Reticular dysgenesis (AK2 deficiency SCID)

SCID (severe combined immunodeficiency) is a group of rare genetic conditions in which a baby is born without a working immune system. Reticular dysgenesis is the most severe and one of the rarest types. It makes up fewer than 2 in 100 reported SCID cases.

In most types of SCID, the problem is mainly in lymphocytes, such as T cells. In reticular dysgenesis, the blood-forming system also fails to make neutrophils, the white blood cells that eat bacteria and fungi. So babies have almost no T cells and very few or no neutrophils (agranulocytosis). European transplant guidelines list it with the SCID types that lack T cells, B cells and natural killer (NK) cells.

Most babies also have hearing loss in both ears that starts in the inner ear or hearing nerve (sensorineural hearing loss). Red blood cells and platelets are usually less affected, though some babies have low counts of them too.

Reticular dysgenesis is caused by changes in the AK2 gene. This gene makes an enzyme called adenylate kinase 2, which works inside mitochondria, the parts of a cell that make energy. Without it, young blood-forming cells cannot survive and mature normally, and white blood cells are hit hardest.

The condition is autosomal recessive. A child is affected only when both copies of AK2 have a change, one from each parent. Parents who carry one changed copy typically have no symptoms. When both parents are carriers, each pregnancy has a 25 percent (1 in 4) chance of an affected child.

It is seen more often when parents are related by blood. In a series from one hospital in Saudi Arabia, all 10 children had parents who were related. Nine shared the same AK2 change, which may come from a shared ancestor. Two of those babies were tested as newborns because of a known family history of immune disease.

Babies usually get sick in the first days or weeks of life. In an international survey, 30 of 32 babies had symptoms before 4 weeks of age. Because they lack neutrophils, the first problems are usually serious bacterial infections, such as blood infections (sepsis), rather than the unusual germs more typical of other SCID types.

Many babies are born early or small. In the Saudi series, 6 of 10 were born early and all had a low birth weight. Fungal infections are also a danger before transplant.

The hearing loss does not go away after transplant. In an international survey, 19 of the 21 children alive after transplant still had hearing loss and used hearing aids or cochlear implants. Hearing was not reported for the other 2.

Every U.S. state has screened newborns for SCID since December 2018, using a heel-prick TREC test that checks whether the baby is making new T cells. Babies with reticular dysgenesis have been found this way in screening programs in Japan and Germany. A low result leads to urgent tests by an immunology team.

Blood tests show very low T cells and very low or absent neutrophils, and the neutrophils usually do not rise with G-CSF. A bone marrow test often shows that the cells that become neutrophils stop maturing at an early stage (the promyelocyte stage). A hearing test that finds hearing loss in both ears is a strong clue that sets it apart from other SCID types.

A genetic test confirms the diagnosis by finding changes in both copies of the AK2 gene. Where there is no screening, the diagnosis usually comes after a newborn has a serious infection, often in the first weeks of life.

From diagnosis, the goal is to keep the baby free of infection until a transplant. Care teams usually keep the baby in protective isolation. They give medicines to prevent Pneumocystis pneumonia and fungal infections, treat any infection quickly, and give antibody replacement (immunoglobulin). Blood transfusions are treated with radiation and chosen to be free of CMV, a common virus. Live vaccines, such as the rotavirus vaccine, are avoided.

G-CSF, a medicine that usually boosts neutrophils, typically does not fix the neutropenia in reticular dysgenesis. A 2026 report describes one baby whose neutrophils rose somewhat on G-CSF, which helped control a severe infection before transplant.

A donor stem cell transplant is the only cure. Unlike some other SCID types, it needs conditioning, meaning chemotherapy before the transplant. Without it, the donor cells may not make neutrophils, and the transplant often fails. In an international survey, every child who died more than 6 months after transplant still lacked neutrophils, because donor blood-forming cells had not taken hold.

The weeks before transplant are hard. Babies are often very sick from birth and may need newborn intensive care. They are kept in isolation to avoid germs. Some babies die of infection before a transplant can happen: in the Saudi series, 3 of 10 died before transplant.

A transplant means a long stay at a specialist children’s hospital. Afterward, checkups continue for years to see how well donor cells have taken hold and how the child is growing. In the Saudi series, 5 of the 6 survivors stopped immunoglobulin, and most had been vaccinated. Two had short stature, and one had an underactive thyroid.

Hearing care is part of life after transplant. Children in published reports have had hearing aids or cochlear implants. Because the condition is recessive, when both parents are carriers, each pregnancy has a 1 in 4 chance of an affected baby. In families that know their AK2 changes, a new baby can be tested at birth.

A transplant for reticular dysgenesis uses blood-forming stem cells from a donor. The donor cells must settle in the bone marrow and make both neutrophils and immune cells, which is why conditioning chemotherapy is given first.

For SCID, European guidelines call a matched brother or sister the gold standard. But many babies do not have one. In an international survey of 31 transplanted children, only 6 had a matched family donor. Most, 17, had a mismatched (half-matched) relative, and 8 had an unrelated bone marrow or cord blood donor. Parents who carry one changed copy typically have no symptoms, so a parent can be a half-matched donor.

European recommendations rate a donor transplant as standard care for SCID. That holds whether the donor is a matched sibling, a matched unrelated volunteer, or a mismatched donor such as cord blood or a half-matched relative. Because these babies are in danger from the first days of life, speed matters. A registry volunteer who is ready to donate quickly, or a stored cord blood unit, can make a transplant possible when there is no matched relative. Joining a registry cannot promise a match for any one baby.

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, reticular dysgenesis is fatal, usually from overwhelming infection shortly after birth.

With a transplant, many children now survive long term. In an international survey, 21 of 31 transplanted children were alive at a mean follow-up of almost 8 years. The children who died more than 6 months after transplant had not gained lasting donor neutrophils. At one Saudi center that gave conditioning for every transplant, 6 of 7 transplanted children were alive after a median follow-up of 10 years. All had fully donor-made blood cells.

Survivors still live with hearing loss. In the international survey, 7 of 16 children with data were shorter than 9 in 10 children their age, and 4 of 16 had learning disabilities. These results come from small groups at a few centers.