Summary
It is unusual for inborn errors of metabolism to be considered in the investigative work-up of pancytopenia. We report a family in which the proband presented with failure to thrive at 2 months of age and subsequent bone marrow failure. A previous sibling had died at 7 months of age with suspected leukaemia. Haematological findings in the proband were significant for pancytopenia, and bone marrow aspiration showed dysplastic changes in all cell lineages. Urinary organic acid analysis revealed elevated methylmalonic acid. The synthesis of transcobalamin II (transcobalamin, TC) by cultured fibroblasts was markedly reduced, confirming the diagnosis of TC deficiency. The proband and his younger asymptomatic sister (also found to have TC deficiency) were homozygous for R399X (c.1195C>T), a novel mutation resulting in the loss of the C- terminal 29 amino acids of TC, a highly conserved region. Response to parenteral vitamin B12 in the proband was dramatic. At 6 years 3 months of age, physical examination is normal and developmental level is age appropriate. His sister is clinically asymptomatic and is also developing normally. Propionylcarnitine concentrations were not elevated in the newborn screening cards from the proband and sister, but that was for specimens retrieved from storage after 7 years and 5 years, respectively. Inherited and acquired cobalamin disorders should both be considered in the differential diagnosis of bone marrow failure syndromes in young children. Early detection of the metabolic causes of bone marrow failure can ensure prompt recovery in some cases involving the vitamin B12 pathway.
Abbreviations
- CBC:
-
complete blood count
- G-CSF:
-
Granulocyte colony-stimulating factor
- Hb:
-
haemoglobin
- IM:
-
intramuscular
- MCV:
-
mean corpuscular volume
- MMA:
-
methylmalonic aciduria (MMA)
- TORCH:
-
Toxoplasma, Rubella, Cytomegalovirus (CMV), and Herpes virus
- WBC:
-
white blood count
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Acknowledgements
The authors would like to thank the family for permission to use their information; we gratefully acknowledge the contributions of Janice Little (Resource associate), Mike Keeney (Haematology laboratory), Roger Dewar (CPRI laboratory), and Dr Pranesh Chakraborty (Metabolic Geneticist, Children’s Hospital of Eastern Ontario). We are grateful to Dr A. N Prasad (Associate Professor, Department of Pediatrics and Clinical Neurosciences) at Children’s Hospital of Western Ontario, London Health Sciences Center, and London, Ontario, Canada) for critically reviewing the manuscript.
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Communicating editor: Bruce Barshop
Competing interests: None declared
References to electronic databases:http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=275350 (transcobalmin deficiency). http://www.hgmd.cf.ac.uk/ac/gene.php?gene=TCN2.TC gene (GenBank accession number: M60396).
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Prasad, C., Rosenblatt, D.S., Corley, K. et al. Transcobalamin (TC) deficiency—Potential cause of bone marrow failure in childhood. J Inherit Metab Dis 31 (Suppl 2), 287–292 (2008). https://doi.org/10.1007/s10545-008-0864-3
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DOI: https://doi.org/10.1007/s10545-008-0864-3