Familial HLH (hemophagocytic lymphohistiocytosis)

HLH stands for hemophagocytic lymphohistiocytosis. It is a state of runaway inflammation. The body makes too many active immune cells, such as T cells, natural killer cells and macrophages, and floods itself with inflammatory signals. This can damage the liver, spleen, bone marrow and brain.

Familial HLH, also called primary HLH, is the inherited form. The immune system’s killer cells cannot destroy infected cells in the normal way, so the immune response never gets the signal to stop. Familial HLH is not a cancer, and it is not contagious.

It is rare. Signs usually appear in infancy, but they can start later in childhood and, occasionally, in adults.

Familial HLH is caused by changes in both copies of one of several genes. The best known are PRF1, UNC13D, STX11 and STXBP2. Changes in PRF1 or UNC13D cause about 40 to 60 percent of cases. In some children, no gene change is found. These genes help killer immune cells destroy infected cells and switch off immune cells that are no longer needed. PRF1, for example, makes perforin, a protein that helps punch a hole in the cell being attacked.

The pattern is autosomal recessive. Each parent usually carries one changed copy and is healthy. When both parents are carriers, each child has a 1 in 4 chance of having familial HLH.

An infection often sets off the first attack, but the infection is only the trigger, and some attacks have no clear trigger. Other inherited immune disorders, such as XLP1 and XIAP deficiency, can also cause HLH. HLH can also happen without an inherited cause, for example after an infection. Genetic testing helps tell these apart.

The most common signs are a fever that will not go away, a swollen liver and spleen, and low blood counts. Low platelets can cause easy bruising and bleeding. Low red cells cause anemia, which can make a child pale and tired. Some children also have a rash.

HLH can also affect the brain. This can cause irritability, a stiff neck, seizures, weak or floppy muscles, poor balance, loss of vision or coma. Without treatment, most people with familial HLH survive only a few months.

Doctors diagnose HLH from a pattern of signs and tests, including blood counts, liver tests and markers of inflammation, and sometimes a bone marrow exam. Genetic testing looks for an inherited cause. When a family already knows its gene changes, a younger brother or sister can be tested in the first months of life, before any illness.

The diagnosis often comes during a sudden, frightening illness in a baby or toddler, sometimes in intensive care. Treatment starts in the hospital and continues for weeks to months, with frequent blood tests, transfusions and steps to prevent infection. Families are often asked about genetic testing and a donor search at the same time.

Transplant brings months of hospital and clinic care. Afterward, the team watches for infection, graft-versus-host disease and the share of donor cells in the blood. Some children need therapy and extra support at school for problems such as developmental delay, seizures or attention difficulties. Long follow-up matters, because some of these problems are found only years later.

When the gene changes are known, parents can learn about testing in future pregnancies, and brothers and sisters can be checked. In an international study of children found through family testing before they had symptoms, those transplanted before HLH began did better than those transplanted after it started. Whether and when to transplant a child without symptoms is a decision for a specialist team and the family.

A child with familial HLH who goes to transplant needs blood-forming cells from another person, because the child’s own cells carry the faulty genes. A healthy brother or sister who is a full match may be chosen. Siblings are first tested for the family’s gene changes, because an affected sibling may not be sick yet. Each full sibling has about a 1 in 4 chance of being a match.

Many children have no matched family donor. Well-matched unrelated volunteers from registries, donated cord blood and half-matched (haploidentical) family donors can all be used. Experts advise keeping the wait for transplant short. HLH can flare again while a child waits, and being in remission at transplant is linked to better survival. That is why teams look at unrelated and other donors early, often soon after diagnosis.

Joining a registry cannot promise a match for any one child. It adds to the pool that transplant teams search when a child needs a donor fast.