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.
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.
Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Xi
X
Yang
Akihiro
A
Hoshino
Takashi
T
Taga
Tomoaki
T
Kunitsu
Yuhachi
Y
Ikeda
Takahiro
T
Yasumi
Kenichi
K
Yoshida
Taizo
T
Wada
Kunio
K
Miyake
Takeo
T
Kubota
Yusuke
Y
Okuno
Hideki
H
Muramatsu
Yuichi
Y
Adachi
Satoru
S
Miyano
Seishi
S
Ogawa
Seiji
S
Kojima
Hirokazu
H
Kanegane
D000483:Alleles; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics*; D008297:Male; D009154:Mutation; D010198:Pancytopenia / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000172:deficiency / Q000235:genetics*
D051636:X-Linked Inhibitor of Apoptosis Protein