NEMO deficiency (ectodermal dysplasia with immunodeficiency)

NEMO is a protein that works like a switch inside cells. It turns on a group of proteins called NF-κB (nuclear factor-kappa-B), which control the body’s response to germs and inflammation. NEMO is also needed to form the skin, hair, teeth and sweat glands.

In NEMO deficiency, the protein is made but works only partly. Immune cells respond poorly to many germs. Many boys make little or no antibody against germs with a sugar coating, such as pneumococcus, even after vaccination. Many also have ectodermal dysplasia, meaning the skin, hair, teeth and sweat glands do not form normally. Doctors also call the condition ectodermal dysplasia with immunodeficiency (EDA-ID).

The international classification lists it as a combined immunodeficiency with other body features (syndromic features). It is very variable. Some boys have severe infections from infancy, while others are milder, and a few have no skin, hair or teeth changes at all.

It is caused by a change in the IKBKG gene, which carries the instructions for NEMO. The gene is on the X chromosome. Boys have one X chromosome, so one changed copy is enough to cause the condition. Girls have a second X chromosome as a backup, so they are very rarely affected. Fathers cannot pass it to their sons.

Most boys inherit the change from their mother, who usually has no immune problems. Each son of a mother who carries it has a one-in-two chance of being affected. In the largest transplant study, more than half of the mothers who were checked had mild signs of incontinentia pigmenti. This is a condition of the skin, hair and teeth. Sometimes the change is new in the child.

The kind of change matters. Changes that leave NEMO partly working cause NEMO deficiency. Changes that stop NEMO completely cause incontinentia pigmenti in girls, and are usually fatal before birth in boys. MedlinePlus Genetics estimates the X-linked form of EDA-ID affects about 1 in 250,000 people. It cannot be caught from another person.

The first sign is often a severe bacterial infection, such as meningitis or pneumonia, in the first months of life. Pneumococcus and Staphylococcus bacteria are the most common causes. Infections can strike the lungs, skin, brain, bones, gut and other organs. Many boys also get infections from mycobacteria, relatives of the germ that causes tuberculosis. Viral and fungal infections, including Pneumocystis pneumonia, also occur.

Ectodermal signs can include dry, thick skin, sparse hair, and teeth that are missing, small or pointed (conical). Most boys sweat very little, so they can overheat dangerously in hot weather or during exercise.

About one in four people with EDA-ID have inflammatory disease, such as inflammatory bowel disease (colitis) or arthritis. Colitis can cause diarrhea and belly pain. A few boys also have abnormally dense bones (osteopetrosis) or swelling of the arms and legs from fluid (lymphedema).

Doctors often suspect it when a baby boy has a severe bacterial or mycobacterial infection. Signs of ectodermal dysplasia, such as sparse hair, dry skin, little sweating or conical teeth, add to the suspicion. In the largest transplant study, symptoms began at a median age of 2 months. Boys without these outward signs can be harder to recognize.

Blood tests often show low antibody (immunoglobulin) levels, and some boys have high IgM. A key clue is a missing antibody response to pneumococcal vaccines. Some boys show only weak signs of inflammation on blood tests, such as C-reactive protein (CRP), even during a serious infection. Specialized labs can test how well immune cells switch on NF-κB.

Genetic testing confirms the diagnosis by finding a change in the IKBKG gene. The mother is usually then tested, since most boys inherit the change from her. Knowing the family’s change also lets relatives be tested, and helps the team check any sister or mother considered as a donor.

The first priority is to find and treat infections quickly. Most boys then need long-term immunoglobulin (antibody) replacement and antibiotics to prevent infection, and some also take medicines against mycobacteria. Care teams usually avoid live vaccines. Colitis and other inflammation may be treated with steroids or other medicines that calm the immune system, such as infliximab. Some boys need extra nutrition, and keeping cool matters because they sweat so little.

A donor stem cell transplant can correct the immune problem. It is usually considered only for severely affected boys. In 2017, the authors of the largest study estimated that transplanted children were fewer than 1 in 10 of those reported worldwide. A 2019 UK patient leaflet calls it a fairly new treatment for NEMO deficiency, whose role is still being established.

A transplant fixes blood and immune cells, not the skin, hair, teeth or sweat glands. It also did not reliably cure colitis, probably because the cells lining the gut still carry the gene change. No gene therapy is approved for NEMO deficiency.

Families often reach the diagnosis after a frightening, severe infection that needs a hospital stay or intensive care. Afterward, many boys have immunoglobulin treatment for years, often given at home, along with antibiotics and regular check-ups to catch infections early. Some boys need extra nutrition, including feeding through a vein.

Because sweating is reduced, overheating in hot weather and during exercise is a real risk. Missing or pointed teeth, sparse hair and dry skin are part of daily life, and a transplant does not change them.

If a transplant is chosen, it means a long hospital stay, usually at a specialist center. Months of close follow-up for infection and graft-versus-host disease come next. Since the condition runs through the mother’s side of the family, mothers and sisters may be offered genetic testing and counseling.

A donor transplant replaces the boy’s blood-forming stem cells, so his new immune cells make working NEMO. In the largest study, 20 of 29 boys had an unrelated donor, 12 matched and 8 mismatched. Seven had a matched brother or sister, and two had a half-matched (haploidentical) mother.

Survival did not differ clearly by donor type in that study, and all 7 boys with a matched brother or sister were alive. Five boys received cells from a sister or mother who carried the family’s IKBKG change. One still had repeated bacterial infections afterward, and three had colitis. The authors said these few cases were too small for firm conclusions.

When no matched relative is available, specialists search national and international registries for an unrelated donor. Joining a registry cannot promise a match for any one boy, but it widens the choices families have.

When a transplant from a donor is planned, the team usually tests brothers and sisters first. Each full sibling has about a one in four chance of being a full match.

Most patients do not have a matched relative. In the words of NMDP, the U.S. registry, “75% of patients don’t have a fully matched donor in their own family.” The team then searches registries of volunteer donors around the world and banks of donated cord blood. In some transplants, a half-matched parent, child or sibling can also be the donor.

Matching depends on inherited tissue markers called HLA, so a patient is most likely to match someone who shares their ancestry. Every person who joins makes the search a little more likely to succeed, especially for patients from groups that are underrepresented on registries.

The outlook varies widely. A 2019 UK patient leaflet says some children grow up to lead a near-normal life, with regular monitoring and prompt treatment of infections. Others have repeated, serious infections that can be life-limiting. MedlinePlus Genetics (2017) says most people with EDA-ID survive only into childhood because of the immune problems. Older published reports describe many early deaths from infection.

For boys who have a transplant, survival in the largest study was 74%. All deaths happened within the first year after transplant, most from severe infections. Boys who had a mycobacterial infection or colitis before transplant seemed to do less well, though these differences were not statistically certain. A transplant fixes the immune system, not the ectodermal features. Colitis continued or began after transplant in some boys.