Leukocyte Adhesion Deficiency
Leukocyte adhesion deficiency is a rare genetic disorder where white blood cells cannot reach infection sites to fight bacteria and other invaders, leading to severe, recurrent infections that often begin in infancy and can be life-threatening.
Table of contents
- What is Leukocyte Adhesion Deficiency?
- Types of Leukocyte Adhesion Deficiency
- Causes and Inheritance
- How Common is This Condition?
- Signs and Symptoms
- Diagnosis
- Treatment Options
- What to Expect
What is Leukocyte Adhesion Deficiency?
Leukocyte adhesion deficiency (LAD) is a disorder that causes the immune system to work improperly. It is a type of immunodeficiency, which means the body cannot protect itself effectively from harmful invaders like bacteria, viruses, and fungi.[1]
In people with LAD, white blood cells called leukocytes lack certain proteins on their surface that help them move and attach to blood vessel walls. Because of this defect, these immune cells cannot travel from the bloodstream to places in the body where infections are happening. The cells remain trapped in the blood vessels, unable to reach tissues where they are needed to fight off germs.[4]
This inability to form a proper immune response means that people with LAD experience frequent and severe bacterial and fungal infections. These infections can affect the skin, gums, lungs, and other soft tissues throughout the body.[2]
Types of Leukocyte Adhesion Deficiency
There are three main types of leukocyte adhesion deficiency, each caused by defects in different proteins that help immune cells function.[1]
Type 1 (LAD1) is by far the most common form. It occurs when there is a defect in a protein called CD18, which is part of a family of proteins known as beta-2 integrins. These proteins normally help white blood cells stick firmly to the walls of blood vessels. When CD18 is missing or doesn’t work properly, immune cells cannot attach to blood vessel walls and therefore cannot leave the bloodstream to reach infected tissues. Several hundred patients with LAD1 have been reported worldwide.[2][5]
Type 2 (LAD2) is extremely rare, with fewer than ten cases reported in medical literature. This type is caused by the absence of certain sugar molecules called fucosylated carbohydrates that help with the initial rolling movement of white blood cells along blood vessel walls. People with LAD2 often have additional problems including growth delays and intellectual disability. They also have an unusual blood type known as the Bombay blood group.[2][3]
Type 3 (LAD3) is also rare, with about 25 patients reported, mainly from the Middle East. In this type, a protein called kindlin-3 is defective, which prevents all types of integrins from being activated properly. People with LAD3 have both immune problems and bleeding disorders similar to those seen in people with problems with blood clotting.[2][5]
Causes and Inheritance
Leukocyte adhesion deficiency is caused by changes, called mutations, in specific genes. LAD has an autosomal recessive pattern of inheritance. This means that a child must inherit two copies of the mutated gene—one from each parent—to develop the condition. Parents who each carry one copy of the mutated gene are called carriers. They typically do not show signs or symptoms of the condition but can pass the gene to their children.[4][6]
LAD Type 1 is caused by mutations in the ITGB2 gene, located on chromosome 21. This gene provides instructions for making the CD18 protein, which is the beta-2 subunit of several important integrin proteins. About half of all cases involve point mutations (single changes in the gene’s DNA sequence), while others involve different types of genetic alterations. Most patients with LAD1 have two different mutations, one inherited from each parent.[3][4]
LAD Type 2 results from mutations in a gene that creates a protein responsible for transporting a sugar called fucose. Without proper fucose transport, white blood cells cannot make the sugar-coated molecules they need to interact with blood vessel walls.[3]
LAD Type 3 is caused by mutations in the FERMT3 gene, which encodes a protein called kindlin-3. This protein is essential for activating integrins in blood cells.[1][6]
How Common is This Condition?
Leukocyte adhesion deficiency Type 1 is estimated to affect about 1 in 1 million people worldwide. At least 300 cases have been reported in scientific literature. The condition affects boys and girls equally.[1][4]
LAD Type 2 is extremely rare, with most cases reported in people of Middle Eastern descent, often from families where parents are related to each other.[3]
LAD Type 3 is also very rare, with only about 25 patients reported, mainly from the Middle East.[2]
These disorders often go unrecognized or are misdiagnosed, which makes it difficult to determine how often they truly occur in the general population.[2]
Signs and Symptoms
Symptoms of leukocyte adhesion deficiency usually begin during infancy, though the severity can vary depending on the type and how much protein function is affected.[6]
One of the first signs of LAD1 is delayed detachment of the umbilical cord stump after birth. Normally, the umbilical cord stump falls off within the first two weeks of life. In infants with LAD1, this separation often occurs at three weeks or later. The umbilical cord area is also frequently inflamed and infected.[2][4]
People with LAD develop severe bacterial and fungal infections that recur frequently. These infections most commonly affect the skin and mucous membranes (the moist linings of the mouth, nose, and other body openings). Common infection sites include the skin, gums, lungs, and intestinal tract.[2][6]
Children with LAD develop severe inflammation of the gums called gingivitis and inflammation of the tissue around the teeth called periodontitis. These dental problems often result in the loss of both baby teeth and permanent teeth.[2][4]
A distinctive feature of LAD is the lack of pus formation at infection sites. Because white blood cells cannot reach the infected area, the body cannot produce the thick, yellowish fluid called pus that normally appears during infection. This makes infections look different from typical bacterial infections.[1][2]
Wounds heal very slowly in people with LAD, which can lead to additional infections and complications.[4][7]
Blood tests typically show extremely high numbers of white blood cells in the bloodstream—often 50,000 to 100,000 cells per microliter, which is 6 to 10 times higher than normal. These cells accumulate in the blood because they cannot leave the blood vessels to reach infected tissues. This elevated white blood cell count, called leukocytosis, persists even when there is no active infection.[5][6]
The severity of LAD1 symptoms depends on how much CD18 protein is present. People with less than 1% of normal CD18 levels have severe disease with life-threatening infections beginning in infancy. Those with 1-30% of normal levels have a milder form with fewer serious infections and may survive into adulthood.[3][6]
People with LAD Type 2 generally have less severe infections than those with LAD1, but they commonly experience delays in physical growth and intellectual development.[3][6]
Diagnosis
Diagnosis of leukocyte adhesion deficiency should be considered in any infant with recurrent skin and lung infections, delayed umbilical cord separation, and very high white blood cell counts.[5]
The diagnosis is confirmed through special blood tests. The most important test uses a technique called flow cytometry, which analyzes proteins on the surface of white blood cells. In LAD1, flow cytometry will show absent or greatly reduced levels of CD18 and CD11 proteins on the cell surface.[5][6]
A complete blood count will reveal the characteristic very high white blood cell count, though this finding alone is not specific to LAD.[6]
For LAD Type 2, testing looks for the absence of a specific sugar molecule called CD15a (also known as Sialyl Lewis X) on the surface of white blood cells.[3]
Genetic testing can identify the specific mutations in the ITGB2 gene (for LAD1), the GDP-fucose transporter gene (for LAD2), or the FERMT3 gene (for LAD3). This testing provides a definitive diagnosis and is recommended for siblings of affected children.[6][7]
Prenatal diagnosis is possible for families with a known history of LAD, allowing early detection of the disease before birth.[5]
Treatment Options
Treatment for leukocyte adhesion deficiency focuses on preventing and aggressively treating infections, with stem cell transplantation offering the only potential cure.[6]
When bacterial infections occur, they require aggressive treatment with antibiotics, frequently given intravenously (directly into a vein). Because people with LAD need frequent antibiotic treatment, they are at increased risk for fungal infections, particularly with Candida species, which must also be treated.[8]
Many patients receive preventive antibiotics on a continuous basis to help prevent infections before they start. The antibiotic combination trimethoprim/sulfamethoxazole is commonly used for this purpose.[6][8]
Hematopoietic stem cell transplantation (HSCT), also called bone marrow transplant, is the only treatment that can cure LAD. In this procedure, stem cells from a healthy donor are transplanted into the patient to create a new, functioning immune system. This treatment is especially recommended for people with severe LAD1 who have less than 1% of normal CD18 expression. The success rate for matched transplants is very high, approximately 80% for matched related donors and for matched unrelated donors, though success rates are lower (about 50%) for haploidentical transplants (from partially matched family members).[5][6][8]
Gene therapy is currently being studied as a potential treatment for LAD. In gene therapy, a corrected copy of the defective gene is inserted into the patient’s own cells. Recent clinical trials have shown promising results, with patients achieving lasting improvement in immune function and a significant reduction in serious infections.[6][8]
Transfusions of white blood cells called granulocytes from healthy donors have been used but require careful screening and may cause complications including lung problems and severe fever reactions.[8]
For people with LAD Type 2, taking supplements of a sugar called fucose, either by mouth or intravenously, has been tried with variable success in improving immune cell function.[6][7]
Surgical procedures in people with LAD carry high risk because of delayed wound healing and increased risk of infection, requiring extremely careful postoperative care.[8]
What to Expect
The outlook for people with leukocyte adhesion deficiency varies greatly depending on the type and severity of the condition.[6]
For people with severe LAD1 (those with less than 1% of normal CD18 expression), the prognosis without treatment is very poor. Mortality was reported as 75% by age 2 years in an early study from 1988. Most children with severe disease die by age 5 unless they are successfully treated with stem cell transplantation. Due to repeated infections, life expectancy is often severely shortened.[1][6][7]
People with moderate LAD1 (those with 2-30% of normal CD18 levels) have a better prognosis. They experience fewer life-threatening infections and can often survive into young adulthood without transplantation. However, even with the milder form, only about 25% of patients survive beyond age 40.[3]
Patients with mild or moderate disease who receive successful stem cell transplantation can be cured and lead normal lives.[6]
LAD Type 2 generally has a less severe course than LAD1 regarding infections, and patients can often be managed without the need for stem cell transplantation. However, the growth delays and intellectual disability associated with LAD2 significantly affect quality of life.[3][8]
