Leukocyte adhesion deficiency is a rare inherited disorder where white blood cells cannot reach infection sites in the body, leading to severe and recurrent infections that often begin in infancy. This condition affects how the immune system responds to bacteria and fungi, making even minor infections potentially life-threatening.

Understanding Leukocyte Adhesion Deficiency

Leukocyte adhesion deficiency (LAD) is a genetic disorder that prevents the immune system from working properly. The condition gets its name from what goes wrong in the body: white blood cells, also called leukocytes, cannot stick or “adhere” to blood vessel walls. This might sound like a small detail, but it has enormous consequences for fighting infections.

In a healthy person, when bacteria or other harmful organisms invade the body, white blood cells travel through the bloodstream to the site of infection. They stick to the walls of blood vessels, then squeeze through to reach the infected tissue where they can destroy the invaders. In people with leukocyte adhesion deficiency, the white blood cells lack certain proteins on their surface that allow this sticking process to happen. As a result, these cells remain trapped in the bloodstream, unable to reach the places where they are desperately needed.^[1]

This is a combined immunodeficiency disorder, meaning it affects both B cells, which produce antibodies to fight infections, and T cells, which directly attack infected cells. The disorder is inherited in an autosomal recessive pattern, which means a child must receive one defective gene from each parent to develop the condition. Parents who carry just one copy of the altered gene typically show no symptoms themselves.^[4]

Types of Leukocyte Adhesion Deficiency

Scientists have identified three main types of leukocyte adhesion deficiency, each caused by defects in different proteins. Type I is by far the most common and accounts for the majority of reported cases worldwide.

LAD Type I results from mutations in a gene called ITGB2, which provides instructions for making a protein called CD18. This protein is part of a family of molecules called beta-2 integrins that sit on the surface of white blood cells. When CD18 is missing or doesn’t work properly, white blood cells cannot form the integrins they need to stick to blood vessel walls. The severity of symptoms depends on how much CD18 protein is present. People with less than one percent of normal CD18 levels develop severe, life-threatening infections early in life, while those with two to thirty percent may have milder symptoms and can sometimes survive into adulthood.^[3]

LAD Type II is much rarer, with fewer than ten cases reported in medical literature. This type is caused by mutations in a gene that transports a sugar molecule called fucose. Without proper fucose transport, white blood cells cannot produce certain sugar-coated structures needed for the initial rolling movement along blood vessel walls. People with LAD Type II typically have less severe infections than those with Type I, but they often develop intellectual disability, growth problems, and distinctive facial features.^[2]

LAD Type III is also rare, with approximately 25 cases reported, mainly from the Middle East. This type involves defects in a protein called kindlin-3, which is needed to activate integrins. People with LAD Type III have both infection susceptibility and bleeding problems similar to those seen in certain blood clotting disorders.^[1]

How Common Is Leukocyte Adhesion Deficiency

Leukocyte adhesion deficiency Type I is estimated to affect approximately one person per million worldwide. At least 300 cases have been documented in scientific literature, though the actual number may be higher since the condition can be misdiagnosed or go unrecognized.^[4]

The disorder affects males and females equally. It has been reported across all racial and ethnic groups, though LAD Type II appears more frequently in people of Middle Eastern descent, particularly in families where parents are related by blood. This happens because related parents are more likely to both carry the same altered gene.^[2]

Several hundred patients with LAD Type I have been reported from around the world. The other types are extremely rare. These disorders often go undiagnosed because many healthcare providers are not familiar with them, and symptoms can initially resemble other, more common conditions.^[2]

What Causes Leukocyte Adhesion Deficiency

Leukocyte adhesion deficiency is caused by genetic mutations that affect how white blood cells function. For LAD Type I, the problem starts with changes in the ITGB2 gene located on chromosome 21. This gene contains the instructions for making the CD18 protein, which is essential for creating beta-2 integrins. About half of all cases involve point mutations, where a single building block of DNA is changed. Other cases involve more complex alterations including missense mutations, nonsense mutations, or problems with how the gene is read and processed.^[1]

Most patients with LAD are compound heterozygotes, meaning they have inherited two different mutations in the same gene, one from each parent. This explains why the condition affects boys and girls equally and why it can appear in families with no previous history of the disorder. Each time two carrier parents have a child, there is a 25 percent chance the child will inherit both defective genes and develop LAD, a 50 percent chance the child will be a carrier like the parents, and a 25 percent chance the child will inherit two normal genes.^[3]

For LAD Type II, mutations affect a gene that makes a transporter protein responsible for moving fucose, a type of sugar, into a specific part of the cell. Without this transporter working correctly, white blood cells cannot create the fucosylated structures they need for proper adhesion. LAD Type III is caused by mutations in the FERMT3 gene, which provides instructions for making kindlin-3 protein in blood cells.^[1]

Risk Factors for Developing Leukocyte Adhesion Deficiency

The primary risk factor for developing leukocyte adhesion deficiency is genetics. Children born to parents who both carry a mutation in one of the genes associated with LAD have a one in four chance of inheriting the condition. Families with a history of consanguinity, meaning the parents are blood relatives such as cousins, have a higher risk because related individuals are more likely to carry the same genetic mutations.^[6]

Geographic and ethnic background can play a role in certain types of LAD. LAD Type II has been reported predominantly in individuals from the Middle East, particularly in communities where marriages between relatives are more common. LAD Type III has also been reported mainly in patients from Middle Eastern countries, with about 25 cases documented.^[2]

Unlike many health conditions, lifestyle factors and environmental exposures do not cause or contribute to the development of leukocyte adhesion deficiency. The condition is entirely genetic and present from birth. However, once someone has the condition, environmental factors such as exposure to bacteria or viruses can trigger the severe infections that characterize the disorder.

Signs and Symptoms of Leukocyte Adhesion Deficiency

The symptoms of leukocyte adhesion deficiency typically begin in infancy, often within the first few weeks or months of life. One of the earliest and most characteristic signs is delayed separation of the umbilical cord stump. In healthy newborns, the umbilical cord stump normally falls off within the first two weeks after birth. In infants with LAD, this separation often takes three weeks or longer, and the area around the stump frequently becomes infected and inflamed, a condition called omphalitis.^[4]

Recurrent bacterial and fungal infections are the hallmark of this disorder. These infections most commonly affect the skin, mouth, and mucous membranes. Children with LAD develop severe inflammation of the gums, known as gingivitis, and inflammation of the tissues surrounding the teeth, called periodontitis. These dental problems often result in the loss of both baby teeth and permanent teeth. Skin infections can spread rapidly over large areas and become increasingly difficult to control.^[2]

One particularly unusual feature of LAD is the lack of pus formation at infection sites. Pus is normally made up largely of white blood cells that have traveled to the site of infection. Because white blood cells cannot reach infected tissues in people with LAD, infections appear different from what doctors typically see. Wounds heal very slowly, which can lead to chronic ulcers and additional infections.^[6]

Blood tests in people with LAD typically show extremely high white blood cell counts, often 50,000 to 100,000 cells per microliter, compared to normal counts of 5,000 to 10,000. This happens because the white blood cells cannot leave the bloodstream to go to infection sites, so they accumulate in the blood. Remarkably, these high counts persist even when no obvious infection is present.^[1]

The severity of symptoms correlates with the amount of functional protein remaining. Infants with severe LAD Type I, who have less than one percent of normal CD18 expression, develop life-threatening infections early in life. Those with moderate disease, having two to thirty percent of normal expression, tend to have fewer serious infections and may survive into young adulthood without transplantation.^[3]

In LAD Type II, infections are generally less severe, but affected children face additional challenges. They often experience delayed intellectual and physical development, short stature, and distinctive facial features. These children also have an unusual blood type known as the Bombay phenotype.^[6]

Prevention of Leukocyte Adhesion Deficiency

Because leukocyte adhesion deficiency is a genetic disorder present from birth, it cannot be prevented through lifestyle changes, vaccines, or other public health measures. The condition is determined at conception when a child inherits genetic mutations from both parents. However, families with a history of LAD or who know they carry the genetic mutation can benefit from genetic counseling.

Genetic counseling can help prospective parents understand their risk of having a child with LAD. If both parents are known carriers of a mutation in one of the genes associated with LAD, genetic counselors can explain that each pregnancy carries a 25 percent chance of producing a child with the condition. Prenatal testing options exist for families who want to know whether their developing baby has inherited the condition.^[4]

For families who already have one child with LAD, genetic testing is recommended for siblings to determine whether they also have the condition or are carriers. Early diagnosis allows for prompt treatment of infections and better long-term outcomes. Some medical centers have established prenatal diagnosis systems that allow early detection of the disease during pregnancy.^[5]

Once a person has LAD, preventing complications becomes the focus. Excellent hygiene and careful skin care are essential because any break in the skin can become a portal for infection. Families are often advised to avoid crowded places during flu season and times when infectious diseases are more common. Prophylactic antibiotics, meaning antibiotics given continuously to prevent infection rather than treat existing infection, are commonly used. The most frequently prescribed medication for this purpose is trimethoprim/sulfamethoxazole.^[6]

How the Body Changes in Leukocyte Adhesion Deficiency

Understanding what happens in the body with leukocyte adhesion deficiency requires looking at how the immune system normally works. When bacteria or other harmful organisms enter the body, a complex cascade of events begins. Chemical signals are released at the site of infection, causing blood vessels to widen and become leaky. The lining of blood vessels displays special proteins that act like molecular signposts.

White blood cells traveling through the bloodstream recognize these signposts and begin to slow down, rolling along the blood vessel wall like a car slowing down on a highway. This rolling is followed by firm adhesion, where the white blood cells stick tightly to the vessel wall. Finally, the cells squeeze between the cells that line the blood vessel and migrate into the infected tissue, where they can destroy invading organisms.^[1]

In leukocyte adhesion deficiency Type I, the problem occurs during the firm adhesion step. Beta-2 integrins, which are made from CD18 protein combined with other proteins, are responsible for this tight sticking. When CD18 is missing or defective, white blood cells cannot form functional integrins. They may begin to roll along the vessel wall, but they cannot stick firmly enough to stop and exit the bloodstream. As a result, they continue circulating uselessly through the blood while infections rage unchecked in the tissues.^[3]

In LAD Type II, the initial rolling step is impaired. White blood cells need special sugar-coated structures containing fucose to interact with selectin proteins on the blood vessel wall. Without these structures, the cells cannot even begin the process of slowing down and adhering. However, under certain conditions with reduced blood flow, LAD Type II white blood cells can still adhere and migrate through alternative mechanisms, which may explain why infections in this type tend to be less severe.^[6]

The accumulated white blood cells in the bloodstream can still function normally in terms of killing bacteria; the problem is purely one of getting to where they need to be. Laboratory tests can show that white blood cells from people with LAD work perfectly well at destroying bacteria when they are brought together in a test tube. This demonstrates that the fundamental killing machinery is intact; it’s the delivery system that has failed.

The chronic inflammation that occurs with repeated infections can cause lasting tissue damage. In the mouth, constant inflammation destroys the structures that support teeth, leading to tooth loss even in young children. Chronic skin infections can lead to scarring and tissue death. Internal organs, particularly the lungs and liver, can also suffer damage from recurrent infections. The lack of pus formation, while diagnostically useful, means that infections can spread more widely before they are noticed because the usual signs of localized infection are absent.^[2]