SUMMARY

 

1.  Fanconi pancytopenia is an autosomal recessive syndrome associated with the following clinical features: 

 

-Short stature
-Microcephaly
-Radial hypoplasia
-Developmental delay
-Skin hyperpigmentation and café au lait spots
-Characteristic facial features (microphthalmia, micrognathia, broad nasal base, epicanthal folds)
-Bone marrow failure (with neutropenia)

 

2.  Progressive bone marrow failure with pancytopenia typically presents in the first decade of life with thrombocytopenia or leukopenia.  Neutropenia secondary to bone marrow failure occurs in more than 95% of patients. T and B cell functions are typically preserved. 

 

3.  There is an increased incidence of hematologic malignancies (AML) and non-hematologic malignancies (approximately 10-30%). 

 

4.  The diagnosis can be made upon the detection of chromosomal aberrations in cells after culture with diepoxybutane (DEB) or mitomycin C (MMC).  At least 13 different genes which correlate with 13 different complementation groups are known to cause Fanconi pancytopenia. 

 

5.  The most common causative genes are FANCA, FANCC, and FANCG (these are reported in 85% of patients).  All mutations are autosomal recessive except for FANCB (X-linked).

 

6.  The administration of oral androgens improves WBC, RBC and platelet counts in 50% of patients.  Neutropenia is responsive G-CSF in some individuals.  HSCT is the only curative therapy for the bone marrow failure.

 

 

 

                                                                                                               

OVERVIEW

          

       Fanconi pancytopenia is an autosomal recessive syndrome associated with the following clinical features: 

 

-Short stature
-Microcephaly
-Radial hypoplasia
-Developmental delay
-Skin hyperpigmentation and café au lait spots
-Characteristic facial features (microphthalmia, micrognathia, broad nasal base, epicanthal folds)
-Bone marrow failure (with neutropenia)

 

         Progressive bone marrow failure with pancytopenia typically presents in the first decade of life with thrombocytopenia or leukopenia.  Neutropenia secondary to bone marrow failure occurs in more than 95% of patients. T and B cell functions are typically preserved.  There is an increased incidence of hematologic malignancies (AML) and non-hematologic malignancies (approximately 10-30%). 

At least 13 different genes which correlate with 13 different complementation groups are known to cause Fanconi pancytopenia. The most common causative genes are FANCA, FANCC, and FANCG (these are reported in 85% of patients).  All mutations are autosomal recessive except for FANCB (X-linked).

 

 

                                 

EVALUATION

 

      The diagnosis of Fanconi pancytopenia should be considered for patients presenting with characteristic clinical features and bone marrow failure.  It should be noted that 25-40% of patients lack the classic physical features of disease.  The initial evaluation should include a CBC with differential as well as bone marrow aspiration. 

 

**All three studies below are available through the Cincinnati Childrens cytogenetics laboratory. 

 

Step 1:  Chromosome Breakage Study

 

-When exposed to DNA cross-linkage agents (DEB and MMC) the chromosomes of FA patients will break and form abnormal patterns (breaks, rearrangements, radials, exchanges)

 

Step 2:  Complementation Study

 

-If the chromosome breakage study is abnormal, complementation analysis is performed to identify the patients complementation group.

 

Step 3:  Gene sequencing


-Sequencing of FANCA, FANCC, or FANCG identifies 85% of gene mutations.

 

 

 

                                                                   

MANAGEMENT

          

        The administration of oral androgens improves WBC, RBC and platelet counts in 50% of patients.  Neutropenia is responsive G-CSF in some individuals.  HSCT is the only curative therapy for the bone marrow failure. 

     

        Patients with this disease have increased sensitivity to the toxicity of chemotherapeutic and radiation regimens used in preparation for BMT (reduced intensity conditioning is recommended).  

 

                                                                           

 

RESOURCES

 

Diagnostic Resources     

 

1. CINCINNATI - Fanconi Anemia(chromosome breakage, complementation, sequencing)

 

 

Literature Resources

 

1.  Alter 2008

     Fanconi anemia - guidelines for diagnosis and management 3rd edition