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A four-year-old boy with a history of a ventricular septal defect is referred to hematology clinic for bicytopenia. He is an only child, was born at term, reached all developmental milestones on time, and has a family history negative for the condition. He required a red blood cell transfusion one month ago for symptomatic anemia. Physical examination reveals a healthy-appearing white child, height third percentile for age, a 3/6 holosystolic murmur at the left sternal border, short thumbs, and three 1-cm hyperpigmented macules on his abdomen. A complete blood count (CBC) showed a white blood cell count of 6,200/mm³, absolute neutrophil count of 2,003/mm³, hemoglobin of 9.8 g/dL, mean corpuscular volume of 99 fL, and platelet count at 16,000/mm³. No blasts or dysplastic cells were seen on peripheral smear. Peripheral lymphocytes demonstrated significantly increased chromosomal breakage when exposed to diepoxybutane (DEB) and mutation analysis showed biallelic FANCD1/BRCA2 mutations. Bone marrow cellularity was 40 percent, and all cell lines were present with normal maturation.

Which of the following is the most appropriate course of treatment?

1. Repeat CBC every three to four months with annual marrow evaluation, and proceed with hematopoietic stem cell transplantation (HSCT) if cytopenias worsen or marrow dysplasia occurs
2. Matched unrelated donor (MUD) HSCT with a busulfan, fludarabine, cyclophosphamide, antithymocyte globulin (ATG), and total-body irradiation (TBI) prep
3. MUD HSCT with busulfan, fludarabine, cyclophosphamide, and ATG prep without TBI
4. Start oxymetholone 2 mg/kg/day with weekly CBC until anemia improves

Answer: C

Explanation

This patient has Fanconi Anemia (FA), a DNA repair defect that results in increased susceptibility to alkylating agents and ionizing radiation. He has evidence of marrow failure by CBC and transfusion requirements. FA is associated with several congenital dysmorphisms including short stature, café au lait spots, thumb and distal radial defects, cardiac defects, and renal or genitourinary abnormalities. For many of the 18 known FANC mutations, CBC monitoring three to four times a year and annual marrow evaluation is an appropriate management strategy in patients without signs of marrow failure. However, biallelic FANCD1/BRCA2 mutations are associated with a dramatically increased risk of myelodysplasia and acute myeloid leukemia, with a cumulative incidence of nearly 80 percent by age 10 years. They don’t necessarily have preceding marrow failure prior to malignant transformation.^1,2[Alter, 2007, Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2;Myers, 2012, The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations] Due to the DNA repair defects of FA, use of reduced-intensity conditioning and avoidance of TBI and high-dose alkylating agents provide the best opportunity to avoid prolonged marrow aplasia and secondary malignancies.³ Androgens such as oxymetholone are not indicated here as they may improve moderate cytopenias but do not treat the underlying hematologic disorder. Additionally, caution should be used with hormonal therapies in children this young due to virilization and hepatotoxicity.⁴

While HSCT is the only curative strategy for FA from a hematologic standpoint, it does not alter the other inherent complications of FA. These patients can have lifelong endocrine problems and have a high risk for secondary malignancies, especially squamous cell carcinoma of the head and neck.

Case study submitted by Alex Boucher, MD, and Adam Nelson, MD, of Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

References

1. Alter BP, Rosenberg PS, Brody LC. . J Med Genet. 2007;44:1-9
2. Myers K, Davies SM, Harris RE, et al. . Pediatr Blood Cancer. 2012;58:462-465.
3. Mehta PA, Davies SM, Leemhuis T, et al. . Blood. 2017;129:2308-2315.
4. Calado RT, Clé DV. . Hematology Am Soc Hematol Educ Program. 2017;2017:96-101.