To help investigate the cause of hypereosinophilia (HE), a condition with persistent increase in the number of eosinophils, a specific type of white blood cell, or hypereosinophilic syndrome (HES), which is HE with associated tissue or organ damage; to help determine if someone with HE or HES can be treated with a tyrosine kinase inhibitor (TKI) such as imatinib
FIP1L1-PDGFRA is an abnormal fusion gene sequence that causes excessive growth of eosinophils, a type of white blood cell. It is a rare cause of hypereosinophilia (HE) and hypereosinophilic syndrome (HES). This test detects the FIP1L1-PDGFRA gene sequence.
While some genetic abnormalities are inherited from our parents, they can also come from changes that occur to genes or chromosomes after a person is born. These are called somatic mutations, which can occur through exposure to various environmental factors (e.g., radiation, certain chemicals), but more often for unknown reasons.
The FIP1LI-PDGFRA gene sequence is one of those genetic changes acquired after birth. It occurs when a mutation on chromosome 4 causes deletion of approximately 800 nucleotides, or DNA building blocks, which normally separate the FIP1L1 and PDGFRA genes. Because of this deletion, the two genes are brought together, producing a new fusion gene. Other types of mutations can also lead to abnormalities of the PDGFRA gene, but this deletion is the most common.
Normally, the PDGFRA gene provides instructions for making a protein that controls processes like cell growth and division. When the mutation occurs and the FIP1L1-PDGFRA fusion gene is present, the gene sequence still provides instructions for making that protein, but the protein that results is different because it is always activated and continues to send signals for growth and division. With constant signals for growth, eosinophils (and sometimes other blood cells) can grow out of control, causing hypereosinophilia (HE) and hypereosinophilic syndrome (HES), which can be fatal if not treated promptly.
Hypereosinophilia (HE) and Hypereosinophilic syndrome (HES)
Eosinophils are a type of white blood cell that are involved in allergic reactions and immune responses to certain parasites. The number of eosinophils in the blood may be elevated with these conditions. Hypereosinophilia is the prolonged overproduction of eosinophils. As increasing numbers of eosinophils infiltrate and inflame tissues, HES develops. HES is a condition caused when infiltrative eosinophils affect and damage a variety of organs, including the heart, lungs and the nervous system.
Common symptoms include chest pain and shortness of breath, if the heart is involved. People with HES may also have anemia or excessive clotting (hypercoaguability), stroke, blurred vision or slurred speech. Other symptoms may involve the gastrointestinal system or the skin. Sometimes, there may be no symptoms, when tissue or organ damage is less severe.
There are a number of causes of HE and HES besides genetic abnormalities. Allergic diseases are the most common cause in the developed world. Parasitic diseases, certain cancers, autoimmune disorders, skin disease, inflammatory bowel syndrome, and Addison disease can also cause HES. If an individual has HES and a health practitioner has ruled out these secondary causes, genetic testing can determine if FIP1L1-PDGFRA or other genetic abnormality is the underlying cause.
Only 0.4% of people with persistently high numbers of eosinophils carry the FIP1L1-PDGFRA gene. It is most common in individuals between 20 and 50 years old. Although it is a rare cause of HE and HES, it is important to identify it because HE/HES with FIP1L1-PDGFRA can be fatal if not treated but is effectively treated with the drug imatinib.
How is the sample collected for testing?
A blood sample is obtained by inserting a needle into a vein in the arm or a bone marrow sample is collected using a bone marrow aspiration and/or biopsy procedure.
Is any test preparation needed to ensure the quality of the sample?
No test preparation is needed.
How is it used?
Eosinophils are part of the body's immune response and can be elevated in the blood with different diseases and conditions. Some common examples are allergic responses and parasitic infections. A complete blood count (CBC) is a test that may show increased numbers of eosinophils in the blood (hypereosinophilia) with these conditions.
The FIP1L1-PDGFRA gene sequence is a rare cause of increased eosinophils. Testing for the mutation may be used to help determine the cause of a persistently elevated number of eosinophils, as determined by a CBC, after other tests have ruled out more common secondary causes. These other tests may include, for example, allergy blood tests or stool tests for parasites. (See Common Questions for more on these.)
FIP1L1-PDGFRA testing may be used to:
- Help diagnose the cause of hypereosinophilia (HE) and hypereosinophilic syndrome (HES), a type of bone marrow disorder
- Help determine HE/HES prognosis and responsiveness to therapy with a tyrosine kinase inhibitor (TKI); people with FIP1L1-PDGFRA respond well to treatment with a TKI called imatinib.
See Common Questions for more details on test methods.
Tests for FIP1L1-PDGFRA may be performed along with other genetic tests for less common mutations related to eosinophilia. It may also be performed along with:
- Chromosme analysis – to detect other genetic abnormalities that may be the cause of HE/HES, such as PDGFRB or FGFR1 rearrangement
- BCR-ABL1 – if chronic myelogenous leukemia (CML) is suspected and thus needs to be ruled out
- KIT mutation – to rule out mutation in the KIT gene; people with KIT D816 mutation (mastocytosis) do not respond to imatinib treatment.
- Interleukin-5 – may be tested because, if elevated, it suggests clonal T-cell disease when found with HES
- Immunoglobulin E (IgE) level – people with elevated IgE levels may have a lower risk of developing hypereosinophilic syndrome-associated cardiovascular disease and may respond well to steroid therapy.
- An initial evaluation of HES may include cardiac tests to look for evidence of organ damage from the condition and a troponin test to make sure imatinib won't cause cardiac shock.
When is it ordered?
FIP1L1-PDGFRA testing is ordered when CBCs indicate that someone has persistently elevated numbers of eosinophils and other causes like allergies, asthma, parasitic infections, adrenal insufficiency, and lymphoma have been ruled out.
Testing may be ordered after an abnormal eosinophil count when HES is suspected due to a person's signs and symptoms. HES and leukemias (either acute or chronic) may have similar presentations, but sometimes there are no early symptoms and the conditions are found only through a routine CBC.
Examples of common HES signs and symptoms include:
- Cough, wheezing, shortness of breath
- Swelling under the skin around the eyes and lips, in the throat, or on the hands and feet
- Swollen lymph nodes or organs
- Muscle pain
- Itching, rash or blistering of the skin
What does the test result mean?
The result of the test may be reported as "positive" (the gene sequence is present) or as "negative" (the gene sequence is not present).
If a person has abnormally high numbers of eosinophils and tests positive for the FIP1L1-PDGFRA fusion gene, then the fusion gene is confirmed as the underlying cause of that person's hypereosinophilia (HE) or hypereosinophilic syndrome (HES).
Note that HE/HES with FIP1L1-PDGFRA may be diagnosed as acute or chronic leukemia, a myeloproliferative or myelodysplastic disorder, or even systemic mastocytosis, based on the World Health Organization's 2008 diagnostic guidelines. Regardless the diagnosis, individuals with the FIP1L1-PDGFRA fusion gene respond very well to treatment with the tyrosine kinase inhibitor imatinib.
If a person tests negative for FIP1L1-PDGFRA, depending on other test results, the person may have another type of myeloproliferative or myelodysplastic neoplasm or may be diagnosed with HES without a specific cause (idiopathic). FIP1L1-PDGFRA-negative cases of HES do not respond as well to imatinib except for rare cases with PDGFRB rearrangement (see below).
Is there anything else I should know?
Sometimes people develop resistance to imatinib even though the tyrosine kinase inhibitor is usually very effective for treating people with the FIP1L1-PDGFRA fusion gene at low doses. For the rare individuals whose HES is resistant to imatinib, stem cell transplants have reversed the organ dysfunction caused by hypereosinophilia. However, health practitioners have limited experience with this treatment, so it is not used routinely. Chemotherapy has also been used with some success for people with the fusion gene who don't respond to treatment with imatinib. Some individuals with the fusion gene are also treated with corticosteroids to lower their eosinophil count and help control organ damage.
People with FIP1L1-PDGFRA may also manifest as acute myeloid or lymphoblastic leukemia, though that is rare. FIP1L1-PDGRA has also been found infrequently in other leukemias and successfully treated with imatinib.
Unlike some other genetic abnormalities, FIP1L1-PDGFRA related change is very subtle and thus cannot be detected with routine karyotyping, which involves looking at chromosomes under a microscope.
If I have the FIP1L1-PDGFRA fusion gene, should my family members be tested?
Should everyone with leukemia be tested?
Are there other genetic abnormalities associated with neoplastic hypereosinophilia or hypereosinophilic syndrome (HE/HES)?
Yes, while the FIP1L1-PDGFRA fusion gene is the most common, there are other mutations that can cause malignant disorders associated with eosinophilia. They include abnormalities of the genes FDGFRB or FGFR1. Similar to PDGFRA, those mutations lead to excess production of the enzyme tyrosine kinase, which is responsible for overactive cell growth. As with FIP1L1-PDGFRA, people with FDGFRB abnormalities respond well to treatment with a tyrosine kinase inhibitor, while those with FGFR1 generally do not. Tests for less common genetic abnormalities associated with eosinophilia may be done as part of a panel for myeloproliferative disorders or eosinophilia or may be ordered separately based on the judgment of the health practitioner.
What other tests may be done to rule out secondary causes of eosinophilia?
Before testing for genetic causes of hypereosiniophilia, your health practitioner will rule out more common causes like allergies, asthma, medication, or parasites and other secondary causes like T-cell lymphoma, Hodgkin lymphoma, other myeloproliferative neoplasms, and leukemias. Since allergic diseases are the most common cause of hypereosinophilia in the developed world, you will likely be given allergy blood tests. Especially if you have been traveling, your stool may be tested for parasites with an ova and parasites exam. Depending on your symptoms, further blood tests may be done to look for other abnormalities like elevated serum vitamin B12, which would indicate a myeloproliferative disorder and possibly lead to a bone marrow biopsy.
What are some types of lab methods used for this testing?
Different types of tests may be ordered to detect FIP1L1-PDGFRA. Samples may be analyzed using fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR). The FISH method uses fluorescent dye-labeled probes to detect the deletion of the portion of DNA (4q12, CHIC2 region) that results in the abnormal gene sequence, whereas the RT-PCR method directly detects the FIP1L1-PDGFRA gene sequence when it is present.
Tests: Complete Blood Count, WBC Differential, Blood Smear, Interleukin-5, Total IgE, Vitamin B12 and Folate, Immunophenotyping, C-KIT Mutation, Bone Marrow Aspiration and Biopsy, Chromosome Analysis, T-Cell Receptor Gene Rearrangement, BCR-ABL1, Genetic Tests for Targeted Cancer Therapy
Features: The Universe of Genetic Testing