Leukocyte adhesion deficiency (LAD)

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.