All about Fanconi anemia- Dr Gunjan Makkar

Fanconi anaemia is the most frequently reported of the rare inherited bone marrow failure syndromes (IBMFSs).

Approximately only 2000 cases of the disease have been reported in the medical literature. In 1927, Guido Fanconi first reported 3 brothers with macrocytosis, pancytopenia, and physical abnormalities. Subsequent cases were clinically diagnosed because of the combination of aplastic anaemia and various characteristic physical anomalies.

The Physical anomalies show up in a child with pancytopenia, short stature, abnormal thumbs, and areas of hyperpigmentation. The first sign of a hematologic problem is usually petechiae and bruises, with later onset of pale appearance, feeling tired, and infections. Because macrocytosis usually precedes a low platelet count, patients with typical congenital anomalies associated with FA should be evaluated for an elevated red blood cell mean corpuscular volume.

Clinically, hematological abnormalities are the most serious symptoms in FA. By the age of 40, 98% of FA patients will have developed some type of hematological abnormality. Because of the failure of hematologic components—white blood cells, red blood cells, and platelets—to develop, the body's capabilities to fight infection, deliver oxygen, and form clots are all diminished. However, a few cases have occurred in which older patients have died without ever developing them. Symptoms appear progressively and often lead to complete bone marrow failure. While at birth, blood count is usually normal, macrocytosis/megaloblastic anemia, defined as unusually large red blood cells, is the first detected abnormality, often within the first decade of life (median age of onset is 7 years).

Fanconi anemia, or constitutional aplastic anemia, is a genetic disorder in which numerous physical abnormalities are often present at birth, and aplastic anemia occurs around the age of 5 years. The more common physical abnormalities include hyperpigmentation, anomalies of the thumb and radius, small size, microcephaly, and renal anomalies (e.g., absent, duplicated, or pelvic horseshoe kidneys). Patients with Fanconi anemia are also susceptible to leukemia and epithelial carcinomas.

In the early 1960s, several groups observed that cultured cells from patients with Fanconi anemia had increased numbers of chromosome breaks; later, the breakage rate was found to be specifically increased by the addition of deoxyribonucleic acid (DNA) cross-linkers, such as diepoxybutane (DEB) or mitomycin C (MMC). This led to the identification of patients with Fanconi anemia and aplastic anemia without birth defects and the diagnosis of Fanconi anemia in patients without aplastic anemia but with abnormal physical findings.

Chromosomal breakage analysis, for example with diepoxybutane (DEB), can be used to make the diagnosis, and molecular diagnosis can confirm the diagnosis and be used to test relatives. In studies of peripheral blood lymphocytes, a high percentage of patients with Fanconi anemia will have chromosomal breaks, gaps, or rearrangements. Many genes causing the Fanconi anemia syndrome have now been identified, and molecular diagnosis has assumed increasing importance as studies linking genotype and phenotypes such as aplastic anemia and leukemia can be analyzed. FA is primarily an autosomal recessive genetic disorder. This means that two mutated alleles (one from each parent) are required to cause the disease. The risk is 25% that each subsequent child will have FA. About 2% of FA cases are X-linked recessive, which means that if the mother carries one mutated Fanconi anemia allele on one X chromosome, a 50% chance exists that male offspring will present with Fanconi anemia.

Treatment with androgens and hematopoietic (blood cell) growth factors can help bone marrow failure temporarily, but the long-term treatment is bone marrow transplant if a donor is available. Because of the genetic defect in DNA repair, cells from people with FA are sensitive to drugs that treat cancer by DNA crosslinking, such as mitomycin C.

Dr Gunjan Makkar is a columnist with medical dialogues and specialises in paediatric updates.