Severe infantile osteopetrosis (ARO)

Diagnosis usually starts when a baby shows signs such as poor growth, low blood counts, a swollen belly from a large liver and spleen, or trouble seeing. X-rays are the key test. In osteopetrosis they show very dense bone across the skull, spine, pelvis, arms and legs. Blood tests check blood counts and calcium, which can be low. A newborn’s normal bones can look dense on X-rays, so doctors read the X-rays together with the baby’s other signs.

Genetic testing confirms the diagnosis and names the type. This step matters, because the gene helps show whether a transplant can work. A brain MRI checks the nerves inside the skull and looks for fluid buildup (hydrocephalus). Doctors also watch for the types that harm the brain directly. Slow development, poor growth and certain changes on an EEG (a test of brain waves) can be early signs of those types. Eye exams, including a test of how the optic nerve carries signals (visual evoked potentials), check for pressure on the nerve to the eye.

Care usually involves a team of specialists. It can include experts in hormones and bone (endocrinology), eyes, genetics and teeth, along with the transplant team. When a family already knows its gene change, testing is possible before birth.

For transplant-responsive types, a donor stem cell transplant is the standard treatment. Donor stem cells produce working osteoclasts that start to clear bone and make room for marrow. European transplant recommendations call it urgent once testing has ruled out the types that a transplant cannot help.

Timing matters because of sight. Transplant in the first year of life, before nerve damage builds up, is strongly favored, and graft failure, when donor cells do not take hold, becomes more common after about 10 months of age. A transplant cannot restore vision or hearing that has already been lost, and some children still lose sight soon after transplant.

A transplant is not advised when the cause is RANKL (TNFSF11), because the problem lies outside the blood-forming system. It is also not advised for OSTM1-related disease or CLCN7-related disease with primary brain involvement, because the brain damage continues. Doctors therefore check the genes and examine the brain with MRI or CT and EEG before deciding.

Other care supports the child while a plan is made or when a transplant is not possible. This includes transfusions, infection treatment, calcium and vitamin D management, and help with breathing, feeding, vision and hearing. In the United States, interferon gamma-1b (Actimmune) is FDA-approved to delay worsening of severe malignant osteopetrosis. It is approved to slow the disease, not to cure it. Gene therapy for the TCIRG1 type is being tested in an early (phase 1/2) clinical trial in Milan, Italy, for children aged 28 days to 2 years. As of September 2026, the trial listing said it was taking new patients. It is not an approved treatment.

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, most children with the severe infantile form die in their first 10 years, usually because the marrow cannot make enough blood cells. Several things shape the outlook, including the gene type, the baby’s age at transplant and how much nerve damage has already happened.

For types that respond to transplant, European guidelines call it the treatment of choice. Experts favor doing it in the first year of life, while nerve damage is still limited. In a large international study, most school-age children who survived were in school, and most were doing well in daily life. But about 7 in 10 had vision problems. Transplant methods have changed since those children were treated. For example, a newer method for half-matched family donors helps donor cells take hold more reliably.

For children with OSTM1-related disease or CLCN7-related disease that affects the brain, the brain disease keeps getting worse even after a transplant. For the RANKL type, a donor transplant does not fix the cause. In these types, care focuses on treating symptoms and supporting the child.