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 the bone marrow to produce too many 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 to help diagnose these conditions.
While some genetic abnormalities are inherited from our parents, they can also come from changes that occur to genes or chromosomes later in life. 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 later in life. It occurs when the chromosome 4 loses approximately 800 nucleotides (DNA building blocks), which normally separate the FIP1L1 and PDGFRA genes. Because of this deletion, the two genes are brought together (fused), 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 FIP1L1-PDGFRA fusion gene is present, the gene sequence still provides instructions for making that protein, but the protein that results is abnormal 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 move into and inflame tissues, HES develops. HES results when these 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 digestive tract or the skin. Sometimes, there may be no symptoms, when tissue or organ damage is less severe.
There are several 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 healthcare practitioner has ruled out these secondary (reactive) causes, genetic testing can determine if FIP1L1-PDGFRA or other genetic abnormality is the underlying cause. If the genetic abnormality is detected, the HE or HES is neoplastic.
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. It can be effectively treated with the drug imatinib.
How is the test used?
FIP1L1-PDGFRA testing may be used to help determine the cause of a persistently elevated number of eosinophils, as determined by a complete blood count (CBC), after other tests have ruled out more common secondary (reactive) causes. These other tests may include, for example, allergy blood tests or stool tests for parasites. (See below 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.
When is it ordered?
FIP1L1-PDGFRA testing is ordered when CBCs indicate that you have persistently elevated numbers of eosinophils and other causes like allergies, asthma, parasitic infections, adrenal insufficiency, and lymphoma have already been ruled out.
Testing may be ordered after an abnormal eosinophil count when HES is suspected due to your signs and symptoms. (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 abnormal gene sequence is present) or as "negative" (the abnormal gene sequence is not present).
If you have abnormally high numbers of eosinophils and you test positive for the FIP1L1-PDGFRA fusion gene, then the fusion gene is confirmed as the underlying cause of your hypereosinophilia (HE) or hypereosinophilic syndrome (HES). Detection of the abnormal fusion gene also indicates the HE or HES is neoplastic.
Note that HE/HES with FIP1L1-PDGFRA may be diagnosed as acute or chronic leukemia, a myeloproliferative neoplasm (MPN) or myelodysplastic syndrome (MDS), 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 you test negative for FIP1L1-PDGFRA, depending on other test results, you may have another type of MPN or MDS 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 for more on this.)
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, healthcare 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.
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, besides 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 other 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 healthcare practitioner.
What other tests may be done to rule out secondary (reactive) causes of increased eosinophils?
Before testing for genetic causes of increased number of eosinophils, your healthcare 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 increased eosinophils 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.
If HE or HES is suspected, what other lab tests in may be done in addition to FIP1L1-PDGFRA?
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:
- Chromosome analysis – to detect other genetic abnormalities that may be the cause of HE/HES, such as PDGFRB or FGFR1 rearrangement. Fluorescence in-situ hybridization (FISH) is also used to detect chromosome abnormalities.
- 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.
- Imaging studies – if an underlying solid tumor or lymphoma is suspected
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. Next-generation sequencing (NGS)-based testing can also be used to detect FIP1L1-PDGFRA.