Aplastic anaemia and bone-marrow failure: SAQ

This boy has severe aplastic anaemia, meeting the Camitta criteria, and the question is how to grade it, how to exclude an inherited syndrome, and how to treat it. The marrow cellularity of 15 percent is under 25 percent, and he meets all three peripheral blood thresholds, so this is severe aplastic anaemia, and very severe by the neutrophil count of 0.3 times ten to the nine per litre. The normal karyotype and the absence of blasts make leukaemia and myelodysplasia unlikely, and the hypocellular marrow points to aplastic anaemia rather than marrow infiltration. ^[8]

Question 1 (10 marks)

Outline the diagnosis, the severity grading, and the investigations to exclude an inherited bone marrow failure syndrome. ^[8]

A full-mark answer addresses the Camitta criteria with the exact numbers, the severity grading, and the panel of tests that excludes the inherited syndromes before any transplant is planned. ^[8]

Diagnosis and severity (4 marks). The boy meets the Camitta criteria for severe aplastic anaemia, defined by a marrow cellularity under 25 percent with at least two of three peripheral blood thresholds. He meets all three: the neutrophils of 0.3 times ten to the nine per litre are under 0.5, the platelets of 12 times ten to the nine per litre are under 20, and the reticulocytes of 10 times ten to the nine per litre are under 60. The severity grade is very severe aplastic anaemia if the neutrophils fall under 0.2 times ten to the nine per litre, which this boy at 0.3 does not quite meet, though he is close and at high risk of sepsis. The normal karyotype and the absence of blasts exclude leukaemia and the hypocellular myelodysplastic syndrome, which are the chief differential diagnoses. ^[1][8]

Excluding the inherited syndromes (4 marks). Before any transplant is planned, the inherited bone marrow failure syndromes must be excluded, because the transplant conditioning regimen differs and the standard cyclophosphamide regimen is fatal in unrecognised Fanconi anaemia. The diepoxybutane chromosomal breakage test is the gateway test, performed on the peripheral blood lymphocytes, and it shows the increased chromosomal breaks and radial figures in Fanconi anaemia and is normal in the acquired disease. The telomere length assay by flow cytometry excludes the telomere biology disorders, and the next-generation sequencing panel for the inherited marrow failure genes confirms or excludes the rarer syndromes. The boy is examined for the radial ray anomalies, the café-au-lait spots, and the nail dystrophy that point to an inherited syndrome, and the family history of marrow failure, early greaying, or pulmonary fibrosis is taken. ^[9]

The HLA typing and the family screen (2 marks). The HLA typing of the boy and his siblings is done early, because a matched sibling donor makes the transplant the first line treatment, and the absence of one makes the immunosuppressive therapy the path. The family is counselled on the inheritance if an inherited syndrome is found, and the siblings are offered the testing. The full workup returns within a few weeks, and the treatment decision is made on the results. ^[8]