Fanconi anemia is a genomic instability syndrome characterized by a wide array of congenital malformations, bone marrow failure, and a predisposition to cancer [1]. These patients usually present with reduced numbers of progenitor cells, including myeloid, erythroid, and multipotent progenitors [2]. In addition, almost 25% of patients develop a neoplastic disorder including acute myeloid leukemia (AML), myelodysplasia, and solid tumors, after a variable period of time [1-3]. The cumulative incidence of leukemia in Fanconi anemia is around 10% by 25 years of age, and the cumulative incidence of any hematological abnormality is up to 90% [1]. In this disorder 94% of leukemias are myeloid as compared to 84% of leukemia’s being lymphoid in non-fanconi patients [3]. To date, only seven cases of acute lymphoblastic leukemia (ALL) with Fanconi anemia have been reported in literature [3]. We report a patient with treatment-naïve Fanconi anemia who developed acute lymphoblastic leukemia.

An 8-year-girl, presented with past medical history of physical anomalies (short stature and hypoplastic radial elements), and aplastic anemia. Laboratory examination was suggestive of pancytopenia. Bone marrow aspirate and biopsy revealed reduced marrow cellularity with increased chromosomal fragility as demonstrated by positive mitomycin C stress test. Based on these, she was diagnosed as Fanconi anemia and started treatment with red blood cell and platelet transfusions.

Fanconi anemia is a member of at least two classes of cancer predisposition syndromes [3]. The first consists of autosomal recessive disorders of DNA repair and the second class comprises of inherited bone marrow failure syndromes [3]. Fanconi anemia patients with abnormal radii have a 5.5 times increased risk of developing bone marrow failure compared with those cases with normal radii [4]. In children without the congenital abnormalities, the development of hematological abnormalities can be the presenting feature of this disorder [5].

The risks for developing myelodysplastic syndrome, leukemia or solid tumors for these patients are about 6%, 10%, and 10% respectively [6]. Biallelic mutations in any of the known thirteen FA genes leads to disruption of regular DNA double stranded break (DSB) repair by homologous recombination (HR), resulting in an increased rates of spontaneous DSBs. This disruption of HR mediated DSB repair may lead to activation of error prone end joining repair mechanisms resulting in misrepairs and further aggravating genetic instability and predisposing to leukemias and solid cancers [6].

In the past decade, three studies of leukemia in Fanconi anemia have been reported [1,3]. On the basis of these studies, the crude risk for leukemia in Fanconi anemia homozygotes is 5-10% [5]. Of the 1301 cases of Fanconi anemia, reported from 1927 through 2001, there were 116 reports of leukemia [3]. Among these patients with Fanconi anemia and leukemia, seven were ALL and the remainders were acute myeloid leukemia. This is in contrast to leukemias in general population wherein lymphoid leukemias predominant. Of the seven cases reported with Fanconi anemia and ALL in this disorder, all the seven cases had received pre-treatment (steroids and androgens, stem cell transplantation) before the leukemic transformation.

There were two intriguing aspects about our case. Firstly, our patient with Fanconi anemia developed ALL. While the occurrence may be a coincidence, but due to underlying genetic instability a predisposition to develop ALL in these patients must be considered. Secondly, though there have been seven cases reported before this, regarding development of ALL in patients of Fanconi anemia, but in all the instances, the patients had been pre-treated with androgens and steroids or had undergone stem cell transplantation. In our patient there was no exposure to any therapeutic intervention before the development of leukemia. This further underscores the fact that genetic instability secondary to DSB repair mechanism may be contributory to development of ALL through yet unknown pathway.

To the best of our knowledge, this is the first report of development of acute lymphoblastic leukemia in a treatment-naïve patient of Fanconi anemia. While this association may be coincidental, but the possibility of transition from Fanconi anemiato to ALL must be contemplated in order to gain more insights on the role of Fanconi anemia genes in leukemogenesis.

Contributors: All authors were involved with the treatment of the patient and writing of the manuscript. VS will act as a guarantor of the case report. All authors approved the manuscript.

Funding: None; Competing interests: None stated.

1. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood. 2003;101:822-6.

2. Velez-Ruelas MA, Martinez-Jaramillo G, Arana-Trejo RM, Mayani H. Hematopoietic changes during progression from Fanconi anemia into acute myeloid leukemia: case report and brief review of the literature. Hematology. 2006;11:331-4.

3. Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer. 2003;97:425-40.

4. Rosenberg PS, Huang Y, Alter BP. Individualized risks of first adverse events in patients with Fanconi anemia. Blood. 2004,104:350-5.

5. Tischkowitz M, Dokal I. Fanconi anaemia and leukaemia - clinical and molecular aspects. Br J Haematol. 2004;126:176-91.