DOCK8 deficiency

DOCK8 deficiency is a combined immunodeficiency. That means both main arms of the immune system are weak: T cells, which attack infected cells, and B cells, which make antibodies. Natural killer cells, which destroy virus-infected cells, are also affected.

DOCK8 is a protein that helps some immune cells squeeze through dense tissue, such as skin, without breaking apart. Without it, these cells break apart and die, so they cannot reach and clear viral infections in the skin. DOCK8 also helps B cells mature and make antibodies, which is one reason lung infections are common.

It was once called autosomal recessive hyper-IgE syndrome, because blood levels of IgE, the antibody linked to allergy, are usually very high. That older name also covers other conditions, so a genetic test is needed to confirm DOCK8 deficiency.

A child has DOCK8 deficiency when both copies of the DOCK8 gene carry a change, one from each parent. Parents who carry one changed copy are usually healthy. When both parents are carriers, each child has a 25% chance of having the condition.

The condition is rare, and how often it occurs is not known. It is not caused by anything the parents did, and it cannot spread from person to person. Genetic counseling can help a family understand testing for brothers, sisters and future pregnancies.

Common problems are severe eczema, skin abscesses, ear, sinus and lung infections, and food allergies or asthma. Viral skin infections are a hallmark. These include stubborn warts, molluscum (small, pearly skin bumps caused by a virus) and severe herpes infections.

Over time, repeated pneumonia can scar the lungs. Long-lasting HPV infection can lead to skin or genital cancers, and poor control of Epstein-Barr virus can lead to lymphoma. Some people have strokes or inflamed blood vessels in the brain, and a gut parasite called Cryptosporidium can damage the liver.

These problems tend to build up with age, and each one can make treatment harder. Newborn screening is designed to find severe combined immunodeficiency (SCID). A small 2011 report found low results on the same test in three affected brothers and sisters, so screening might catch some cases. How often it does is not known.

Before transplant, life can revolve around infections, hospital stays and skin that itches, cracks and gets infected. Many children miss school and sleep poorly. Parents may spend years looking for an answer before the diagnosis is made.

Transplant brings its own hard months. Conditioning treatment, a long hospital stay and close follow-up for infection and graft-versus-host disease are part of it. In the same study, most patients who were tested had mostly donor T cells at last follow-up, which means the new immune system had taken hold. Long-term follow-up continues, because the cancer and blood-vessel risks after transplant are still being studied.

A transplant needs blood-forming cells from a donor with a close HLA match. A brother or sister can be a good match, but family members are checked to make sure they do not have DOCK8 deficiency themselves.

Unrelated donors are an established route. In the international study, 35 of 81 people received cells from an unrelated donor. Survival was 81% with unrelated donors and 89% with matched family donors. A 2019 expert review of that study said there was no survival difference between the two. When no matched donor is found, half-matched family members, such as a parent, have also been used. Some experts think cord blood may be less suited here, because cord blood cells have not yet learned to fight the viruses these children often carry.

Because damage builds up over time, a donor search often starts soon after diagnosis. New registry members widen the choices for patients who need an unrelated donor, though joining cannot promise a match for any one person.