CEBPA Deficiency – Definition
CEBPA deficiency or CEBPA-associated familial acute myeloid leukemia (OMIM #601626, #116897) is a leukemia predisposition syndrome caused by a heterozygous germline mutation of the CEBPA gene. Typically, acute myeloid leukemia (AML) with an underlying CEBPA mutation occurs at an earlier stage than sporadic AML. In addition, several family members are often affected.
Synonym:
CEBPA-associated familial AML
Gene:
CEBPA
Gene product:
C/EBPα (CCAAT/enhancer binding protein-alpha)
Function:
Transcription factor with a key role in granulocyte maturation
Pattern of inheritance:
autosomal dominant
Prevalence:
Presumably 5-10% of presumably sporadic CEBPA-associated AML have a pathogenic CEBPA germline variant.
Genotype-phenotype correlation:
A germline mutation is typically a frameshift mutation in the region of the CEBPA gene coding for the N-terminal of the C/EBPα protein, whereas somatic mutations are typically localized in the region coding for the C-terminal.
Hereditary C-terminal mutations occur less frequently and show lower penetrance.
Penetrance:
for AML >80%
CEBPA Deficiency – Diagnosis
Suspected Diagnosis
The presence of CEBPA deficiency is suspected if the following findings are present:
Clinical:
- People with AML who have a positive family history of AML
- People who develop AML at a young age (<50 years)
Laboratory Parameters:
- Young patients with AML whose leukemic cells have mutations in both copies of the CEBPA gene
- A normal karyotype in leukemic cells
- A predominance of FAB subtypes M1 or M2
- Auer rods in blasts
- Aberrant CD7 expression
Genetic Diagnostics
The diagnosis of “familial CEBPA deficiency” is confirmed by detecting a germline mutation in the CEBPA gene using sequence or deletion/duplication analysis. Panel examinations, in which several genes are recorded, can also be helpful.
Since CEBPA-associated familial AML develops from cells with mutations in both copies of the CEBPA gene, leukemic cells often show both a germline and a somatic CEBPA mutation.
Further Clinical Diagnostics After Diagnosis
- HLA typing with a view to possible stem cell transplantation
- After diagnosis of leukemia, extensive diagnostics according to the respective study protocol
Human Genetics
- Human genetic connection of the patient
- Detailed family history to find other affected family members and mutation carriers
- Genetic counseling/diagnostics for all family members at risk of having CEBPA-associated familial AML
Differential Diagnoses
- Sporadic AML with somatic CEBPA mutation
- AML due to environmental exposures (benzenes, radiation, chemotherapy)
- Sporadic AML with more than one affected relative
Clinical Presentation
CEBPA-associated familial AML is usually of FAB subtype M1, M2, or, more rarely, M4.
AML in the context of familial CEBPA deficiency appears earlier than sporadic AML. The average age at diagnosis is 25 years, although this varies greatly from just under 2 years to >45 years. In comparison, the average age at diagnosis of sporadic AML is 65 years.
The prognosis of familial AML appears favorable, with a 10-year overall survival (OS) of 67% compared to sporadic AML, where the OS is 54% with a double CEBPA mutation and 29% with a single CEBPA mutation.
Patients with familial CEBPA deficiency are at risk of developing another leukemia after successfully treating AML. This is usually a second new disease with a favorable prognosis and not a relapse.
Special Features of Treatment
The treatment of AML in patients with a CEBPA mutation should be discussed in detail with the relevant study center and, if possible, should follow a study protocol. This usually includes cytarabine/anthracycline-based induction and cytarabine-based consolidation. A hematopoietic stem cell transplant can be performed without remission or secondary disease. In principle, pre-emptive stem cell transplantation is possible, i.e., in CEBPA mutation carriers, before developing the first leukemia. Due to the not-inconsiderable risks associated with transplantation, this is currently the subject of controversial debate.
Diagnosis of CEBPA Deficiency- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of CEBPA Deficiency- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
Asymptomatic Mutation Carriers
- Complete blood count every 6-12 months
- Bone marrow puncture in case of clinical abnormalities or abnormal blood count
Individuals with AML
As long as the patient has AML, the procedure follows the study protocol and must be discussed with the relevant study center.
The screening recommendations after complete remission in CEBPA-associated familial AML are similar to those for sporadic AML:
- CBC every 1-3 months for two years, then every 3-6 months for up to 5 years
- Bone marrow puncture in case of cytopenia and/or abnormal peripheral blood smears
As leukemia can recur even after a long period, lifelong screening is recommended for patients with CEBPA-associated familial AML.
CEBPA Deficiency – Further Information
Resources
Unfortunately, we are currently not aware of any support groups for patients with CEBPA Deficiency. New information will be added as soon as it becomes available.
