infection and it is to see if the baby has any undetected given either intravenously (into a vein) infection and will include chest x-rays and or subcutaneously (injection into the scans and samples of blood, urine, faeces, skin). The child will receive regular and mucus from the throat. immunoglobulin therapy from the time Most children with SCID will have similar of diagnosis up until approximately six symptoms and will receive the same months after a bone marrow transplant. treatments whatever the type of SCID. Because it is derived from donor blood, If the child is having many blood tests giving immunoglobulin carries a small risk and needs a number of intravenous of transmitting viruses. Parents will have medications, or intravenous nutrition, it is the chance to discuss immunoglobulin usual to put in a central line (sometimes therapy in more detail and the method called a central venous catheter). This is a by which it will be given with the latex tube which is put into a large vein immunologist or nurse specialist caring for and fixed to the skin surface usually on the child before treatment starts. the chest, under general anaesthetic. It Blood Transfusions requires a small operation to put it in, but The child may need blood, platelet or it allows blood to be taken and medicine plasma transfusions. It is important to be given without the need for any that these treatments are given, but needles. precautions need to be taken first. If the child needs a transfusion, they will

Sheet 6 of 10 Ref: 2012F0479 © GOSH NHS Foundation Trust April 2012 receive specially prepared ‘irradiated’ As part of the hospital’s regular care for blood. Irradiating donor blood preserves families there is a team psychologist and the red blood cells and platelets but team social worker who can offer help removes any immune cells which may with particular problems. cause a bad reaction. The donor blood It may be possible for the child to go will also be screened to ensure it does home for a period of time before they not contain a virus called cytomegalovirus need further treatment. (CMV) - which could cause problems for a child with SCID. The ward staff will contact local doctors and community nurses beforehand to The child’s blood, platelet or plasma make arrangements if any particular transfusion will be labelled “CMV treatments need to be given. Parents are negative” and “irradiated”. always able to ring the hospital and speak If a mother is breast-feeding a child to an immunologist or a nurse if they are with SCID, doctors will do their best to worried at any time. encourage and support that to continue. Most parents are delighted to get home, Facilities are available for mothers to but it can be a worrying time. Anxiety express and store breast milk when about catching or passing on an infection necessary. can make life very stressful. The hospital It is possible that despite all efforts to team, nurses and support groups can maintain sufficient feeding, a baby may provide families with all the information need some extra calories, vitamins and they need to protect the child from minerals. These can be given in special infection, keep the house clean and cope drinks or medicines. If the baby has with a child’s diet and medication. difficulty taking enough feed they may Babies with SCID also have to avoid some need to be given extra feeds through a vaccinations which may be dangerous. A naso-gastric tube (a tube inserted into the child should not have live such stomach through the nose). If the baby is as vaccination, measles mumps and still not tolerating feeds it may be necessary rubella (MMR) or BCG. to give feeding called TPN (total parenteral nutrition), in which all the nutrients and In addition, the polio virus can be calories are given intravenously, directly excreted by people who have recently through a drip into a vein. been immunised, so anyone in close contact with the child requiring polio Repeated hospitalisation, separation immunisation should have the alternative from extended family, blood tests and ‘killed polio’ , which is available uncomfortable procedures will contribute from the doctor. to a great deal of stress and anxiety and even guilt for parents of a child with The child will be receiving regular SCID. immunoglobulin treatment and this will provide protection against a number Ask about support groups and counselling of germs including diphtheria, pertussis services. and tetanus (DPT). The normal triple

Sheet 7 of 10 Ref: 2012F0479 © GOSH NHS Foundation Trust April 2012 vaccination programme is therefore If there is no suitable family donor an unnecessary while the child receives unrelated donor will be sought from regular immunoglobulin therapy. the world-wide donor panels. Donating bone marrow involves having a general anaesthetic but it is a relatively minor What happens next in procedure, involving minimal risk to the the treatment of SCID? donor. Bone Marrow Transplant (BMT) offers the Before the BMT can be arranged only long-term ‘cure’ for SCID at present. the donor will meet members of the transplant team who will ensure that they The aim is to replace the faulty immune have ample opportunity to see the BMT system with an immune system from a unit, discuss worries and to ask questions. healthy donor. Healthy bone marrow is rich in stem cells, from which all the The BMT will usually be carried out in cells of the immune system develop, a room on the BMT unit and the donor and it is possible to take bone marrow will be admitted a few days before the from a healthy individual and give it by drugs are given. transfusion into the child with SCID. It is usually necessary for the affected A BMT is not an operation like a heart or child to have chemotherapy drugs to kidney transplant. Stem cells contained prepare the body to receive a new in the donor bone marrow are able to immune system. find their way from the bloodstream Chemotherapy is given to reduce the to the child’s bone marrow where they chance of rejection of the new bone start to produce healthy blood cells. A marrow by the child’s own immune cells. BMT does involve a number of risks, and complications can arise - some of which If a perfectly matched bone marrow are temporary, others of which can be donor has been found within the life-threatening. immediate family then chemotherapy is not always necessary. However, in all other Parents will have the opportunity to circumstances chemotherapy is required. discuss this in detail with an immunologist and BMT consultant on a number of Not all children will receive exactly occasions. the same drug combinations. There are a number of side effects related to Early during the child’s stay in hospital, chemotherapy. blood will be collected from members of the family to determine the tissue type of each of member. If a family member is found to have an identical, tissue type to the affected baby, they will be selected to be the bone marrow donor.

Sheet 8 of 10 Ref: 2012F0479 © GOSH NHS Foundation Trust April 2012 What next? genes that can be passed on to offspring is known as germ line gene therapy and is Now, more than ever, developments and not permitted by law. improvements are being made that are transforming life for children with SCID. If there is a family history of SCID, it may be possible to offer genetic counselling Better diagnostic techniques and genetic and pre-natal diagnosis for future technology, better treatments and better pregnancies medications enable children with SCID to proceed through bone marrow transplant safely. The future too holds some exciting Further help and advice developments. Talk to the child’s doctor or health visitor. Gene therapy is currently undergoing clinical trials in selected patients and has It can also be helpful to meet another been successful in correcting or ‘curing’ family who have a child with SCID and a small number of children affected by who have gone through bone marrow X-linked SCID. transplant. Speak to the immunologist, who may be able to arrange a meeting Gene therapy aims to correct the with a suitable family. underlying genetic abnormality causing SCID. For the child, gene therapy is a The Association relatively straightforward procedure and (PIA) is a national charitable organisation if successful would offer a cure. that supports people with primary immunodeficiency and their families. The process being tested involves taking stem cells from an affected child’s The organisation has a number of blood or bone marrow and then, under regional groups around the country. The laboratory conditions, manipulating and PIA organises special days where families correcting these cells using complex gene can meet each other as well as doctors technology. Once corrected the cells are and nurses, and it also runs an after returned a few days later by transfusion hours line which puts parents in touch into the child. As in a bone marrow with someone personally involved with a transplant, these new stem cells find their primary immunodeficiency. way to the bone marrow where they start The PIA is affiliated to the International to produce healthy immune cells. This is Patient Organisation for Primary known as somatic gene therapy - altered Immunodeficiency (IPOPI). In addition genetic material is only present in the to its supportive role to families, the child’s own immune cells and cannot be PIA aims to raise awareness of primary passed on to offspring. immunodeficiency through education, People worry about the idea of gene research and advice. therapy because of the possibilities Primary Immunodeficiency of eugenics (generating an improved Association population through selection of its best After hours line (6 to 9pm Mon-Thu) characteristics for breeding). Manipulating 0845 6039158

Sheet 9 of 10 Ref: 2012F0479 © GOSH NHS Foundation Trust April 2012 Website: www.pia.org.uk „„How to become a bone marrow donor which can be accessed from the Booklets on this condition and treatments Anthony Nolan Bone Marrow Trust. available include: Anthony Nolan Bone Marrow Trust „„Bone Marrow Transplantation for Donor recruitment office Primary Immunodeficiencies booklet Tel: 020 7284 1234 which can be accessed from the Primary Website: www.anthonynolan.org Immunodeficiency Association

Notes

Compiled by the GOSH web team

Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London WC1N 3JH

www.gosh.nhs.uk

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