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Leukocyte adhesion deficiency (LAD)

Leukocyte adhesion deficiency (LAD) is a primary immunodeficiency that causes individuals to be abnormally susceptible to developing frequent soft-tissue infections, gum inflammation, and tooth loss.

Overview 

Leukocyte adhesion deficiency (LAD) is a primary immunodeficiency that causes individuals to be abnormally susceptible to developing frequent soft-tissue infections, gum inflammation, and tooth loss. The white blood cells, or leukocytes, lack a protein on their surface, making them unable to enter infection sites and kill bacteria and other foreign invaders. The disorder is caused by inherent gene variants associated with cell attachment and movement.

Affected populations

LAD affects boys and girls in equal numbers. The exact incidence of these disorders in the general population is unknown. LAD1 is by far the most common form of the disorder, with several hundreds of patients reported from all over the world. LAD2 is rare, reported in less than ten patients in the medical literature. LAD3 is also rare, with reports of 25 patients, mainly from the Middle East. These disorders often go unrecognized and may be misdiagnosed, making it difficult to determine their true frequency in the general population.

Forms of LAD

Leukocyte adhesion deficiency is classified into three types based on its genetics, signs, and symptoms:

Starting from birth, infants with LAD1 develop serious bacterial infections and inflammation. One of the first signs is the delayed detachment of the umbilical cord stump, which usually falls off within the first two weeks of life; in infants with LAD1, this separation can occur at three weeks or later. In addition, the umbilical cord stump is often inflamed due to bacterial infection. 

Bacterial infections and inflammation most commonly occur on the skin and mucous membranes, such as the mouth and gums. Children develop severe inflammation of the gums (gingivitis) and other tissue that surround and support the teeth (periodontitis), which usually results in the loss of primary and permanent teeth. These infections can spread to cover a large area. 

A hallmark of LAD1 is the lack of pus formation at sites of infection. Wounds are slow to heal, which can lead to additional infection. Because of repeat infections, the life expectancy of individuals with LAD1 is often severely shortened. LAD1 is caused by variants in the ITGB2 gene, which codes for the molecule CD18.

Infants with LAD2, also known as congenital disorder of glycosylation type IIc, develop recurrent bacterial infections. However, the infections and their complications are usually milder than those seen in infants with LAD1. Pneumonia, chronic middle ear infections (otitis media), periodontitis, and localized infections of the skin (cellulitis) are common. No pus formation is seen at the site of infection. However, the infections are not usually life-threatening, are treatable, and their frequency decreases after the age of 3. As children grow older, severe periodontitis is often the main complication.

Individuals with LAD2 have additional complications not seen in LAD1, including a rare blood type, the Bombay (hh) blood group. They also have diminished or poor muscle tone (hypotonia), distinctive facial features, severe mental retardation, and severe growth deficiencies resulting in short stature. LAD2 is caused by variants in the SLC35C1 gene, which affects the metabolism of fucose (a form of sugar).

Individuals with LAD3 have recurrent bacterial infections that follow a similar course of infection as seen in individuals with LAD1. Affected individuals have a tendency to bleed easily and profusely, especially after surgical procedures. Other symptoms may include susceptibility to bruising, nosebleeds (epistaxis), bleeding from the gums (gingival), and large red- or purple-colored spots on the skin caused by bleeding under the skin. LAD3 is caused by variants in the FERMT3 gene.

Find LAD clinical trials

See if you qualify to participate in clinical trials evaluating new treatments and/or diagnostics for LAD.

Diagnosing LAD

A diagnosis of LAD syndrome is based on thorough clinical evaluation, detailed patient history, identification of characteristic findings, and various tests such as a complete blood count (CBC). A CBC can detect elevated levels of neutrophils and lymphocytes. A diagnosis of LAD1 should be considered in any infant with recurrent soft tissue infections and a high white cell count.

A diagnosis of any of the three forms of LAD can be confirmed through molecular genetic testing. Testing can reveal the characteristic variants of the genes associated with each type: the ITGB2 gene with LAD1, the SLC35C1 gene with LAD2, or the FERMT3 gene with LAD3.

Treatment

The mainstay treatment is the aggressive use of antibiotics to treat the repeated infections associated with LAD. Individuals with moderate or mild forms of LAD1 or LAD2 usually respond to prompt antibiotic treatment for episodes of acute infection. Preventive or prophylactic antibiotic therapy may be advisable for individuals with LAD1.

In rare cases, transfusions of neutrophils (the white blood cells most affected in LAD) may help treat life-threatening infections. However, these are not widely available and should be used only in severe cases when all other therapeutic options have failed. Blood transfusions are required for individuals with LAD3 who experience severe bleeding episodes.

The only corrective therapy for individuals with LAD1 and LAD3 is hematopoietic stem cell transplantation. Stem cell transplants can correct the genetic variants of the white blood cells and are recommended early in life if possible. The initial results of stem cell transplants for individuals with severe LAD1 have been very encouraging. Overall survival of individuals with LAD1 who have had a stem cell transplant is almost 75%.

Researchers are studying whether gene therapy, the implanting of healthy copies of the ITGB2 gene into the blood stem cells of individuals with LAD1 can potentially cure the disorder.

Supplementation with fucose, a form of sugar, is being investigated as a way to treat individuals with LAD2. A few patients have had significant improvement in symptoms, including the prevention of recurrent infections. However, not all patients respond to fucose supplementation. Further research is necessary to determine the long-term safety and effectiveness of this treatment strategy.

This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice.

Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition 
Copyright ©2019 by Immune Deficiency Foundation, USA