CD40 ligand deficiency (X-linked hyper-IgM syndrome)

CD40 ligand is a protein on the surface of T cells, the white blood cells that direct an immune response. T cells use it to “talk” to B cells, the cells that make antibodies, and to other germ-fighting cells. When CD40 ligand is missing or does not work, that conversation breaks down.

B cells can still make IgM, the first antibody the body produces. But they cannot switch to IgG, IgA and IgE, the longer-lasting antibodies that protect against most germs. Blood tests usually show low IgG and IgA with normal or high IgM, which is where the name hyper-IgM comes from.

Doctors confirm the diagnosis with a genetic test that finds a change in the CD40LG gene. Many places screen newborns for severe combined immunodeficiency (SCID) by looking for babies who make very few new T cells. Boys with CD40 ligand deficiency usually have normal numbers of T cells, B cells and natural killer cells, so that screen is not expected to find them.

The condition is caused by a change in the CD40LG gene, which sits on the X chromosome. Boys have one X chromosome, so one changed copy is enough to cause the condition. Girls have two, and a girl with one changed copy usually has no symptoms, although some do have signs of the condition.

A mother who carries the change has a 50% chance of passing it on in each pregnancy. Sons who inherit it are affected, and daughters who inherit it are carriers. Sometimes the change is new in the child. A genetic counselor can explain what a result means for the family, and newborn boys in a family with a known change can be tested early.

It is very rare. Published estimates are roughly one to two cases for every million boys. It cannot be caught from another person.

Symptoms usually begin in infancy. More than half of affected boys have symptoms by age 1, and more than 90% by age 4. Repeated ear, sinus and lung infections are common, and a serious lung infection called Pneumocystis pneumonia is often the first sign.

Many boys have long-lasting diarrhea and trouble gaining weight. About half of boys have neutropenia, a low count of infection-fighting white blood cells called neutrophils, which adds to the risk of infection. A parasite called Cryptosporidium, spread through water, can infect the gut and bile ducts. Over time it can lead to sclerosing cholangitis, a scarring of the bile ducts that damages the liver.

Liver and bile duct disease is one of the most serious long-term problems and is linked with shorter survival. The condition also raises the risk of some cancers, including cancers of the liver, bile ducts and gut, and lymphoma. A smaller number of boys have serious brain infections or autoimmune problems.

Life with CD40 ligand deficiency often means regular immunoglobulin treatments, daily medicines and frequent checkups. Families plan around safe water at home, at school and when traveling. A fever, cough or diarrhea that will not go away may need fast medical attention.

Deciding whether and when to have a transplant is a big choice. The team weighs infection history, liver and lung health, age and available donors. A transplant means conditioning treatment, weeks in the hospital and months of close follow-up for infection, graft failure and graft-versus-host disease. In one large study, about a third of people still needed immunoglobulin five years after transplant.

Mothers and sisters may want genetic counseling to learn whether they carry the change. Hyper-IgM and primary immunodeficiency patient groups can connect families with others who understand.

A transplant needs healthy blood-forming stem cells from a donor whose HLA tissue type closely matches the patient. A matched brother or sister is often the first choice, but family members are checked first to make sure they do not have the family’s gene change. Many boys have no matched sibling.

When there is no suitable family match, a matched unrelated donor from a registry is an established option. Partly matched (haploidentical) family donors and cord blood are also used, mainly at centers with experience in these transplants. In the large international study, transplants from 2000 on did better with matched donors, which is one reason a full-match search matters.

Timing can make the search urgent. Results are better before the liver or lungs are damaged, so teams often begin looking for a donor soon after diagnosis. Joining a registry cannot promise a match for any one child, but more volunteers of every background widen the choices.