Final Diagnosis -- Fanconi Anemia and Chromosome 16 Uniparental Disomy


Fanconi Anemia and Chromosome 16 Uniparental Disomy


Fanconi anemia is a rare genetic disease that affects about 1 in every 100,000 births and occurs in all racial and ethnic groups (3,4). It was originally characterized in 1927 in three siblings with a combination of pancytopenia, hyperpigmentation, and multiple congenital anomalies including short stature and urogenital and skeletal manifestations (1). While this classical presentation with hyperpigmentation, short stature and pancytopenia remains the most frequent phenotype, manifestations in some patients are subtle. In addition to congenital anomalies patients with Fanconi anemia are predisposed to hematological malignancies and solid tumors. Up to this point, mutations in 19 genes are known to cause Fanconi anemia, with all sharing a common pathway. These genes have all been shown to be involved in DNA repair pathway for inter-strand cross-links (4). Thus the inability to respond to DNA damage is thought to be the cause of bone marrow failure as well as the propensity for these patients to develop malignancies(3).

Fanconi anemia can be either autosomal recessive or X-linked recessive, though 98% of cases are autosomal recessive and ~80% are associated with the FANCA gene, located on chromosome 16 (2).


The phenotype of Fanconi anemia can be quite variable, though bone marrow failure, multiple congenital anomalies and development of cancer are the hallmarks. Almost all organ systems can be affected, but skin pigment changes or café-au-lait spots, short stature, upper limb anomalies, hypogonadism, eye anomalies and renal malformations are the most common and seen in over 20% of patients (1,2). Not all patients with Fanconi anemia have characteristic physical anomalies resulting often in delayed diagnosis; the mean age of diagnosis in patients without congenital abnormalities is significantly higher than those with congenital abnormalities (1). Bone marrow failure is seen in ~80% of patients and hematologic manifestations often prompt evaluation for Fanconi anemia. Virtually all patients develop bone marrow failure by the age of 40, with the median age of bone marrow failure of 7 years of age (1). This bone marrow failure is progressive and all hematopoietic lineages are affected (2).

Cancer is highly prevalent in patients with Fanconi anemia, with hematologic cancers being most common. The risk of AML in these patients is 52% by age 40, with MDS also being quite common (1). Solid tumors are also of great concern in these patients, especially if they live to middle age. The incidence of head and neck and anogenital squamous cell carcinomas is 500-700 -fold higher than in the general population with a cumulative incidence of 14% by age 40. Liver tumors are the next most common, followed by brain, kidney, breast and adrenal gland (1,2). Largely because of this increased risk of malignancy, these patients have a short life expectancy with a median estimated survival of 23 years (1).


The first laboratory anomalies noted in these patients are hematologic and found on routine complete blood counts. Thrombocytopenia and macrocytosis are often the first irregularities with development of granulocytopenia, anemia and eventually severe aplasia (2). When Fanconi anemia is expected, the initial functional test includes analysis for an excessive chromosome breakage. When cultured with DNA clastogenic agents such as diepoxybutane (DEB) and mitomycin C, the patient's peripheral blood lymphocytes are unable to repair DNA damage resulting in multiple chromosome breakages and formation of chromosome radial structures. (2). This testing can also be done on samples collected by chorionic villus sampling, amniocentesis or percutaneous umbilical blood sampling (2). Definitive diagnosis of Fanconi anemia is identified with increased chromosome breaks per cell with an average range of 1.06 to 23.9 compared to a normal control range of 0.00 to 0.10 breaks (2). Following a positive DEB test, patients should be further tested by DNA sequencing to define molecular cause of Fanconi anemia. Other DNA techniques including classical chromosome analysis, comparative genomic hybridization/single nucleotide polymorphism microarray might be helpful to elucidate concomitant chromosomal alterations or detect regions of homozygosity pointing toward plausible candidate genes for molecular resting.


Treatment for patients with Fanconi anemia is dependent on the primary manifestations. Congenital and physical anomalies can occasionally be surgically repaired. Because of the risk of bone marrow failure and hematologic malignancy, the best therapy for these patients involves hematopoietic stem cell transplantation. Transplants with HLA matched donors have greatly improved the outcomes of these patients, especially for those transplanted before the age of 10 (3). Prior to transplantation, blood transfusions can be used treat anemia and thrombocytopenia. Androgen therapy can often increase reticulocytosis, hemoglobin, white blood cell and platelet counts over the course of months. G-CSF therapy can also increase granulocyte counts though only temporarily, with progression of bone marrow failure and an eventual loss of response usually within a year (3).

Because of the improved survival with respect to hematologic manifestations, screening for the development of solid malignancies has become more important as they become increasingly common with survival into adulthood. Management and treatment of these malignancies is complicated by extreme sensitivity to certain chemotherapeutic agents because of the aforementioned defects in DNA repair pathways. Vaccination against HPV can help to prevent development of squamous cell carcinomas of the head and neck and cervix (3). Endocrine abnormalities such as hypothyroidisim, glucose intolerance and growth hormone deficiency are common and should be screened for and treated in a similar fashion as in non-Fanconi anemia patients (2,3,5).

Uniparental Disomy

Uniparental disomy (UPD) is defined as the presence of two copies of chromosomes originating from a single parent (6). This can further be broken down into uniparental heterodisomy with two different alleles from a single parent being transmitted, and uniparental isodisomy with two copies of the same allele from the single parent being transmitted (5). UPD is caused by errors in meiotic and mitotic nondisjunction, and can result in aneuploidy or chromosomal rearrangement (5). These types of abnormalities have been shown to be related to the age of the mother at conception. Uniparental isodisomy is characterized by long regions of homozygosity affecting a single chromosome.. As a result patients with UPD can be affected by an autosomal recessive condition or/and imprinting disorder.

In this particular patient, the UPD16 likely results in Fanconi anemia due to the presence of two identical DNA segments on two chromosome 16 homologs which were inherited from a parent who carries a mutation in the FANCA gene, or other FA associated genes on chromosome 16, thus resulting in homozygous mutation.


Contributed by Contributed by Eric Statz; MD and Svetlana Yatsenko; MD

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