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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 that makes them unable to enter infection sites and kill bacteria and other foreign invaders. The disorder is caused by inherent defects in genes associated with cell attachment and movement.

Forms of LAD

Leukocyte adhesion deficiency is classified into 3 types based on its genetics, signs, and symptoms:

Leukocyte adhesion deficiency type I (LAD1): 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 2 weeks of life; in infants with LAD1, this separation can occur at 3 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, life expectancy of individuals with LAD1 is often severely shortened. LAD1 is caused by defects in the ITGB2 gene, which makes the molecule CD18.

Leukocyte adhesion deficiency type II (LAD2): Infants with LAD2 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 defects in the SLC35C1 gene, which affects metabolism of fucose (a form of sugar).

Leukocyte adhesion deficiency type III (LAD3): 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 defects in the FERMT3 gene.

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 10 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.

Diagnosis of LAD

Diagnosis of a 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 neutrophilsinfo-icon and lymphocytesinfo-icon. 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 3 forms of LAD can be confirmed through molecular genetic testing.  Testing can reveal the characteristic mutations of the genes associated with each type: the ITGB2 gene with LAD1, the SLC35C1 gene with LAD2, or the FERMT3 gene with LAD3.

Treatment for LAD

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 neutrophilsinfo-icon (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 defects 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 of 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.

 

References

Etzioni A. Leukocyte Adhesion Deficiency Syndromes. National Organization for Rare Disorders. rarediseases.org /rare-diseases/leukocyte-adhesion-deficiency-syndromes/. Published 2015. Accessed April 5, 2017.

Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-1205.

Genetics Home Reference. leukocyte adhesion deficiency type 1. Genetics Home Reference. https://ghr.nlm.nih.gov/condition/leukocyte-adhesion-deficiency-type-1. Accessed April 6, 2017.

Leukocyte Adhesion Deficiency - Immune Disorders. Merck Manuals Consumer Version. http://www.merckmanuals.com/home/immune-disorders/immunodeficiency-disor.... Accessed April 6, 2017.