Miot Charline, Imai Kohsuke, Imai Chihaya, Mancini Anthony J, Kucuk Zeynep Yesim, Kawai Tokomki, Nishikomori Ryuta, Ito Etsuro, Pellier Isabelle, Dupuis Girod Sophie, Rosain Jeremie, Sasaki Shinya, Chandrakasan Shanmuganathan, Pachlopnik Schmid Jana, Okano Tsubasa, Colin Estelle, Olaya-Vargas Alberto, Yamazaki-Nakashimada Marco, Qasim Waseem, Espinosa Padilla Sara, Jones Andrea, Krol Alfons, Cole Nyree, Jolles Stephen, Bleesing Jack, Vraetz Thomas, Gennery Andrew R, Abinun Mario, Güngör Tayfun, Costa-Carvalho Beatriz, Condino-Neto Antonio, Veys Paul, Holland Steven M, Uzel Gulbu, Moshous Despina, Neven Benedicte, Blanche Stéphane, Ehl Stephan, Döffinger Rainer, Patel Smita Y, Puel Anne, Bustamante Jacinta, Gelfand Erwin W, Casanova Jean-Laurent, Orange Jordan S, Picard Capucine
Study Center for Immunodeficiencies, Assistance Publique-Hopitaux de Paris, Necker Hospital for Sick Children, Paris, France.
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Blood. 2017 Sep 21;130(12):1456-1467. doi: 10.1182/blood-2017-03-771600. Epub 2017 Jul 5.
X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of mutations.
X连锁隐性外胚层发育不良伴免疫缺陷是一种罕见的原发性免疫缺陷病，由编码核因子κB必需调节因子（NEMO）蛋白的基因的亚效突变引起。这种疾病表现出巨大的等位基因、免疫学和临床异质性，由于NEMO在造血细胞和非造血细胞中均起作用，因此治疗决策很困难。造血干细胞移植（HSCT）可能挽救生命，但现有的少量病例报告表明仅将其用于最严重的病例。在此，我们报告了来自11个国家的无关亲属的29例患者进行HSCT之前的健康状况、移植结果和临床随访情况。这些患者之间携带23种不同的亚效突变。HSCT的供体包括 HLA 相同的相关供体（n = 7）、HLA匹配的无关供体（n = 12）、HLA不匹配的无关供体（n = 8）和HLA单倍型相同的相关供体（n = 2）。24例患者记录有植入，13例患者发生移植物抗宿主病。多达7例患者在HSCT后0.2至12个月死亡。在HSCT后中位随访57个月（范围4 - 108个月）时，NEMO缺陷儿童HSCT后的总体生存率为74%。既往存在的分枝杆菌感染和结肠炎与HSCT不良结果相关。潜在突变似乎没有任何影响，因为具有相同突变的患者有不同的结果。移植似乎无法治愈结肠炎，可能是由于上皮屏障的细胞内在紊乱所致。总体而言，HSCT可以治愈具有多种突变患者的大多数临床特征。
