Two-year-old Aarav was constantly getting fever and appeared tired and lethargic for over a month. His parents were worried about him and finally took him to Lilavati Hospital and Research Center in Mumbai. The pediatrician referred the patient to Dr Swati Kanakia, a paediatric haemato-oncologist.
On clinical examination, Aarav had fever with low hemoglobin, low WBC and low platelets, which were initially attributed to an infection, which Aarav did have at the time. While there were no other obvious abnormalities, Aarav showed pallor and had macrocytosis (large RBC), slightly smaller stature, darkness around the lips and 4 Café au lait spots on his chest and back. In combination with these observations and the pancytopenia, Dr Kanakia ordered a hemoglobin chromatography. The results showed very high Hb F levels, which are indicative of stressed erythropoiesis and of bone marrow failure or aplastic anaemia. Aplastic anaemia can be inherited or acquired following infections. A bone marrow biopsy was done to confirm bone marrow failure. Bone marrow results also showed a pancytopenia and the aplastic anemia was likely to be inherited. Further, placing the family history in this light, Aarav was born to a 3rd degree consanguineous marriage, and an inherited syndrome was suspected.
Inherited bone marrow failure syndromes are a group of heterogeneous disorders involving bone marrow failure. These are often presented during childhood and are associated with somatic abnormalities. Fanconi anaemia is one of the most frequently reported of such inherited bone marrow failure syndromes and it typically manifests before the age of 10. However, it is still very rare and only 1 out of 1.3 million children are diagnosed with Fanconi anaemia. Classical features include short stature, abnormal thumbs and hyperpigmentation of the skin. About 30% of Fanconi anaemia patients have no somatic abnormalities, while about 80% develop bone marrow failure by age 20. The primary signs of hematologic origin are petechiae and bruises, which may graduate to a pale appearance and infections.
Fanconi anaemia is an autosomal recessive genetic disorder, requiring 2 copies of the mutant gene. At least 17 genes have been identified to carry mutations that result in Fanconi anaemia. These genes encode for a cluster of proteins important for DNA repair. Mutant genes result in abnormal proteins, such that the repair of the DNA is less effective and it is easily damaged by cross-linking agents. Bone marrow is particularly sensitive to such defects.
To determine the type of possible bone marrow failure and to see if Aarav had Fanconi anaemia, a cytogenetic stress test was done. Diepoxybutane analysis is the preferred test for Fanconi anaemia. As part of the test, chromosomes are exposed to a stress agent such as diepoxybutane or mitomycin C and the number of chromosome breakages are assessed.
The test showed that Aarav had a 7- to 14-fold increase in the number of induced breaks compared to the control, and Aarav was suspected to have Fanconi anaemia. This was then confirmed by genetic testing, which showed that he was homozygous for a mutation in the FANCL gene, one of the most common mutations in India.
Fanconi anaemia can be treated with androgen therapy or an administration of growth factors. Androgen therapy helps improve blood counts, but can result in a long list of side effects ranging from vomiting, and behavioral changes to liver toxicity. Growth factors such as G-Colony Stimulating Factor or GM- Colony Stimulating Factor can temporarily improve white blood cell counts. Neither androgen therapy nor growth hormone administration are curative options. The only known cure is a stem cell transplant or bone marrow transplant. The success of a bone marrow transplant is dependent on a close match with the donor; with the best donors being healthy siblings. In addition, Fanconi anaemia makes individuals sensitive to chemotherapy and radiation therapy required as part of the bone marrow transplant. Thus, bone marrow transplant may not be suitable for all Fanconi anaemia patients. Several reduced intensity conditioning options have been standardized to aid bone marrow transplant in Fanconi anaemia patients.
In Aarav’s case, his parents and 2 siblings were screened for the mutation and all 4 were found to be heterozygous. Since Aarav needed immediate treatment and one of his siblings was found to be a good match, a bone marrow transplant was performed from the matched sibling at a specialized centre in Pune. Aarav is doing very well now. However, he will need to be under surveillance to ensure that the transplant is not rejected.
Dr Kanakia has major hope for bone marrow transplantation in India. “Bone marrow transplant is the way forward for many malignant and non-malignant conditions. More and more centres for bone marrow transplant for paediatric patients are coming up and that is the need for the hour.” As the technique becomes more affordable and popular in coming decades, it may become as simple as a blood transfusion and is likely to be a common-place treatment for many different types of conditions.