NORD gratefully acknowledges Amos Etzioni, MD, Professor of Pediatrics and Immunology, Ruth Children's Hospital, Bat-Galim, Haifa, Israel, for assistance in the preparation of this report.
Leukocyte adhesions deficiency (LAD) syndromes are a group of rare disorders affecting the immune system. LAD syndromes are characterized by defects affecting how white blood cells (leukocytes) respond and travel to the site of a wound or infection. Three distinct types of leukocyte adhesion syndrome have been identified. The specific symptoms and the severity of LAD syndromes vary from one person to another. All affected individuals develop an increased susceptibility to developing recurrent bacterial and fungal infections. Additional symptoms may occur depending upon the specific subtype present. LAD syndromes are caused by mutations of specific genes that contain instructions for creating certain proteins that are necessary for white blood cells to travel from the bloodstream to the site of an infection or inflammation. Individuals with severe forms of LAD may have near complete absence of these proteins. Individuals who have milder forms of LAD syndromes have deficient levels of these proteins, but retain some residual protein activity.
The symptoms of LAD syndromes can vary greatly from one person to another based upon the subtype present, the amount of residual protein activity and additional factors. The LAD syndromes are primary immunodeficiency disorders that cause individuals to be abnormally susceptible to developing infections. Affected individuals also have elevated levels of white blood cells (leukocytosis).
LEUKOCYTE ADHESION DEFICIENCY TYPE I
The symptoms of LAD I can vary from one to person to another. Some individuals have a severe form of the disorder that can cause life-threatening complications; other individuals have a milder form. LAD I is usually characterized by recurrent, often severe, bacterial infections, and delayed detachment of the umbilical cord. Fungal infections are also common. Bacterial and fungal infections most often affect the skin and mucous membranes (mucosal surfaces). The absence of pus formation at the site of infection is an important feature that can indicate a leukocyte adhesion deficiency. Delayed detachment of the umbilical cord often occurs along with infection of the umbilical cord stump (omphalitis). Recurrent, bacterial infections usually develop shortly after birth in LAD I and can cause life-threatening complications in many cases. Individuals with the milder form of LAD I have fewer and less severe infections.
After infancy, affected children may develop progressive inflammation of the tissues that surround and support the teeth (periodontitis) and inflammation of the gums (gingivitis). Periodontitis can eventually cause tooth loss. Wounds either from surgery or trauma are slow to heal (delayed wound healing) and may be more likely to scar. Affected individuals may also develop sores in the area surrounding.
LEUKOCYTE ADHESION DEFICIENCY TYPE II
Infants with LAD II develop recurrent, bacterial infections. However, the infections and their complications are usually milder than those seen in infants with LAD I. Pneumonia, chronic middle ear infections (otitis media), infection of the tissues that surround and support the teeth (periodontitis) and localized infection of the tissue underneath the surface of the skin (cellulitis) commonly occur in LAD II. The infections are usually not life-threatening and are often treated in an outpatient basis. No pus formation is seen at the site of infection. Generally, the frequency of infections in LAD II decreases after affected individuals reach three years of age. As affected individuals grow older, severe periodontitis is the main infectious complication.
Unlike LAD I, infants with LAD II do not experience a delay in the separation of the umbilical cord. Individuals with LAD II do have additional complications not seen in LAD I including a unique blood type called the Bombay (hh) blood type. Additional features that characterize LAD II include diminished muscle tone resulting in floppiness (hypotonia), distinctive facial features, severe mental retardation and severe growth deficiencies resulting in short stature.
LAD II may also be known as congenital disorder of glycosylation type IIc due to the primary defect in fucose metabolism.
LEUKOCYTE ADHESION DEFICIENCY TYPE III
Individuals with LAD III have recurrent bacterial and fungal infections that follow a similar course of infection as seen in individuals with LAD I. However, these affected individuals also have a bleeding tendency that can cause life-threatening complications. The bleeding complication of LAD III resembles a rare disorder known as Glanzmann thrombasthenia, which is characterized by impaired function of blood cells required for clotting (platelets). Affected individuals have a tendency to bleed easily and profusely especially after surgical procedures. Other symptoms may include susceptibility to easy bruising, nosebleeds (epistaxis), bleeding from the gums (gingival), and/or large red or purple colored spots on the skin that are caused by bleeding under the skin (subcutaneous). The bleeding problem usually starts at birth.
Individuals who were once classified as having LAD I variant (because of the similar disease expression) are now considered to have LAD III because the underlying genetic cause of LAD III is different from the underlying genetic cause of LAD I.
Leukocyte adhesion syndromes are rare, genetic disorders. LAD I is caused by mutations of the ITGB2 gene. LAD II is caused by mutations of the SLC35C1 gene. The genetic defect in LAD III is a mutation in the gene for Kindlin 3, a protein essential for all integrins activation. Lack of integrins activation affects the ability of leukocytes and platelets to bind to the endothelium. In some cases, there is also a mutation in the gene for CalDAGGEF1, another protein important in integrins activation.
The mutations that cause LAD I, LAD II and III are each inherited as autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and 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.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
LAD syndromes are classified as a primary immunodeficiency disorders. The immune system protects the body from bacteria, viruses, parasites and other foreign, harmful substances. White blood cells (leukocytes) are part of the immune system. White blood cells continually look for signs of disease, infection or injury. Normally, white blood cells circulate in the bloodstream. When they detect an infection or foreign substance, white blood cells race to the site of infection or inflammation to protect the body. White blood cells may destroy foreign material by ingesting it themselves or producing unique antibodies that destroy harmful material. A specific type of white blood cell, called a neutrophil, is most often affected in LAD syndromes. The main role of neutrophils is to defend the body against bacteria and fungi.
White blood cells travel (migrate) to the site of inflammation or infection in the body through a complex process sometimes referred to as the adhesion cascade. This process requires several, precise steps. These steps include the tethering of white blood cells to the thin layer of cells that line the inside surface of blood vessels (endothelium), the rolling of white blood cells along the endothelium, leukocyte activation and the eventual attachment (adhesion) of white blood cells directly to the endothelium. Ultimately, white blood cells move from the endothelium through the blood vessel wall and into the surrounding tissue, eventually traveling to the site of an infection or inflammation to protect the body.
Specific chemicals such as proteins are necessary for white blood cells to be able to tether, roll along and stick (adhere) to the endothelium. Individuals with LAD syndromes do not have sufficient levels of these proteins and their white blood cells cannot tether, roll along or fail to stick to the endothelium. Therefore, the white blood cells of individuals with LAD syndromes fail to reach the site of infection or inflammation.
The ITGB2 gene, which causes LAD I, contains instructions for creating (encoding) a protein known as CD18. CD18 is a subunit of integrin or a cell surface protein and is normally found on the surface of white blood cells. Mutations of the ITGB2 gene result in defective CD18 or deficient levels of CD18. Without sufficient levels of functional CD18, white blood cells cannot stick (adhere) to the endothelium. In rare cases, CD18 is expressed normally but because of a specific ITGB2 mutation, the protein is nonfunctional. These cases are referred to as LAD I variant.
Specific proteins are also necessary for white blood cells to roll along the endothelium. Individuals with LAD II do not have sufficient levels of these proteins. The SLC35C1 gene contains instructions for creating (encoding) an enzyme (GPD-fucose transporter) that is required to transport a specific sugar (fucose) in the body. Fucose is necessary for a carbohydrate structure known as CD15 (sialyl Lewis x antigen) to bind to a type of protein (glycoprotein) called selectin found on the endothelium. This process is required for white blood cells to be able to roll along the endothelium. Since white blood cells cannot roll along the endothelium in LAD II, they are unable to stick to the endothelium and fail to travel to the site of infection and inflammation.
LAD syndromes affect males and females in equal numbers. The exact incidence of these disorders in the general population is unknown. LAD I is by far the more common one with several hundreds of patients reported in the medical literature from all over the world. LAD II is very rare reported in less than 10 patients and LAD III is also rare with 25 patients mainly from the Middle East region. These disorders often go unrecognized and may be misdiagnosed, making it difficult to determine their true frequency in the general population. LAD I was first described in the medical literature in 1979. LAD II was first reported in 1992. LAD III was first reported in 1997.
A diagnosis of a LAD syndrome is suspected based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of tests such as a complete blood count (CBC). A CBC can detect elevated levels of a type of white blood cell known as a neutrophil (neutrophilia) and also lymphocytes. A diagnosis of LAD I should be ruled out in any infant with recurrent soft tissue infections and a very high white blood cell count (leukocytosis).
A diagnosis of LAD I or LAD II or III can be confirmed through molecular genetic testing, which can reveal the characteristic mutations of the ITGB2, the SLC35C1 or the FERMT3 genes that cause these disorders. Molecular genetic testing is available on a clinical basis.
Diagnosis before birth (prenatal diagnosis) is possible in families where the exact molecular defect has already been identified. A test known as chorionic villi biopsy is performed. Chorionic villi are thin, hair-like structures found on the placenta. Chorionic villi cells contain the same genetic material found in the cells of the fetus. A sample of tissue is taken from the placenta and studied to detect the presence of the specific genetic mutation that has caused LAD I, LAD II or LAD III in that family. LAD II can also be detected before birth by identifying the characteristic blood type (Bombay blood phenotype) associated with the disorder. This is possible at approximately 20 weeks gestation.
The treatment of LAD syndromes are directed toward the specific symptoms that are apparent in each individual. The main aspect of treatment is antibiotic therapy to treat the repeated, characteristic infections associated with the LAD syndrome disorders. Prompt antibiotic therapy is essential during acute infectious episodes. Individuals with moderate or mild forms of LAD I or LAD II usually respond to conservative therapy and prompt treatment for acute episodes. Preventive (prophylactic) antibiotic therapy may be necessary for some individuals with more serious forms of LAD I.
In the absence of tissue neutrophils in patients with LAD I, inhibition of the IL-23/IL-17 axis is deficient, resulting in an unregulated hyperinflammatory response, which leads to chronic inflammation. In patients with LAD I, this process is particularly important in the gingivae but may also be involved in poorly healing cutaneous wounds that often affect these patients. A case report described in vivo beneficial effects of ustekinumab, a monoclonal antibody that binds the p40 subunit shared by IL-12 and IL-23, in a patient with LAD I, with dramatic improvement of periodontitis and of sacral wound.
In some cases, white blood cell (granulocyte) transfusions may be required to treat life-threatening infectious complications. Because of the possibility of adverse side effects, white blood cell transfusions are rarely used and only in severe cases when all other therapeutic options have failed. Blood transfusions are required for individuals with LAD III who experience severe bleeding episodes.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
The only curative therapy for individuals with LAD syndromes is a bone marrow transplant. A bone marrow transplant may also be known as a stem cell transplant. Hematopoietic stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, white blood cells, platelets). In allogeneic stem cell transplantation, stem cells are donated from another person, usually from a closely matched family member. Stem cell transplants have the potential to correct the inherent, genetic defect of the white blood cells of individuals with LAD syndromes. However, because stem cell transplants can cause severe, even life-threatening complications, they are usually reserved for individuals with severe complications or individuals who have no other viable treatment options. The initial results of bone marrow transplants for individuals with the severe form of LAD I have been very encouraging. In a recent publication from several main centers in the world the overall survival of individuals who have had a bone marrow transplant for LAD I is almost 75%.
Researchers are studying gene therapy as a potential treatment for individuals with LAD syndromes. Gene therapy is an experimental therapy that involves replacing mutated genes with healthy copies, inactivating mutated genes, or introducing a new gene into the body that helps the body fight disease. Researchers are studying the use of implanting healthy copies of the ITGB2 gene into the hematopoietic (bone marrow) stem cells of individuals with LAD I, which could potentially cure the disorder. Gene therapy is still a very experimental therapy and more research is necessary to determine its viability, effectiveness and safety to treat genetic disorders such as LAD I. While in a canine model of LAD I encouraging results were seen after gene therapy, it seems that in human we still have to go a long way before seeing such results.
Researchers have also been studying the use of fucose supplementation to treat individuals with LAD II. Initial results have demonstrated significant improvement of symptoms including the prevention of recurrent infectious, but not all patients respond to fucose supplementation. More research is necessary to determine the long-term safety and effectiveness of fucose supplementation for the treatment of individuals with LAD II.
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 web site.
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