Main triggers

1. Delayed cord separation. The stump normally falls off within about 1 to 3 weeks. In LAD-1 it often stays beyond 3 to 4 weeks, and this is frequently the first clue. The Epocrates summary notes it is often complicated by omphalitis. The Dermatology 5e text calls a history of delayed stump separation "a clue to the diagnosis."
2. Omphalitis or recurrent skin and soft tissue infection. Look for a red, indurated, necrotic or ulcerating cord stump or periumbilical area. Perirectal cellulitis, necrotic abscesses and pyoderma gangrenosum-like ulcers can also occur (Andrews' Diseases of the Skin).
3. Persistent leukocytosis with no infection-related pus. Harrison's 22E says LAD can be suspected with pus-free skin or tissue infections and massive hyperleukocytosis (>30,000/μL, mostly granulocytes). Goldman-Cecil also lists persistent leukocytosis. Cells cannot leave the blood to reach the tissues, so counts stay high even when the child is well.
4. Severe or recurrent bacterial and fungal infections from early infancy. These include otitis, pneumonia, cellulitis, and later gingivitis and periodontitis. Neutrophils are normal in number but cannot reach the infection.
5. Poor wound healing. Minor injuries or surgical wounds heal slowly or break down.

Clues to the other types

• LAD-1: ITGB2 mutation causing absent or low CD18. Severe disease has less than 2% CD18 expression.
• LAD-2: Defective fucosylation (SLC35C1), so there is no sialyl-Lewis X. Features are milder infections, short stature, developmental delay and the Bombay (hh) blood group.
• LAD-3: Kindlin-3 defect (FERMT3). It looks like LAD-1 but also has a bleeding tendency from defective platelet aggregation (Cellular and Molecular Immunology).

Confirming the diagnosis

• CBC with differential. It typically shows marked neutrophilia. This is a screening clue, not proof.
• Flow cytometry for CD18 and CD11b on neutrophils. This is the key test for LAD-1.
• ITGB2 sequencing. It confirms the diagnosis and allows family counselling.
• LAD-2 and LAD-3: Test for the Bombay phenotype or fucosylation defect, and for FERMT3 mutation or platelet function.

Practical points

• The absence of pus does not exclude serious infection, because neutrophils cannot migrate into tissue.
• Parental consanguinity or an earlier sibling death from infection raises suspicion, since inheritance is autosomal recessive.
• Severe LAD-1 is usually fatal in infancy without early hematopoietic stem cell transplantation, so refer early to an immunologist. Until then, treat infections promptly and consider prophylactic antibiotics.