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Last updated:
January 02, 2019
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NORD gratefully acknowledges Lisa Vawter, PhD, Medical Writer, and Eric Allenspach, MD, PhD, University of Washington, for assistance in the preparation of this report.
Severe combined immunodeficiency (SCID) is a group of rare congenital syndromes with little or no immune responses. This results in frequent recurring infections with bacteria, fungi, and viruses. Infections that are minor in most people can be life‑threatening in people with SCID.
The immune system includes specialized white blood cells that work together to fight off bacteria, fungi, and viruses. These white blood cells include T lymphocytes (T cells) that are central mediators of the immune response and also directly attack viruses. B lymphocytes (B cells) produce antibodies that attach to invaders and mark them to be destroyed, but they need T cells to work effectively. Natural killer (NK) cells are specialized to help fight viruses as well. Patients with SCID have a genetic defect that affects T cells and at least one other type of immune cell (hence “combined immunodeficiency”).
Types of SCID are classified by which immune cells, T, B, and/or NK cells, are defective. There are several types of SCID, each caused by a different genetic (hereditary) defect. Despite the type of SCID, the primary symptom is reduced or absent immune function and all forms of classic SCID are lethal unless treated appropriately. The type of SCID helps determine the best treatment.
Most states now have newborn screening for SCID to help detect and treat babies prior to them becoming sick. Early detection by newborn screening has dramatically increased the success of the bone marrow transplantation as babies with SCID can avoid early infections.
All newborn babies receive antibodies from their mothers during pregnancy that protect them from infections during the first few months of their lives. In the absence of family history of SCID and prior to newborn screening, babies with SCID often presented to medical attention between three and six months with severe infections as their maternal antibodies naturally decreased. Symptoms included rashes, diarrhea, recurrent infections, difficulty gaining weight, weakness and/or growth delay.
Organisms that would cause mild to moderate illnesses in healthy people may cause life‑threatening infections in babies with SCID. Even organisms that do not ordinarily make people sick may make a child with SCID very ill. Babies with SCID typically suffer from many, severe cases of yeast (thrush or diaper rash), chicken pox, measles, herpes virus (cold sores), ear infections, meningitis (brain infections), or pneumonia that do not respond well to standard medical treatments. Children with SCID may also become infected with viruses (cytomegalovirus) from breastmilk, other live viruses (for example, the rotavirus or chickenpox) from vaccination or from common colds (viruses or bacteria) from siblings or surrounding children with healthy immune systems that can get rid of those infections.
It is critical that a child with SCID receive a stem cell transplant as soon as possible and preferably in the first few months of life. Children with SCID should avoid any live vaccines, young children that can often transmit common infections, and breast feeding until the milk can be tested to ensure the best success of the bone marrow transplant.
Typical or Classic SCID
SCID may be inherited as an autosomal recessive genetic trait or an X-linked trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes: one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
SCID can also be inherited as an X-linked disorder. X-linked genetic disorders are caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Newborn babies with SCID develop similar symptoms including difficulty gaining weight, diarrhea and recurrent infections. There are four main categories of typical or classic SCID based upon which immune cells (T, B, or NK cells) are defective. The categories are most important for treatment considerations.
B-positive, NK-negative severe combined immunodeficiency (T-B+NK- SCID)
T-negative, B-positive, natural killer (NK)-negative (T-B+NK-) SCID is a type of SCID that occurs when T cells and NK cells cannot respond to growth factors (cytokines) needed to develop and survive in the body. The most common cause of T-B+NK- SCID, is X‑linked recessive SCID (X-SCID) caused by an altered IL2RG gene found on the X chromosome. The IL2RG gene codes for the protein gamma subunit (γc) of the cytokine receptors for interleukin (IL-)2, IL-4, IL-7, IL-9, IL-15, and IL-21. The γc receptor is defective in boys with X-SCID and cannot send signals from the growth factors needed to make functional T cells and NK cells. The B cells in these patients are also non-functional without the help from T cells.
T-B+NK- SCID can also be caused by autosomal recessive mutations in the JAK3 gene. As in X-SCID, the T cells and NK cells in the body need the JAK3 protein to respond to the growth factors needed to develop and survive in the body. Defects in the JAK3 gene are now known to cause most autosomal recessive cases of T-B+NK- SCID.
B-negative, NK-positive severe combined immunodeficiency (T-B-NK+ SCID)
T-B-NK+ SCID is caused by a defect in both T and B cells, but not NK cells. The T cells and B cells in the body need both growth factors and expression of an antigen receptor to develop and survive. Each T cell or B cell recognizes a unique antigen (part of an invading bacteria, fungi or virus) through its particular antigen receptor. The cellular machinery needed to make a unique antigen receptor includes recombinase activating genes 1 (RAG1) and 2 (RAG2). Many mutations in RAG1 or RAG2 result in absent or non-functional protein causing T-B-NK+ SCID. If a mutation causes a reduced function the RAG1 or RAG2 proteins, then Atypical or Leaky SCID can occur (see below).
Other rarer causes of T-B-NK+ SCID result from defects in other genes also needed to make the antigen receptor including DCLRE1C gene that encodes for Artemis protein, notably with a higher frequency in the southwestern Athabascan-speaking Native American population. Other radiation sensitive disorders caused by autosomal recessive genes (PRKDC, LIG4, NHEJ1) have been rarely reported to cause T-B-NK+ SCID as well. These are all autosomal recessive forms of SCID.
B-negative, NK-negative severe combined immunodeficiency (T-B-NK- SCID)
Adenosine deaminase deficiency is the most common cause of T-B-NK- SCID. ADA‑SCID, caused by an altered ADA gene, is autosomal recessive. Individuals with ADA‑SCID have no T, B, or NK cells and so tend to get bacterial, fungal, and viral diseases. There is some variation in when ADA-SCID patients develop symptoms depending upon the particular defect in the ADA gene. Some patients develop symptoms shortly after birth (early onset), and others later (delayed or late onset). Individuals with delayed ADA-SCID can be missed by the newborn screening test because they may have detectable numbers of lymphocytes. ADA functional testing is then needed to make the diagnosis.
Another form of T-B-NK- SCID is caused by mutations in adenylate kinase 2 (AK2), a gene involved in the development of lymphocytes and other white blood cells in the bone marrow needed to fight infection. Defects in AK2 result in a severe form of SCID termed reticular dysgenesis and is usually accompanied by defects in hearing and low neutrophils as well. The profound neutropenia results in earlier risk for severe infections.
B-positive, NK-positive severe combined immunodeficiency (T-B+NK+ SCID)
Defects selective only to the T cells cause T-B+NK+ SCID and result from either loss of a cytokine (or growth factor) receptor or T cell antigen receptor, both needed for T cells to develop and survive. Deficiency of the alpha chain of the IL‑7 receptor (IL7R gene) is the most common form of this category of SCID. In humans, IL-7 is critical for the survival of T cells, but not B cells nor NK cells. Rarer defects in the components of the T cell antigen receptor have been reported to cause T-B+NK+ SCID including mutations in CD3D, CD3E, and CD247. In addition, PTPRC gene encodes a CD45 protein that is a critical regulator of the T cell antigen receptor. Several cases of mutations in PTPRC gene have been reported to cause T-B-NK+ SCID. All of these genes are autosomal recessive.
Leaky SCID (also known as Omenn syndrome or atypical SCID)
Some infants with SCID may have detectable or even elevated T cell numbers in a condition termed atypical or leaky SCID. These patients have only partial defects in known SCID-causing genes allowing for production of small numbers of T cells. These T cells do not provide protection from infections but are over-activated causing inflammation and damage similar to an autoimmune disease. Leaky SCID is the clinical syndrome that occurs with severe itchy rashes, enlarged lymph nodes, spleen and liver and chronic diarrhea. Typically leaky SCID is from partial function of either RAG1 or RAG2 genes, but has been reported in other forms of SCID as well. Importantly, leaky SCID must be distinguished from engraftment of maternal T cells that can cross the placental during pregnancy or delivery and in the absence of fetal T cells can persist in the baby after birth. These cells can be destructive to the infant and cause similar symptoms further complicating the diagnosis.
Variant SCID (persistently low T-cells but no defect in known SCID genes)
The rise of newborn screening has increased the detection of infants with persistently low T-cells with no known defect in a known SCID gene. These children require special considerations for further work up and management and may represent a combined immunodeficiency or SCID-like disorder.
All types of SCID are very rare disorders that occur in approximately 1 or fewer births in 100,000 in the United States. SCID may be more common in people with Navajo, Apache, or Turkish ancestry.
SCID is now diagnosed mainly through from newborn screening in most states. The screen is performed using the dried blood spot from newborn screening (or Guthrie) cards measuring levels T-cell receptor excision circles (or TREC). Although each state has a slightly different methods and thresholds, a low TREC test means the infant has low numbers of lymphocytes in the blood at the time of the test. The result must then be confirmed with additional testing. A complete blood count (CBC) coupled with lymphocyte subset testing may show low levels of B, T, and/or NK cells. Additional tests can show that one or more of these cell types aren’t functioning properly. Genetic and biochemical (protein expression) tests are available for some forms of SCID. A combination of these tests may be required to make an accurate diagnosis needed to plan treatment.
Treatment
Transplant of stem cells taken from the bone marrow of a healthy, matching donor, usually by the age of about 3 months, is generally considered the best treatment for SCID. A bone marrow transplantation center is needed to evaluate the patient for potential matching donors through national searches, determine the options for each patient and explain the risks of each treatment option. The type of SCID and the bone marrow match available to the patient are both two important considerations. While waiting for a bone marrow transplant, avoiding sick contacts and avoiding breast feeding is critical to prevent transmission of infections that can make a transplant less successful. If diagnosis is delayed and infections occur, they must be treated aggressively. Gene therapy for SCID is still considered to be experimental (investigational), but considered in patients not eligible for a bone marrow transplant.
An enzyme replacement therapy, where a missing enzyme is injected regularly into the patient, is available for ADA SCID. This is a treatment, not a cure. Transplant of stem cells from the bone marrow of a healthy, matching, donor is the only cure for SCID currently.
An enzyme replacement therapy, where a missing enzyme is injected regularly into the patient, is available for ADA SCID. This is a treatment, not a cure. Transplant of stem cells from the bone marrow of a healthy, matching, donor is the only cure for SCID currently.
In 2018, the enzyme replacement therapy Revcovi (elapegademase-lvlr) was approved for the treatment of ADA-SCID in pediatric and adult patients. Revcovi is manufactured by Leadiant Biosciences.
Gene therapy for SCID is being investigated, because it can be difficult or impossible to find a tissue match for a stem cell transplant in some cases, and because stem cell transplants are not always successful.
The first gene therapy trial for X-SCID used a retroviral vector to deliver a normal copy of the IL2RG gene and restored T cell function in children with X-SCID. Unfortunately, in 2005, five of those children developed leukemia after being treated in Paris and London. Since that time the vectors have been redesigned with new safe guards to remove the likely cancer-causing elements. Several new clinical trials are underway at several children’s hospital and at the National Institutes of Health. The goal of this type therapy is to restore immune function while avoiding complications such as repeat transplants, incomplete cure of the immune system, exposure to chemotherapy, and graft versus host disease.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Sullivan KE, Stiehm ER, eds. Stiehm’s Immune Deficiencies. 1st ed. Academic Press, Waltham, Massachusetts, 2014.
JOURNAL ARTICLES
Cicalese MP, Aiuti A. Clinical applications of gene therapy for primary immunodeficiencies. Hum Gene Ther. 2015 Apr;26(4):210-9.
Cirillo E, Giardino G, Gallo V, D’Assante R, Grasso F, Romano R, Lillo CD, Galasso G, Pignata C. Severe combined immunodeficiency-an update. Ann N Y Acad Sci. 2015 Jul 31.
de la Morena MT, Nelson RP Jr. Recent advances in transplantation for primary immune deficiency diseases: a comprehensive review. Clin Rev Allergy Immunol. 2014 Apr;46(2):131-44.
Dvorak CC, Cowan MJ, Logan BR, Notarangelo LD, Griffith LM, Puck JM, et al. The natural history of children with severe combined immunodeficiency: baseline features of the first fifty patients of the primary immune deficiency treatment consortium prospective study 6901. J Clin Immunol. 2013 Oct;33(7):1156-64.
Hernandez-Trujillo V. New genetic discoveries and primary immune deficiencies. Clin Rev Allergy Immunol. 2014 Apr;46(2):145-53.
Kohn DB. Gene therapy outpaces haplo for SCID-X1. Blood. 2015 Jun 4;125(23):3521-2.
Lombardo A, Naldini L. Genome editing: a tool for research and therapy: targeted genome editing hits the clinic. Nat Med. 2014 Oct;20(10):1101-3.
Pai SY, Cowan MJ. Stem cell transplantation for primary immunodeficiency diseases: the North American experience. Curr Opin Allergy Clin Immunol. 2014 Dec;14(6):521-6.
Qasim W, Gennery AR. Gene therapy for primary immunodeficiencies: current status and future prospects. Drugs. 2014 Jun;74(9):963-9.
Touzot F, Hacein-Bey-Abina S, Fischer A, Cavazzana M. Gene therapy for inherited immunodeficiency. Expert Opin Biol Ther. 2014 Jun;14(6):789-98.
van der Spek J, Groenwold RH, van der Burg M, van Montfrans JM. TREC Based Newborn Screening for Severe Combined Immunodeficiency Disease: A Systematic Review. J Clin Immunol. 2015 May;35(4):416-30.
INTERNET
Allenspach E, Rawlings DJ, Scharenberg AM. X-Linked Severe Combined Immunodeficiency. 2003 Aug 26 [Updated 2015 Jul 30]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1410/ Accessed February 24, 2016.
McKusick VA., Ed. Online Mendelian Inheritance in Man (OMIM). Severe Combined Immunodeficiency, X-linked. Available at https://omim.org/entry/300400 Last Update: 02/11/2014. Accessed February 24, 2016.
Patient and Family Handbook for Primary Immunodeficiency Diseases. Available at: https://primaryimmune.org/wp-content/uploads/2013/06/IDF_Patient_Family_Handbook_5th_Edition.pdf. Copyright 2013 Immune Deficiency Foundation.
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