Griscelli syndrome type 2 (GS2)

Griscelli syndrome type 2 (GS2) is a rare inherited condition that affects the immune system and, in many people, the color of the skin and hair. Hair is often silvery gray, and skin may be lighter than expected (partial albinism).

The main problem is that killer immune cells cannot destroy infected cells in the normal way, so the immune response does not switch off. This leads to HLH (hemophagocytic lymphohistiocytosis), a runaway inflammation that can damage organs, including the brain. Because of this, doctors group GS2 with familial HLH as a form of primary, or inherited, HLH. GS2 is not a cancer, and it is not contagious.

There are three types of Griscelli syndrome, caused by different genes. Only type 2 causes the immune problems and HLH. Type 1 also causes serious problems with brain function, and type 3 affects only the color of the skin and hair.

GS2 is caused by changes in both copies of the RAB27A gene. This gene makes a protein that helps move small packets inside cells. Killer T cells and natural killer cells need it to release the contents that destroy infected cells. Pigment cells need it to move color out into the hair and skin.

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 GS2. In a 2024 review of 149 patients, about two in three had parents who were related by blood. The review also found three gene changes shared by many unrelated families, mostly of Middle Eastern and European descent.

Infections, such as viruses, can set off HLH, but a trigger is not always found. Some RAB27A changes still allow a little of the protein to work. People with these changes tended to become ill later and more often had normal hair color.

Signs often begin in the first years of life. In the 2024 review, the median age at diagnosis was 1.5 years, but it ranged from 10 days to 42 years. Common first signs were fever, a large spleen and a large liver. About half of patients had silvery-gray hair, and some had frequent infections.

Most people with GS2 develop HLH. It causes fever, low blood counts and organ damage, and it can be fatal without treatment. In GS2, HLH often affects the brain and spinal cord. In the review, brain and nerve signs included seizures, crossed eyes (strabismus), poor balance, weakness and developmental delay. In some people, HLH affects only the brain, which can make it hard to recognize.

About 1 in 5 patients in the review had no sign of partial albinism, so normal hair and skin color do not rule out GS2.

GS2 is often found when a child becomes very ill with HLH. Blood tests check blood counts, ferritin, triglycerides and fibrinogen, and a bone marrow sample may show immune cells eating other blood cells. Doctors use the HLH-2004 criteria, which need 5 of 8 findings or a known gene cause. A spinal tap (lumbar puncture) and brain MRI check whether HLH has reached the brain.

Hair can give a clue. Under a light microscope, hair from people with Griscelli syndrome shows clumps of pigment. Unlike in Chediak-Higashi syndrome, the white blood cells in GS2 do not have giant granules on a blood smear, which helps tell the two apart.

A flow cytometry test called a granule release (CD107a) assay checks whether killer cells can release their contents. Genetic testing that finds changes in both copies of RAB27A confirms the diagnosis. Some people with GS2 have normal hair color, and a few have normal granule-release results, so the 2024 review recommends genetic testing to confirm it.

The first goal is to calm HLH. Teams often follow the HLH-94 or HLH-2004 treatment plans. These combine a steroid called dexamethasone with the chemotherapy medicine etoposide, and HLH-2004 adds the immune-suppressing medicine cyclosporine. Medicine may also be given into the spinal fluid when the brain is involved. Infections are treated at the same time.

In the United States, emapalumab (Gamifant) is approved for primary (inherited) HLH that does not respond, comes back or gets worse. It is also approved when standard treatment cannot be tolerated. In the European Union, approval for children was refused in January 2021, so access differs by country. None of these medicines corrects GS2. They are a bridge to transplant.

A donor stem cell transplant is the only cure for GS2. It gives the child an immune system that can switch inflammation off. In the 2024 review, people who had a transplant did much better than those who did not. The authors suggest getting HLH under control and then moving to transplant early. Transplant can bring serious side effects, including blocked blood vessels in the liver (veno-occlusive disease) and graft-versus-host disease. A 2023 report notes that gentler, reduced-toxicity treatment before transplant is preferred to lower these risks.

Some children are found before they are ever ill, because a brother or sister already has GS2. A transplant before HLH starts (a pre-emptive transplant) may help them. Because some gene changes cause milder illness, teams decide this case by case with the family.

For many families, GS2 is found during a sudden, frightening illness in a baby or toddler, sometimes in intensive care. Silvery hair in a child with HLH is a clue that points doctors toward GS2. HLH treatment takes place in the hospital over weeks to months, with frequent blood tests, transfusions and steps to prevent infection. The donor search often starts at the same time.

Transplant brings months of hospital and clinic care. Afterward, teams watch for infection, graft-versus-host disease, liver problems and the share of donor cells in the blood. When HLH has affected the brain, recovery can take time. Some children’s brain symptoms improve after transplant, while others keep lasting problems and need therapy and school support.

Once the family’s gene changes are known, brothers and sisters can be tested. Genetic counseling helps parents understand the chance of GS2 in a future pregnancy.

A child with GS2 who goes to transplant needs blood-forming cells from another person, because the child’s own cells carry the RAB27A changes. A healthy brother or sister who is a full tissue (HLA) match may be chosen. Each full sibling has a 1 in 4 chance of being a full match. Siblings are first checked for GS2, because a sibling can have it before any illness.

Many children have no matched family donor. In the 2024 review, a matched unrelated donor was the most common kind of donor among transplants where the donor type was reported. Half-matched (haploidentical) family donors and cord blood have also been used. European recommendations from 2025 call primary HLH, whatever the gene behind it, a clear reason for a donor transplant, including with these other donors.

HLH can flare again while a child waits, and results are better when transplant follows soon after HLH is controlled. That is why teams often start a donor search at 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.

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.

Without a transplant, GS2 is very serious. In the 2024 review of 149 patients, about one in three had died by the last report. The authors report that everyone with HLH throughout the body who did not have a transplant soon after either died or was left with major health problems.

Transplant has changed the outlook for many children. In the same review, 38 of 44 transplanted patients survived after transplant. In a series of 35 children at one center in Saudi Arabia, estimated five-year survival was 100% for children who had not had HLH before transplant. Children who had HLH before transplant did worse. Survival also looked lower when HLH had reached the brain, but in this small group that difference could have been chance.

These numbers come from published case reports and single centers, which may not include every child. They cannot predict how any one child will do.