An Overview of Congenital Neutropenia

Congenital neutropenia is the name for a cluster of genetic diseases that cause the body to produce very low levels of neutrophils—a type of white blood cell that is a critical part of the immune system.

These conditions are present at birth and can lead to complications involving skin, bones, the heart, and the nervous system. It also makes it very difficult to fight off infection. The condition is rare, but it’s considered serious because of its effects on the immune system.

This article will discuss the signs, symptoms, and treatment for congenital neutropenia.

White blood cell

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Neutrophils and the White Blood Cell Count

Your immune system has different components that help your body resist disease in several ways. The first level of defense is the innate immune system—an all-purpose collection of generalized tools designed to fight off infections.

The innate immune system includes tools like your skin, signaling molecules, and, perhaps most importantly, white blood cells.

There are five types of white blood cells: 

  • Neutrophils 
  • Lymphocytes
  • Eosinophils 
  • Monocytes 
  • Basophils

Neutrophils are the most common type of white blood cell. They are primarily responsible for patrolling your body and looking for signs of infection. If they find any, they close in and kill invading microbes or send signals that recruit other cells in the immune system. They’re particularly important for fighting off bacterial infections.

A white blood cell count is part of a complete blood count (CBC). The total white blood cell count is always reported. In general, the level of white blood cells is a good indicator of how well your immune system is equipped to fight off pathogens.

Depending on the method the lab uses, the percentage of each type of white blood cell present may also be reported with a CBC. A white blood cell differential may also be ordered, in which a blood smear is used to perform a microscopic count to determine the percentage of each type of white blood cell.

There are some things that might cause white blood cell counts to fluctuate. About 5% of people without long-lasting white blood cell issues will have white blood cell counts outside regular ranges when tested.

For instance, if you are sick or physically or emotionally distressed, your white blood cell count might increase temporarily. If you undergo chemotherapy or have a vitamin B12 deficiency, it might decline. If white blood cell count falls beyond certain thresholds after repeated tests, it could signify an underlying immune condition.

What Is Congenital Neutropenia?

Congenital neutropenia is a condition in which the body produces low levels of neutrophils. Low neutrophil levels are called neutropenia. Congenital means the condition is present at birth, which may be due to genetic mutations.

A normal absolute neutrophil count is between 2,500 and 6,000 neutrophils per microliter of blood. It's considered neutropenia when absolute neutrophils count below 1,000 per microliter of blood. If it dips below 500 neutrophils per microliter of blood, that's considered severe neutropenia.

In those cases, a doctor will then try to determine why neutrophil counts are so low. In congenital neutropenia, the underlying cause often comes down to mutations in certain genes that affect neutrophil production, function, or longevity.

There are a handful of different types of congenital neutropenia that are linked to different genetic mutations and neutrophil issues.

For example, a type of congenital neutropenia called Kostmann syndrome is characterized by a neutrophil count below 500 per microliter of blood, and a lack of mature neutrophils. It is due to mutations of a gene called HAX1. About 10% of congenital neutropenia cases are caused by HAX1 mutations.

Mutations in another gene, called ELANE can cause deficiencies with key proteins found on neutrophils (in some cases, these limit their lifespans or cause them to die off). About 50% of all severe congenital neutropenia cases are caused by mutations in the ELANE gene.

But, in about one-third of severe cases of congenital neutropenia, there’s no obvious genetic mutation behind the low neutrophil count. In that case, the cause is unknown. 

Signs and Symptoms of Congenital Neutropenia

Usually, congenital neutropenia becomes apparent at or near birth. Infants born with neutrophil deficiencies are likely to develop recurring infections.

These infections often present as frequent fevers, ear infections, mouth sores, pneumonia, rectal sores, or infections of the sinuses, lungs, or liver. Other rare side effects might involve heart issues or developmental delays.

Another common issue for people with congenital neutropenia is bone health (white blood cells are primarily made in the bone marrow). Osteoporosis (progressive bone thinning) is seen in about 40% of people with severe congenital neutropenia.

On the more extreme end of the spectrum, congenital neutropenia can predispose some people to develop a cluster of conditions called myelodysplastic syndromes (MDS), in which bone marrow doesn’t produce sufficient amounts of healthy white blood cells.

Over time, MDS can lead to a type of blood cancer called acute myeloid leukemia, where unhealthy white blood cells build up in bone marrow and prevent regular blood production. Some studies suggest that some people with severe congenital neutropenia have a high risk of developing acute myeloid leukemia.

However, the most typical signs of congenital neutropenia are recurring infections that appear more severe than expected.

Diagnosis

Congenital neutropenia diagnosis often begins soon after birth, with a physical exam once severe infections become recurring. A doctor can order a complete blood count (CBC). The test is done via a blood draw and doesn’t require any special preparations.

If that test indicates low levels of white blood cells (specifically, neutrophils), the doctor might order it again to be sure. If it repeatedly comes back low, then a doctor can perform a bone marrow aspiration, in which a doctor takes a sample of the bone marrow and analyzes it for signs of neutrophil issues.

Finally, a genetic test can confirm that the neutropenia is due to some type of genetic mutation, rather than cancer or an underlying immune disease. 

Treatment

Some people with congenital neutropenia will be prescribed antibiotics when they get sick, even if it's just a fever. That can help prevent infections from becoming worse due to the lack of neutrophils in the immune system.

However, the primary way to treat congenital neutropenia is to boost the immune system’s strength using granulocyte colony-stimulating factor (G-CSF)—a drug that prompts the bone marrow to make more white blood cells.

People on these drugs become less susceptible to infection than they would be without the drugs but still face elevated risks. And, while these drugs can protect people from the primary consequence of congenital neutropenia (infection), they don’t fix the underlying genetic mutations causing the problem.

A stem cell (bone marrow) transplant is an option if congenital neutropenia has progressed to MDS or acute myeloid leukemia, or if G-CSF drugs aren’t working. In this procedure, donor stem cells are harvested and infused into the recipient after their bone marrow has been cleared of abnormal stem cells.

Aside from drugs, children diagnosed with congenital neutropenia may need to avoid places that harbor bacteria (like sandboxes or manure from animals), quickly attend to wounds to prevent infection, and keep up good hygiene habits like hand washing and dental care.

What to Expect During Treatment

G-CSF drugs are given via injections. People with congenital neutropenia usually start off with two injections per day. The dosage can depend on the severity of the neutropenia and how people’s white blood cells respond to the drugs.

Patients on G-CSF don’t often report side effects, but there are some. For example, some participants reported bone pain, mild headache, and rash in a clinical trial. The bone pain tended to subside over time. Other side effects might include diarrhea, loss of feeling in some parts of the body, or alopecia (hair loss). 

Summary

Congenital neutropenia is a disease in which the body doesn't produce regular levels of certain white blood cells, called neutrophils, often due to genetic mutations. This can lead to a weakened immune system and more susceptibility to infection. Treatment includes drugs that stimulate the production of white blood cells, antibiotics to fight infections, and good hygiene.

A Word From Verywell

Congenital neutropenia is a rare and serious condition. However, there are drugs that make it manageable. It may require careful monitoring of health, avoiding potential sources of infection, and regular doctor’s visits. The Cincinnati Children’s hospital reports that plenty of children born with this condition are able to lead healthy lives.

Frequently Asked Questions

  • How many people are affected by congenital neutropenia?

    Congenital neutropenia is considered a rare disease. Though there is not very comprehensive data on how many people have it, one paper estimated that about 6 out of every 1 million people have some form of congenital neutropenia.

    The National Library of Medicine estimates 5 out of every 1 million people have severe congenital neutropenia.


  • Is congenital neutropenia inherited?

    Most forms of congenital neutropenia are inherited from parents. The disease can be inherited in different patterns.

    In the case of Kostmann’s syndrome, a very severe form of congenital neutropenia, the genetic mutations responsible must be present in both parents. This often means parents are carriers but do not show symptoms themselves.

    In other cases just one parent needs to have a mutation for congenital neutropenia to occur. For example, mutations in the ELANE gene (responsible for many cases of severe congenital neutropenia) can be inherited via one parent.

    However, there are some cases in which genetic causes of neutropenia can’t be identified, although the condition is still present at birth. That occurs in about one-third of severe congenital neutropenia cases.


  • Which genes are associated with congenital neutropenia?

    There are numerous genes linked with congenital neutropenia. But two especially severe forms of the disease are linked to the HAX1 gene and ELANE gene. Mutations in the HAX1 gene often lead to the premature death of neutrophils. Certain mutations in this gene are responsible for Kostmann’s syndrome.

    Mutations in the ELANE gene can cause cyclic neutropenia, which is when neutrophils have shortened lifespans and become depleted on three-week cycles. Other mutations can damage proteins used by neutrophils, leading to their death. Such mutations cause severe congenital neutropenia.

    Other genes linked to congenital neutropenia include: 

    • G6PC3
    • nGFI1
    • CSF3R
    • X-linked WAS (generally only affects males) 
    • CXCR4
    • VPS45A
    • JAGN1



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