Dataset Information

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations.

ABSTRACT: X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor ?B 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 IKBKG 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 IKBKG mutations.

SUBMITTER: Miot C

PROVIDER: S-EPMC5609334 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic <i>IKBKG</i>/NEMO mutations.

Miot Charline C Imai Kohsuke K Imai Chihaya C Mancini Anthony J AJ Kucuk Zeynep Yesim ZY Kawai Tokomki T Nishikomori Ryuta R Ito Etsuro E Pellier Isabelle I Dupuis Girod Sophie S Rosain Jeremie J Sasaki Shinya S Chandrakasan Shanmuganathan S Pachlopnik Schmid Jana J Okano Tsubasa T Colin Estelle E Olaya-Vargas Alberto A Yamazaki-Nakashimada Marco M Qasim Waseem W Espinosa Padilla Sara S Jones Andrea A Krol Alfons A Cole Nyree N Jolles Stephen S Bleesing Jack J Vraetz Thomas T Gennery Andrew R AR Abinun Mario M Güngör Tayfun T Costa-Carvalho Beatriz B Condino-Neto Antonio A Veys Paul P Holland Steven M SM Uzel Gulbu G Moshous Despina D Neven Benedicte B Blanche Stéphane S Ehl Stephan S Döffinger Rainer R Patel Smita Y SY Puel Anne A Bustamante Jacinta J Gelfand Erwin W EW Casanova Jean-Laurent JL Orange Jordan S JS Picard Capucine C

Blood 20170705 12

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the <i>IKBKG</i> 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 ...[more]

PMID: 28679735

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Project description:BackgroundNF-κB essential modulator (NEMO), encoded by IKBKG, is necessary for activation of the ubiquitous transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Animal studies suggest NEMO is required for NF-κB mediated bone homeostasis, but this has not been thoroughly studied in humans. IKBKG loss-of-function mutation causes incontinentia pigmenti (IP), a rare X-linked disease featuring linear hypopigmentation, alopecia, hypodontia, and immunodeficiency. Single case reports describe osteopetrosis (OPT) in boys carrying hypomorphic IKBKG mutations.MethodWe studied the bone phenotype in women with IP with evaluation of radiographs of the spine and non-dominant arm and leg; lumbar spine and femoral neck aBMD using DXA; μ-CT and histomorphometry of trans-iliac crest biopsy specimens; bone turnover markers; and cellular phenotype in bone marrow skeletal (stromal) stem cells (BM-MSCs) in a cross-sectional, age-, sex-, and BMI-matched case-control study. X-chromosome inactivation was measured in blood leucocytes and BM-MSCs using a PCR method with methylation of HpaII sites. NF-κB activity was quantitated in BM-MSCs using a luciferase NF-κB reporter assay.ResultsSeven Caucasian women with IP (age: 24-67 years and BMI: 20.0-35.2 kg/m2) and IKBKG mutation (del exon 4-10 (n = 4); c.460C>T (n = 3)) were compared to matched controls. The IKBKG mutation carriers had extremely skewed X-inactivation (>90:10%) in blood, but not in BM-MSCs. NF-κB activity was lower in BM-MSCs from IKBKG mutation carriers (n = 5) compared to controls (3094 ± 679 vs. 5422 ± 1038/μg protein, p < 0.01). However, no differences were identified on skeletal radiographics, aBMD, μ-architecture of the iliac crest, or bone turnover markers. The IKBKG mutation carriers had a 1.7-fold greater extent of eroded surfaces relative to osteoid surfaces (p < 0.01), and a 2.0-fold greater proportion of arrested reversal surface relative to active reversal surface (p < 0.01).ConclusionUnlike mutation-positive males, the IKBKG mutation-positive women did not manifest OPT.

Dataset Information

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations.

Publications

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic <i>IKBKG</i>/NEMO mutations.

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