Severe congenital neutropenia is a condition that increases the risk of repeated infections in affected individuals. People with this condition have an abnormally low level (deficiency) of neutrophils, a type of white blood cell that plays a role in inflammation and in fighting infection. The shortage of neutrophils, called neutropenia, is apparent at birth or soon afterward. It leads to frequent infections beginning in infancy, including infections of the sinuses, lungs, and liver. Affected individuals can also develop fevers and inflammation of the gums (gingivitis) and skin. Approximately 40 percent of affected people have decreased bone density (osteopenia) and may develop osteoporosis, a condition that makes bones progressively more brittle and likely to fracture. In people with severe congenital neutropenia, bone disorders can begin at any time from infancy through adulthood.

Approximately 20 percent of people with severe congenital neutropenia develop certain cancerous conditions of the blood, particularly myelodysplastic syndrome or leukemia during adolescence.

Some people with severe congenital neutropenia have additional health problems such as seizures, developmental delay, or heart and genital abnormalities.

Congenital neutropenia syndromes are a group of rare disorders present from birth that are characterized by low levels of neutrophils, a type of white blood cell necessary for fighting infections. NIAID supports basic scientific research on the immune system and the nature and development of neutrophils, which may lead to insights for addressing congenital neutropenia syndromes. Congenital neutropenia syndromes are primary immune deficiency diseases (PIDD).

Congenital neutropenia syndromes may also be called congenital agranulocytosis, severe congenital neutropenia, severe infantile genetic neutropenia, infantile genetic agranulocytosis, or Kostmann disease.

Researchers have identified numerous genetic mutations that cause congenital neutropenia syndromes. Generally, mutations that result in congenital neutropenia affect the development, lifespan, or function of neutrophils.

Congenital neutropenia syndromes are inherited through autosomal recessive, autosomal dominant, and X-linked inheritance patterns. The genes linked to these syndromes include the following:

• ELANE
• HAX1
• G6PC3
• GFI1
• CSF3R
• X-linked WAS
• CXCR4
• VPS45A
• JAGN1

In some people, however, the disease-causing mutation of their congenital neutropenia syndrome is unknown.

People with congenital neutropenia experience bacterial infections early in life. These may cause inflammation of the umbilical cord stump, abscesses (or boils) on the skin, oral infections, and pneumonia.

Congenital neutropenia also increases one’s risk for developing myelodysplastic syndromes (MDS), blood disorders that are distinguished by low levels of various blood cells. MDS may progress to a type of blood-cell cancer called acute myeloid leukemia.

Bone marrow and blood tests can measure the levels of various white blood cells to test for deficiencies. A person suspected of having congenital neutropenia also may undergo genetic testing for one of the genetic mutations known to cause the syndromes.

Standard therapy for congenital neutropenia includes injections of granulocyte colony-stimulating factor (G-CSF), an immune-cell-growth molecule that can help restore the function of the immune system. People on G-CSF therapy may have a lower incidence and severity of infections, improving their quality of life, but effects vary. For some individuals, a bone-marrow transplant may be recommended to replace defective immune cells with healthy ones from a donor.

Severe congenital neutropenia can result from variants (also known as mutations) in one of many different genes. These genes play a role in the maturation and function of neutrophils, which are cells produced by the bone marrow. Neutrophils surround foreign invaders and break them down. These cells also release substances, some of which break down foreign invaders and others of which strengthen the immune response.

Gene variants that cause severe congenital neutropenia lead to the production of neutrophils that die off quickly or do not function as they should. Some gene variants result in the production of unstable proteins that build up in neutrophils, leading to cell death. Other gene variants result in the production of abnormal proteins that prevent neutrophils from developing or functioning properly, which limits the cells' ability to respond appropriately to immune signals.

About half of all cases of severe congenital neutropenia are caused by variants in the ELANE gene. Another 10 percent are caused by variants in the HAX1 gene. The other associated genes each account for only a small percentage of all cases of this condition. In about one-third of people with severe congenital neutropenia, the cause of the disorder is unknown.

Normal Function

The ELANE gene provides instructions for making a protein called neutrophil elastase. This protein is found in neutrophils, a type of white blood cell that plays a role in inflammation and in fighting infection. When the body starts an immune response to fight an infection, neutrophils release neutrophil elastase. This protein then modifies the function of certain cells and proteins to fight the infection.

Health Conditions Related to Genetic Changes

Cyclic neutropenia

More than 15 mutations in the ELANE gene have been found to cause cyclic neutropenia, a condition characterized by episodes of neutrophil shortages (neutropenia) and increased risk of infection. ELANE gene mutations that cause cyclic neutropenia change single protein building blocks (amino acids) in neutrophil elastase. These mutations are thought to create an abnormal protein that retains some function. However, neutrophils that produce abnormal neutrophil elastase proteins appear to have a shorter lifespan than normal. The shorter neutrophil lifespan is thought to be responsible for the cyclic nature of this condition. When the affected neutrophils die early, there is a period in which there is a shortage of neutrophils because it takes time for the body to replenish its supply. For most affected individuals, neutropenia recurs every 21 days.

Severe congenital neutropenia

More than 70 mutations in the ELANE gene have been found to cause severe congenital neutropenia, a condition characterized by neutropenia beginning in infancy. Most of these mutations alter the structure of neutrophil elastase, causing it to fold into an incorrect 3-dimensional shape. Research findings indicate that misfolded neutrophil elastase protein accumulates in neutrophils. This accumulation likely damages and kills these infection-fighting cells. A deficiency of neutrophils results in recurrent infections, episodes of inflammation, and other immune problems in people with severe congenital neutropenia.

Other Names for This Gene

• bone marrow serine protease
• ELA2
• elastase-2
• ELNE_HUMAN
• granulocyte-derived elastase
• NE
• neutrophil elastase

Genomic Location

Normal Function

The HAX1 gene provides instructions for making a protein called HS-1-associated protein X-1 (HAX-1). This protein is involved in the regulation of apoptosis, which is the process by which cells self-destruct when they are damaged or no longer needed. Apoptosis is a common process that occurs throughout life. The HAX-1 protein is also thought to be involved in cell movement (migration). The HAX-1 protein is found primarily in the mitochondria, the energy-producing centers within cells.

Different versions of the HAX-1 protein can be produced from the HAX1 gene by a mechanism called alternative splicing. This mechanism produces different version of the protein by cutting and rearranging the genetic instructions in different ways. The purpose of these multiple versions of the HAX-1 protein is unclear.

Health Conditions Related to Genetic Changes

Severe congenital neutropenia

At least 10 mutations in the HAX1 gene have been found to cause severe congenital neutropenia, a condition characterized by a shortage (deficiency) of neutrophils. Neutrophils are a type of white blood cell that play a role in inflammation and in fighting infection. Most of the mutations that cause severe congenital neutropenia change single protein building blocks (amino acids) in the HAX-1 protein. HAX1 gene mutations that cause severe congenital neutropenia result in the production of a nonfunctional HAX-1 protein. A lack of functional HAX-1 protein disrupts regulation of apoptosis, leading to the premature death of neutrophils. A deficiency of neutrophils results in recurrent infections, episodes of inflammation, and other immune problems in people with severe congenital neutropenia.

People with certain HAX1 gene mutations have neurological problems such as seizures and developmental delay in addition to severe congenital neutropenia. These mutations disrupt two of the alternatively spliced versions of the HAX-1 protein. The gene mutations that lead to severe congenital neutropenia alone disrupt only one version of the HAX-1 protein. It is unclear how nonfunctional HAX-1 proteins cause neurological features seen in some affected individuals.

Other Names for This Gene

• HAX-1
• HAX1_HUMAN
• HCLS1-associated protein X-1
• HCLSBP1
• HS1 binding protein
• HS1-associating protein X-1
• HS1-binding protein 1
• HS1BP1
• HSP1BP-1

Genomic Location

Normal Function

The TCIRG1 gene provides instructions for making one part, the a3 subunit, of a large protein complex known as a vacuolar H+-ATPase (V-ATPase). V-ATPases are a group of similar complexes that act as pumps to move positively charged hydrogen atoms (protons) across membranes. This movement of protons helps regulate the relative acidity (pH) of cells and their surrounding environment. Tight control of pH is necessary for most biological reactions to proceed properly.

The V-ATPases containing the a3 subunit play an essential role in specialized cells called osteoclasts. These cells break down bone tissue as part of the normal process of bone remodeling, in which old bone is removed and new bone is created to replace it. Bones are constantly being remodeled, and the process is carefully controlled to ensure that bones stay strong and healthy.

On the surface of osteoclasts, V-ATPases are embedded in a specialized, highly folded membrane called the ruffled border. The ruffled border faces the surface of bone, where it helps form a tightly sealed compartment between the osteoclast and the bone surface. V-ATPases pump protons into the compartment, making it very acidic. This acidic environment is necessary to break down bone.

Health Conditions Related to Genetic Changes

Osteopetrosis

More than 60 mutations in the TCIRG1 gene have been identified in people with osteopetrosis. These mutations cause the most severe form of the disorder, autosomal recessive osteopetrosis (ARO).

Many TCIRG1 gene mutations change how the gene's instructions are used to make the a3 subunit of V-ATPase. Other mutations change single protein building blocks (amino acids) in the a3 subunit or lead to the production of an abnormally short version of the subunit. Studies suggest that most of the TCIRG1 gene mutations responsible for osteopetrosis eliminate the function of the a3 subunit.

Without the a3 subunit, V-ATPases cannot pump protons out of osteoclasts. As a result, the compartment between the ruffled border and the bone surface is not acidified, and bone cannot be broken down. When old bone is not broken down as new bone is formed, bones throughout the skeleton become unusually dense. The bones are also structurally abnormal, making them prone to fracture. These problems with bone remodeling underlie the major features of autosomal recessive osteopetrosis.

Severe congenital neutropenia

MedlinePlus Genetics provides information about Severe congenital neutropenia

Other Names for This Gene

• Atp6i
• ATP6N1C
• ATP6V0A3
• ATPase, H+ transporting, 116kD
• OC-116
• OC-116 kDa
• OC-116kDa
• OC116
• OPTB1
• osteoclastic proton pump 116 kDa subunit
• specific 116-kDa vacuolar proton pump subunit
• Stv1
• T cell immune response cDNA7 protein
• T-cell immune regulator 1
• T-cell immune regulator 1, ATPase H+ transporting V0 subunit a3
• T-cell immune response cDNA 7
• T-cell immune response cDNA7 protein
• T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 protein a
• T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 protein A3
• T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3
• TIRC7
• V-ATPase 116 kDa
• V-ATPase 116-kDa
• V-type proton ATPase 116 kDa subunit a
• V-type proton ATPase 116 kDa subunit a isoform 3
• vacuolar proton translocating ATPase 116 kDa subunit A
• Vph1
• VPP3_HUMAN

Genomic Location

Normal Function

The WAS gene provides instructions for making a protein called WASP. This protein is found in all blood cells. WASP is involved in relaying signals from the surface of blood cells to the actin cytoskeleton, which is a network of fibers that make up the cell's structural framework. WASP signaling triggers the cell to move and attach to other cells and tissues (adhesion). In white blood cells, which protect the body from infection, this signaling allows the actin cytoskeleton to establish the interaction between cells and the foreign invaders that they target (immune synapse).

Health Conditions Related to Genetic Changes

Wiskott-Aldrich syndrome

More than 350 mutations in the WAS gene have been found to cause Wiskott-Aldrich syndrome, a condition characterized by abnormal immune system function (immune deficiency) and a reduced ability to form blood clots leading to prolonged bleeding episodes.

Most of the mutations lead to the production of an abnormally short, nonfunctional version of WASP or prevent the production of any WASP. As a result, WASP cannot relay signals, which disrupts the function of the actin cytoskeleton in developing blood cells.

White blood cells that lack WASP have a decreased ability to respond to their environment and form immune synapses. As a result, white blood cells are less able to respond to foreign invaders, causing many of the immune problems related to Wiskott-Aldrich syndrome. Similarly, when cells that aid blood clot formation (platelets) lack functional WASP, their development is impaired. A reduction in platelet size and early cell death leads to the bleeding problems in affected individuals. The impairments of white blood cells and platelets are largely responsible for the immune deficiency and bleeding problems characteristic of Wiskott-Aldrich syndrome.

X-linked thrombocytopenia

More than 60 mutations in the WAS gene have been found to cause X-linked thrombocytopenia, a blood disorder characterized by a decrease in the amount and size of platelets, leading to prolonged bleeding episodes. Immune problems such as an increased susceptibility to infections may also occur.

Most of these WAS gene mutations change single protein building blocks (amino acids) in WASP. Mutations typically lead to the production of an altered protein that cannot efficiently relay signals from the cell membrane to the actin cytoskeleton. In people with X-linked thrombocytopenia, these signaling problems primarily affect the development of platelets. In some cases, white blood cells are affected. When WASP function is impaired in white blood cells, these cells are less able to respond to foreign invaders and immune disorders are more likely to occur.

Some WAS gene mutations cause X-linked thrombocytopenia in some individuals and a related condition called Wiskott-Aldrich syndrome (described above) in others. These mutations usually prevent the production of any WASP. It is unknown why some people with these mutations have the relatively mild features of X-linked thrombocytopenia and others have the severe symptoms of Wiskott-Aldrich syndrome. Because they have overlapping features and the same genetic cause, Wiskott-Aldrich syndrome, X-linked thrombocytopenia, and severe congenital neutropenia are sometimes collectively referred to as WAS-related disorders.

Severe congenital neutropenia

MedlinePlus Genetics provides information about Severe congenital neutropenia

Other Names for This Gene

• IMD2
• WASP
• WASP_HUMAN
• WASPA

Genomic Location

Most cases of severe congenital neutropenia are classified as sporadic and occur in people with no apparent history of the disorder in their family. Some of these cases are associated with changes in specific genes; however in some cases the cause of the disorder is unknown.

When severe congenital neutropenia is caused by variants in the ELANE gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Variants in a few other genes that cause this condition are also inherited in an autosomal dominant pattern.

When severe congenital neutropenia is caused by variants in the HAX1 gene, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition. Many cases of this condition are caused by genetic variants that are inherited in an autosomal recessive pattern.

In rare cases, severe congenital neutropenia is inherited in an X-linked recessive pattern. In these cases, the gene that causes the condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a variant would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

The incidence of severe congenital neutropenia is estimated to be 1 in 200,000 individuals.