Abstract
X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency that often leads to hemophagocytic lymphohistiocytosis (HLH). XLP can be classified as XLP1 or XLP2, caused by mutations in SH2D1A and XIAP, respectively. In women, X-chromosome inactivation (XCI) of most X-linked genes occurs on one of the X chromosomes in each cell. The choice of which X chromosome remains activated is generally random, although genetic differences and selective advantage may cause one of the X chromosomes to be preferentially inactivated. Here we describe three patients with pancytopenia, including one female patient, in a Japanese family with a novel XIAP mutation. All three patients exhibited deficient XIAP protein expression, impaired NOD2/XIAP signaling, and augmented activation-induced cell death. In the female patient, the paternally derived X chromosome was non-randomly and exclusively inactivated in her peripheral blood and hair root cells. In contrast to asymptomatic females, this patient exhibied non-random XCI skewed towards the wild-type XIAP allele. This is the first report of a female patient with incomplete HLH resulting from a heterozygous XIAP mutation in association with non-random XCI.
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Acknowledgments
This study was supported by the Research on Measures for Intractable Disease Project, and grants from the Ministry of Health, Labour, and Welfare of Japan. We thank Chikako Sakai, Hitoshi Moriuchi, Dr. Yuichi Shiraishi, Dr. Kenichi Chiba, and Dr. Hiroko Tanaka for their excellent technical assistance. We are grateful to Dr. Sylvain Latour and the late Dr. Toshio Miyawaki for critical discussions.
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Yang, X., Hoshino, A., Taga, T. et al. A Female Patient with Incomplete Hemophagocytic Lymphohistiocytosis Caused by a Heterozygous XIAP Mutation Associated with Non-Random X-Chromosome Inactivation Skewed Towards the Wild-Type XIAP Allele. J Clin Immunol 35, 244–248 (2015). https://doi.org/10.1007/s10875-015-0144-6
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DOI: https://doi.org/10.1007/s10875-015-0144-6