Aplastic anaemia and bone-marrow failure: Case

This boy has the classic presentation of Fanconi anaemia declaring itself as severe aplastic anaemia. The short stature, the café-au-lait spots, the absent thumbs with the hypoplastic radii, and the macrocytosis of 104 femtolitres are the physical and laboratory signs of the inherited syndrome, and the hypocellular marrow of 12 percent with the pancytopenia is the marrow failure. The examiner is testing whether the fellow recognises the inherited syndrome, confirms it with the right test, plans the transplant with the right conditioning, and counsels the family on the inheritance and the cancer risk. [9]

Confirming the diagnosis

The first task is to confirm the Fanconi anaemia, and the test is the diepoxybutane chromosomal breakage test. The test is performed on the peripheral blood lymphocytes, and it adds a cross-linking agent and counts the chromosomal breaks and the radial figures, which are markedly increased in Fanconi anaemia and normal in the acquired disease. The next-generation sequencing panel for the FANC genes confirms the mutation and identifies the specific gene, which matters for the family counselling and the prenatal diagnosis. The boy meets the Camitta criteria for severe aplastic anaemia, with a cellularity of 12 percent under 25 percent and all three blood thresholds met, and the mean corpuscular volume of 104 femtolitres and the raised fetal haemoglobin are the quiet signs of the inherited syndrome that the fellow should not miss. [9]

The distinction from the acquired disease is the single most important step, because the transplant conditioning differs. A child with the acquired aplastic anaemia is transplanted with the cyclophosphamide based regimen, and a child with Fanconi anaemia is transplanted with the reduced intensity fludarabine based regimen, because the DNA repair defect makes the child exquisitely sensitive to the standard chemotherapy and radiation. The fellow who plans a transplant for this boy holds the conditioning until the diepoxybutane test returns, because the standard regimen in unrecognised Fanconi anaemia can be fatal. [9]

The transplant plan

The treatment of the marrow failure in Fanconi anaemia is the haematopoietic stem cell transplant, and the plan is shaped by the diagnosis. The boy is offered a transplant with a reduced intensity fludarabine based conditioning regimen, which spares him the toxicity of the cyclophosphamide. The stem cell source is the bone marrow, and the donor is the HLA matched sibling, who must be confirmed negative for Fanconi anaemia by the diepoxybutane test before the harvest, because an undiagnosed carrier donor will engraft poorly. If no matched sibling donor is available, the matched unrelated donor or the umbilical cord blood is used, with the fludarabine based conditioning and the careful donor selection. [1][9]

The transplant cures the marrow failure, but it does not correct the DNA repair defect, so the boy remains at the high risk of the solid tumours for life. This is the counselling that shapes the long term follow up, and the fellow who treats the marrow failure and forgets the cancer risk treats only half the disease. The transplant is performed at the specialist centre, the family is prepared for the several weeks of the inpatient stay, and the boy is followed closely for the engraftment, the graft-versus-host disease, and the infections. [9]

The cancer risk and the surveillance

The cancer risk in Fanconi anaemia is the counselling the fellow revisits at every visit, and the study of Alter and colleagues quantified it. The cumulative incidence of the haematological malignancy, the myelodysplastic syndrome and the leukaemia, reaches about a third by the age of 40, and the incidence of the solid tumour, especially the squamous cell carcinoma of the head and neck and the gynaecological tract, rises steeply after the transplant and with the age. The boy is followed with the annual marrow cytogenetics and the regular screening for the solid tumours, and the human papillomavirus vaccination, the avoidance of the tobacco and the alcohol, and the sun protection are the preventive measures reinforced at every visit. [10]

The pulmonary and the hepatic surveillance are added for the child with a possible telomere component, and the boy with Fanconi anaemia is also monitored for the endocrine failure, the growth hormone deficiency, and the glucose intolerance that accompany the syndrome. The long term follow up is shared between the paediatric haematology, the oncology, the endocrinology, and the primary care teams, and the transition to the adult service is planned in good time. [10]

Counselling the family

The counselling addresses the inheritance, the family testing, and the reproductive options. Fanconi anaemia is autosomal recessive, so the two carrier parents have a one in four chance of an affected child in each pregnancy, and the siblings are offered the diepoxybutane test and the genetic testing. The parents are counselled that each subsequent child carries the same one in four risk, and the prenatal diagnosis by the chorionic villus sampling and the preimplantation genetic diagnosis are discussed for the future pregnancies. The family is connected to the Fanconi anaemia support group, and the psychosocial support is offered alongside the medical care. [9]

The family is told that the transplant will cure the marrow failure but not the cancer risk, and that the boy will need the lifelong surveillance for the solid tumours. They are told that the boy can expect to reach adulthood with the modern care, and that the chief threats have shifted from the marrow failure to the cancer and the late effects of the transplant. The counselling is honest, it is hopeful, and it is given over several visits, because the family needs the time to absorb the diagnosis and the plan. [10][11]