Abstract
X-linked agammaglobulinemia is a rare primary immunodeficiency due to a BTK mutation. The patients are characteristically deficient in peripheral B cells and serum immunoglobulins. While they are susceptible to infections caused by bacteria, enteroviruses, and parasites, fungal infections are uncommon in XLA patients. Here, we report a boy of Malay ethnicity who suffered from recurrent upper respiratory tract infections and severe progressive necrotizing fasciitis caused by Saksenaea erythrospora. Immunological tests showed a B cell deficiency and hypogammaglobulinemia. Whole-exome sequencing identified a dinucleotide deletion (c.1580_1581del) in BTK, confirmed by Sanger sequencing and predicted to be disease causing by in silico functional prediction tools (Varsome and MutationTaster2) but was absent in the gnomAD database. This mutation resulted in a frameshift and premature termination (p.C527fs), which disrupted the protein structure. The mother was heterozygous at the mutation site, confirming her carrier status. Flow cytometric analysis of monocyte BTK expression showed it to be absent in the patient and bimodal in the mother. This study describes a novel BTK mutation in a defined hotspot and an atypical fungal phenotype in XLA. Further studies are required to understand the pathogenesis of fungal infection in XLA.
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Acknowledgements
We would like to thank the Director General of Health Malaysia for his permission to publish this article. We thank all the clinicians who have been involved in the patient’s management. Also, we gratefully acknowledge Koay BT and Chiow MY for helpful discussions, and Gill HK for language editing.
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This project was supported by the Ministry of Health, Malaysia, Grant NMRR-16-892-31023.
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C.T.C. performed experiments, analyzed results, and drafted manuscript; R.N. and K.W.C. managed and treated the patient, provided a clinical summary, and revised manuscript; R.M.T. performed and analyzed fungal identification tests and drafted manuscript; M.F.B. and S.B.M. involved in data interpretation and revised manuscript; S.N.H.S.Y. performed the experiment; P.B.K. involved in data interpretation; A.M.R. initiated and designed the study, analyzed results, and revised manuscript. All authors read and approved the final manuscript.
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This study was approved by the Medical Research Ethics Committee, Ministry of Health, Malaysia [KKM/NIHSEC/P16-837].
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Chear, C.T., Nallusamy, R., Chan, K.C. et al. Atypical Presentation of Severe Fungal Necrotizing Fasciitis in a Patient with X-Linked Agammaglobulinemia. J Clin Immunol 41, 1178–1186 (2021). https://doi.org/10.1007/s10875-021-01017-3
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DOI: https://doi.org/10.1007/s10875-021-01017-3